1 00:00:05,000 --> 00:00:07,760 >>IT'S MY PLEASURE TO WELCOME 2 00:00:07,760 --> 00:00:08,960 YOU. 3 00:00:08,960 --> 00:00:11,160 I'M THE DIRECTOR OF THE DIVISION 4 00:00:11,160 --> 00:00:13,320 OF ALLERGY AND TRANSPLANTATION 5 00:00:13,320 --> 00:00:19,680 AND I'M VERY MUCH LOOKING 6 00:00:19,680 --> 00:00:22,680 FORWARD TO THIS AFTERNOON'S 7 00:00:22,680 --> 00:00:23,320 SESSION. 8 00:00:23,320 --> 00:00:25,520 WE HAVE TOPICS ON SCIENTIFIC AND 9 00:00:25,520 --> 00:00:27,360 CLINICAL UNDERSTANDING OF THE 10 00:00:27,360 --> 00:00:31,560 ROLE OF HLA AS A DETERMINANT OF 11 00:00:31,560 --> 00:00:33,680 OUTCOMES IS TRULY EVOLVING AND 12 00:00:33,680 --> 00:00:35,120 MUCH THROUGH THE WORK OF THIS 13 00:00:35,120 --> 00:00:39,840 AFTERNOON'S SPEAKERS. 14 00:00:39,840 --> 00:00:45,040 I'M GOING TO LEAVE IT TO NANCY 15 00:00:45,040 --> 00:00:47,840 BRIDGES WHO IS THE 16 00:00:47,840 --> 00:00:48,840 TRANSPLANTATION BRANCH CHIEF FOR 17 00:00:48,840 --> 00:00:50,480 INTRODUCTION OF SPEAKERS AND 18 00:00:50,480 --> 00:00:55,680 COMMENTS ON THE TOPIC IN 19 00:00:55,680 --> 00:00:56,600 GENERAL. 20 00:00:56,600 --> 00:00:58,280 AFTER THESE TALKS WE'LL HAVE 21 00:00:58,280 --> 00:01:02,240 COUNCIL CONSIDERATIONS FOR THE 22 00:01:02,240 --> 00:01:04,240 FIVE FISCAL 2025 CONCEPT 23 00:01:04,240 --> 00:01:05,520 CLEARANCES. 24 00:01:05,520 --> 00:01:12,000 AS USUAL WE NEED YOUR INPUT ON 25 00:01:12,000 --> 00:01:19,160 THOSE AND YOUR RECOMMENDATIONS 26 00:01:19,160 --> 00:01:20,840 IN THAT DIRECTION AND THANK YOU, 27 00:01:20,840 --> 00:01:25,400 NANCY FOR PULLING TOGETHER A 28 00:01:25,400 --> 00:01:28,600 TERRIFIC SESSION AND WE'LL GO 29 00:01:28,600 --> 00:01:31,920 FROM THERE. 30 00:01:31,920 --> 00:01:35,080 OKAY, CAN I HAVE MY FIRST SLIDE, 31 00:01:35,080 --> 00:01:45,200 PLEASE. 32 00:02:00,600 --> 00:02:04,080 >> AND SECOND, THIS MAY SOUND 33 00:02:04,080 --> 00:02:05,520 COUNTER INTUITIVE BUT ANYBODY ON 34 00:02:05,520 --> 00:02:07,440 BY ZOOM PLEASE DO NOT PUT ANY 35 00:02:07,440 --> 00:02:09,280 COMMENTS IN THE CHAT BOX BECAUSE 36 00:02:09,280 --> 00:02:11,880 THAT WILL GENERATE A BACKUP 37 00:02:11,880 --> 00:02:12,600 REQUIREMENT FOR THIS MEETING 38 00:02:12,600 --> 00:02:20,440 WHICH IS NOT WHAT WE WANT. 39 00:02:20,440 --> 00:02:21,320 >> GOOD AFTERNOON. 40 00:02:21,320 --> 00:02:27,200 THIS AFTERNOON'S TOPIC FOR OUR 41 00:02:27,200 --> 00:02:29,840 SPEAKERS IS HLA AND ALOE 42 00:02:29,840 --> 00:02:32,040 TRANSPLANTATION OUR EVOLVING 43 00:02:32,040 --> 00:02:32,360 UNDERSTANDING. 44 00:02:32,360 --> 00:02:33,520 AND PROBABLY EVERYBODY IN THE 45 00:02:33,520 --> 00:02:38,680 ROOM KNOWS THAT HLA IS A TOPIC 46 00:02:38,680 --> 00:02:40,200 THAT CAN BE MADE AS COMPLICATED 47 00:02:40,200 --> 00:02:42,560 AS YOU WOULD WISH TO MAKE IT. 48 00:02:42,560 --> 00:02:44,520 OUR PERSPECTIVE FOR THIS 49 00:02:44,520 --> 00:02:45,520 AFTERN 50 00:02:45,520 --> 00:02:48,920 AFTERNOON'S TALK IS SPECIFICALLY 51 00:02:48,920 --> 00:02:50,360 HOW TRANSPLANTERS THINK OF HLA 52 00:02:50,360 --> 00:02:52,600 AND HOW OUR INFORMAUNDERSTANDIN 53 00:02:52,600 --> 00:02:55,560 HAS EVOLVED OVER TIME. 54 00:02:55,560 --> 00:02:57,880 SO DIFFERENCES IN HLA BETWEEN 55 00:02:57,880 --> 00:03:08,360 DONOR AND RECIPIENT ARE THE 56 00:03:08,840 --> 00:03:12,760 DETERMINATE AND THEY DETERMINE 57 00:03:12,760 --> 00:03:15,680 THE LIKELIHOOD OF GRAPH ACC 58 00:03:15,680 --> 00:03:17,840 ACCEPTANCE AND ANTI-TUMOR 59 00:03:17,840 --> 00:03:18,160 ACTIVITY. 60 00:03:18,160 --> 00:03:19,480 PERFECT MATCHING WOULD BE THE 61 00:03:19,480 --> 00:03:23,880 IDEAL FOR ANY ORGAN TRANSPLANT. 62 00:03:23,880 --> 00:03:26,720 IT ONLY OCCURS AMONG IDENTICAL 63 00:03:26,720 --> 00:03:29,520 BIRTHS EVEN THOSE SAID TO BE HLA 64 00:03:29,520 --> 00:03:31,240 IDENTICAL ARE NOT COMPLETELY 65 00:03:31,240 --> 00:03:33,720 IDENTICAL UNLESS THEY'RE 66 00:03:33,720 --> 00:03:37,240 IDENTICAL TWINS ETCETERA AND FOR 67 00:03:37,240 --> 00:03:39,520 ORGANS AND LIVERS IT'S NOT 68 00:03:39,520 --> 00:03:41,440 POSSIBLE TO WAIT FOR A BETTER 69 00:03:41,440 --> 00:03:42,000 MATCH. 70 00:03:42,000 --> 00:03:43,800 PEOPLE WAITING FOR THOSE ORGAN 71 00:03:43,800 --> 00:03:47,240 DYING AND WE TAKE USUALLY AN 72 00:03:47,240 --> 00:03:48,160 ORGAN PHYSIOLOGICALLY 73 00:03:48,160 --> 00:03:52,760 APPROPRIATE AND DON'T WORRY TOO 74 00:03:52,760 --> 00:03:58,320 MUCH ABOUT HLA MATCHING. 75 00:03:58,320 --> 00:04:01,240 SO OUR VIEW OF HLA HAS REALLY 76 00:04:01,240 --> 00:04:03,640 CHANGED QUITE A BIT FROM THE 77 00:04:03,640 --> 00:04:07,240 1950s WHEN PEOPLE FIRST STARTED 78 00:04:07,240 --> 00:04:11,000 TALKING ABOUT HLA IN ANY 79 00:04:11,000 --> 00:04:12,600 CLINICAL WAY. 80 00:04:12,600 --> 00:04:16,760 THE TYPES WERE DETERMINED S 81 00:04:16,760 --> 00:04:18,640 SEROLOGICALLY LOOKING FOR 82 00:04:18,640 --> 00:04:20,240 ACTIVITY. 83 00:04:20,240 --> 00:04:23,720 SHORTLY AFTER DOING THAT PEOPLE 84 00:04:23,720 --> 00:04:26,440 STARTING RECOGNIZING 85 00:04:26,440 --> 00:04:27,080 CROSS-REACTIVE GROUPS AN 86 00:04:27,080 --> 00:04:31,240 INDICATION THAT MULTIPLE HLA 87 00:04:31,240 --> 00:04:33,440 TYPES HAD SHARED ANTIGENIC SITES 88 00:04:33,440 --> 00:04:35,400 ON THEM. 89 00:04:35,400 --> 00:04:39,360 IT WASN'T ONE ANTIBODY TO ONE 90 00:04:39,360 --> 00:04:40,160 HLA ANTIGEN. 91 00:04:40,160 --> 00:04:41,960 IT WOULD POTENTIALLY REACT TO 92 00:04:41,960 --> 00:04:44,760 MANY DIFFERENT HLA TYPES. 93 00:04:44,760 --> 00:04:47,800 ONCE WE HAD PROTEIN SEQUENCING 94 00:04:47,800 --> 00:04:49,240 AND HIGH RESOLUTION TYPING WE 95 00:04:49,240 --> 00:04:54,040 WERE ABLE TO SEE THE MOLECULAR 96 00:04:54,040 --> 00:04:59,080 BASIS OF REACTIVITY AND TWO 97 00:04:59,080 --> 00:05:01,040 IDEAS GREW. 98 00:05:01,040 --> 00:05:04,760 EPITOPES WERE DEFINED AS 99 00:05:04,760 --> 00:05:08,440 POLYMORPHIC CLUSTERS IN THE 100 00:05:08,440 --> 00:05:13,120 MOLECULE FOR BINDING AND THERE 101 00:05:13,120 --> 00:05:18,200 WAS AN EPLETS TRIGGER' 102 00:05:18,200 --> 00:05:19,920 FUNCTIONAL ANTIBODY RESPONSE. 103 00:05:19,920 --> 00:05:22,560 IT'S BECOME CLEAR THE 104 00:05:22,560 --> 00:05:24,760 IMMUNOGENICITY OF THESE 105 00:05:24,760 --> 00:05:26,280 ANTIGENIC SITES ARE INFLUENCED 106 00:05:26,280 --> 00:05:30,480 BY THE MOLECULAR MILIEU AND NOT 107 00:05:30,480 --> 00:05:34,120 ANTIGENIC SITES ARE CREATED 108 00:05:34,120 --> 00:05:34,320 EQUAL. 109 00:05:34,320 --> 00:05:36,760 THESE IDEAS ARE ALREADY 110 00:05:36,760 --> 00:05:40,080 INFLUENCING HOW WE CLINICAL 111 00:05:40,080 --> 00:05:40,440 TRANSPLANTATION. 112 00:05:40,440 --> 00:05:41,040 AND THAT'S WHAT YOU WILL BE 113 00:05:41,040 --> 00:05:51,400 HEARING ABOUT TODAY. 114 00:05:51,880 --> 00:05:56,160 SOME QUESTIONS ARE MOLECULAR OR 115 00:05:56,160 --> 00:05:59,520 GROUPS OF MISS MATCHES MORE 116 00:05:59,520 --> 00:06:01,080 IMPORTANT THAN OTHERS IN CORP 117 00:06:01,080 --> 00:06:03,680 RATING THIS INTO DECISION MAKING 118 00:06:03,680 --> 00:06:05,600 IMPACTS THE EFFICIENCY OF ORGAN 119 00:06:05,600 --> 00:06:07,680 ALLOCATION, THE EQUITY AND 120 00:06:07,680 --> 00:06:09,120 OUTCOMES OF ORGAN ALLOCATION AND 121 00:06:09,120 --> 00:06:12,640 ORGAN TRANSPLANTATION. 122 00:06:12,640 --> 00:06:16,680 AND CAN KNOWLEDGE OF MOLECULAR 123 00:06:16,680 --> 00:06:19,160 MATCHING OR MISMATCHING BE USED 124 00:06:19,160 --> 00:06:20,360 AFTER TRANSPLANT TO GUIDE 125 00:06:20,360 --> 00:06:22,320 IMMUNOEXPRESSION AND PREDICT THE 126 00:06:22,320 --> 00:06:26,480 DEVELOPMENTMENT OF ANTI-HLAA 127 00:06:26,480 --> 00:06:31,000 ANTIBODIES, REJECTION, GVHD OR 128 00:06:31,000 --> 00:06:34,880 ENGRAFTMENT AND WILL THEY 129 00:06:34,880 --> 00:06:38,120 PREDICT RESPONSE TO TOLEROGENIC 130 00:06:38,120 --> 00:06:39,080 RESPONSES AFTER. 131 00:06:39,080 --> 00:06:40,280 WE HAVE THREE SPEAKERS 132 00:06:40,280 --> 00:06:44,760 ADDRESSING SOME OF THESE TOPICS. 133 00:06:44,760 --> 00:06:47,720 DR. ANNETTE JACKSON OF DUKE 134 00:06:47,720 --> 00:06:48,760 UNIVERSITY FROM CLINICAL 135 00:06:48,760 --> 00:06:50,360 TRANSPLANTATION AND IMMUNOLOGY 136 00:06:50,360 --> 00:06:52,760 AT DUKE AND DIRECTOR OF THE 137 00:06:52,760 --> 00:06:54,720 CLINICAL TRANSPLANTATION 138 00:06:54,720 --> 00:06:56,000 IMMUNOLOGY LIBRARY. 139 00:06:56,000 --> 00:06:59,480 SHE'LL BE TALKING ABOUT THE 140 00:06:59,480 --> 00:07:03,560 IMPORTANCE OF ANTIBODIES IN 141 00:07:03,560 --> 00:07:03,920 TRANSPLANTATION. 142 00:07:03,920 --> 00:07:12,760 DR. EFFIE PETERSDORF IS THE 143 00:07:12,760 --> 00:07:15,040 ENDOWED CHAIR AT THE FRED HUTCH 144 00:07:15,040 --> 00:07:16,320 INSON CANCER CENTER AND TALKING 145 00:07:16,320 --> 00:07:17,760 ABOUT CREATION AND 146 00:07:17,760 --> 00:07:19,320 IMPLEMENTATION OF TOOLS TO 147 00:07:19,320 --> 00:07:28,800 INFORM RISK ASSESSMENT PRE AND 148 00:07:28,800 --> 00:07:32,800 ALLOGENEIC TRANSPLANTATION AND 149 00:07:32,800 --> 00:07:35,160 ROBERT MONT GRI WILL TALK ABOUT 150 00:07:35,160 --> 00:07:36,360 CLINICAL TRIALS OF INTERVENTIONS 151 00:07:36,360 --> 00:07:40,640 TO MITIGATE THE CONSEQUENCES OF 152 00:07:40,640 --> 00:07:43,080 ANTI-HLA ANTIBODIES 153 00:07:43,080 --> 00:07:44,400 DESENSITIZATION, TREATMENT AND 154 00:07:44,400 --> 00:07:45,520 AMR AND PATIENT SELECTION 155 00:07:45,520 --> 00:07:45,840 STRATEGIES. 156 00:07:45,840 --> 00:07:47,600 I THINK BY THE END OF THESE 157 00:07:47,600 --> 00:07:49,120 THREE TALKS YOU'LL HAVE A PRETTY 158 00:07:49,120 --> 00:07:51,720 GOOD IDEA OF THE STATE OF THE 159 00:07:51,720 --> 00:07:53,440 SCIENCE, THE STATE OF CLINICAL 160 00:07:53,440 --> 00:07:56,440 PRACTICE AND WHERE WE NEED TO GO 161 00:07:56,440 --> 00:07:57,160 NEXT. 162 00:07:57,160 --> 00:08:00,760 WITHOUT FURTHER ADO, 163 00:08:00,760 --> 00:08:11,000 DR. JACKSON. 164 00:08:11,760 --> 00:08:16,760 >> THANK YOU FOR THE INVITATION 165 00:08:16,760 --> 00:08:20,200 TO SPEAK TODAY. 166 00:08:20,200 --> 00:08:23,120 SO NANCY TOLD ME THIS WAS GOING 167 00:08:23,120 --> 00:08:24,920 TO BE A DIVERSE AUDIENCE AND I 168 00:08:24,920 --> 00:08:29,400 KNEW I WAS SPEAKING AFTER LUNCH 169 00:08:29,400 --> 00:08:30,960 AND WE HLA PEOPLE CAN GET IN THE 170 00:08:30,960 --> 00:08:33,800 WEEDS AND I TRIED TO KEEP THIS 171 00:08:33,800 --> 00:08:35,920 AT A 30,000 FOOT LEVEL TO TALK 172 00:08:35,920 --> 00:08:39,280 ABOUT THE ROLE OF HLA IN 173 00:08:39,280 --> 00:08:40,760 CLINICAL TRANSPLANTATION. 174 00:08:40,760 --> 00:08:43,640 I WOULD LIKE TO BEGIN BECAUSE 175 00:08:43,640 --> 00:08:46,840 I'LL TALK ABOUT BARRIERS TO 176 00:08:46,840 --> 00:08:52,440 TRANSPLANTATION BUT IN 2021 WE 177 00:08:52,440 --> 00:08:55,120 CELEBRATED ONE MILLION IMPLANTS 178 00:08:55,120 --> 00:08:59,040 AND WE IMPACTED THE PATIENTS, 179 00:08:59,040 --> 00:09:00,040 FAMILIES, SPOUSES, PARENTS AND 180 00:09:00,040 --> 00:09:00,280 FRIENDS. 181 00:09:00,280 --> 00:09:08,560 WE CAN BE PROUD OF THIS. 182 00:09:08,560 --> 00:09:10,800 THERE'S A LOT OF WORK TO BE 183 00:09:10,800 --> 00:09:11,000 DONE. 184 00:09:11,000 --> 00:09:14,320 THERE'S OVER 100,000 PATIENTS ON 185 00:09:14,320 --> 00:09:15,920 THE TRANSPLANT WAITING LIST MANY 186 00:09:15,920 --> 00:09:20,000 WITH END STAGE KIDNEY FAILURE. 187 00:09:20,000 --> 00:09:21,800 AND THIS LIST IS GROWING AS YOU 188 00:09:21,800 --> 00:09:24,760 ARE WELL AWARE WITH A GROWING 189 00:09:24,760 --> 00:09:26,960 PROBLEM OF OBESITY AND DIABETES, 190 00:09:26,960 --> 00:09:27,600 CARDIOVASCULAR DISEASE AND LUNG 191 00:09:27,600 --> 00:09:31,520 DISEASE. 192 00:09:31,520 --> 00:09:34,680 SO IT'S VERY IMPORTANT THAT WE 193 00:09:34,680 --> 00:09:36,760 DISCUSS THE BARRIERS TO 194 00:09:36,760 --> 00:09:40,640 TRANSPLANTATION. 195 00:09:40,640 --> 00:09:44,760 SO ONE OBVIOUS BARRIER IS ORGAN 196 00:09:44,760 --> 00:09:46,000 SHORTAGE DESPITE EFFORTS TO 197 00:09:46,000 --> 00:09:47,680 INCREASE THE DONOR POOL. 198 00:09:47,680 --> 00:09:52,760 THERE'S ABO BLOOD GROUP BARRIERS 199 00:09:52,760 --> 00:09:56,480 THAT MARGINALIZE CERTAIN ETHNIC 200 00:09:56,480 --> 00:09:58,560 POPULATIONS THAT HAVE 201 00:09:58,560 --> 00:10:00,320 PARTICULARLY DIFFERENT BLOOD 202 00:10:00,320 --> 00:10:01,680 GROUP FREQUENCIES AND HLA 203 00:10:01,680 --> 00:10:03,160 ANTIBODIES AS BARRIERS. 204 00:10:03,160 --> 00:10:07,040 FOR THOSE NOT FAMILIAR WITH HLA 205 00:10:07,040 --> 00:10:13,280 IT'S ANALOGOUS TO ABO THE RED 206 00:10:13,280 --> 00:10:20,600 BLOOD ANTIGEN AND IT'S NUCLEATED 207 00:10:20,600 --> 00:10:27,560 CELLS AND WHEN PEOPLE ARE 208 00:10:27,560 --> 00:10:29,680 EXPOSED TO THEM THEY CAN DEVELOP 209 00:10:29,680 --> 00:10:30,000 ANTIBODIES. 210 00:10:30,000 --> 00:10:31,120 HLA IS DIVERSE. 211 00:10:31,120 --> 00:10:35,520 THERE'S CURRENTLY OVER 30,000 212 00:10:35,520 --> 00:10:37,280 GENE VARIANTS ACROSS THE HLA 213 00:10:37,280 --> 00:10:47,120 GENES AS OUR METHODS FOR TYPING 214 00:10:47,120 --> 00:10:50,600 BECAME BETTER AND BETTER EVERY 215 00:10:50,600 --> 00:10:51,800 DAY WE'RE DISCOVERING NEW HLA 216 00:10:51,800 --> 00:10:52,000 TYPES. 217 00:10:52,000 --> 00:10:53,720 IT CONTINUES TO AMAZE US. 218 00:10:53,720 --> 00:10:56,200 SO AS NANCY MENTIONED, MATCHING 219 00:10:56,200 --> 00:10:58,560 HLA MOLECULES IS VERY DIFFICULT 220 00:10:58,560 --> 00:11:04,760 AND NOT VERY PRACTICAL IN 221 00:11:04,760 --> 00:11:05,120 TRANSPLANTATION. 222 00:11:05,120 --> 00:11:06,240 THUS THE DIVERSITY BETWEEN 223 00:11:06,240 --> 00:11:07,760 INDIVIDUALS AND WITHIN US WE 224 00:11:07,760 --> 00:11:11,040 HAVE DIFFERENT HLA MOLECULES. 225 00:11:11,040 --> 00:11:16,640 EACH OF US HAVE HLA 1, ABC AND 226 00:11:16,640 --> 00:11:17,920 CLASS 2 MOLECULES. 227 00:11:17,920 --> 00:11:19,920 EACH PLAYING A DIFFERENT ROLE IN 228 00:11:19,920 --> 00:11:22,280 SAMPLING DIFFERENT COMPARTMENTS. 229 00:11:22,280 --> 00:11:25,280 SO THIS IS A SIDE IMAGE OF AN 230 00:11:25,280 --> 00:11:26,200 HLA MOLECULE. 231 00:11:26,200 --> 00:11:28,720 YOU'LL NOTICE AT THE TOP THERE'S 232 00:11:28,720 --> 00:11:32,040 A POCKET OR CLEFT INTO WHICH YOU 233 00:11:32,040 --> 00:11:34,400 SEE A RED LINEAR STRUCTURE. 234 00:11:34,400 --> 00:11:36,760 THIS IS A SMALL PROTEIN OR 235 00:11:36,760 --> 00:11:39,040 PEPTIDE BEING PRESENTED BY HLA 236 00:11:39,040 --> 00:11:42,720 TO THE ADAPTIVE IMMUNE SYSTEM. 237 00:11:42,720 --> 00:11:45,840 SO T CELLS PROBE THIS ANTIGEN 238 00:11:45,840 --> 00:11:48,760 PRESENTED BY HLA TO DETERMINE 239 00:11:48,760 --> 00:11:52,680 WHETHER IT'S FRIEND OR FOE. 240 00:11:52,680 --> 00:11:55,160 AND THIS DIVERSITY IN HLA GENES 241 00:11:55,160 --> 00:11:56,800 WITHIN OURSELVES AND BETWEEN 242 00:11:56,800 --> 00:12:00,120 OURSELVES ALLOWS A TREMENDOUS 243 00:12:00,120 --> 00:12:05,800 VARIETY OF PEPTIDES AND IT'S A 244 00:12:05,800 --> 00:12:08,360 WAY OF THE HUMAN SPECIES TO STAY 245 00:12:08,360 --> 00:12:11,000 AHEAD OF EVOLVING PATHOGEN. 246 00:12:11,000 --> 00:12:14,720 OUR ROLE IN THE HLA LABORATORY 247 00:12:14,720 --> 00:12:18,320 IS TO LOOK AT GENOTYPING AND 248 00:12:18,320 --> 00:12:20,760 PAIRS AND SURVEY PATIENT SERA 249 00:12:20,760 --> 00:12:26,640 FOR THE PRESENCE OF HLA 250 00:12:26,640 --> 00:12:28,800 ANTIBODIES AT TIME OF BEING 251 00:12:28,800 --> 00:12:31,080 LISTED ON THE ORGAN WAIT LIST 252 00:12:31,080 --> 00:12:34,160 AND POST TRANSPLANT BECAUSE THE 253 00:12:34,160 --> 00:12:36,760 ANTIBODY TO THE DONOR IS 254 00:12:36,760 --> 00:12:37,760 ASSOCIATED WITH REJECTION AND 255 00:12:37,760 --> 00:12:39,040 POOR OUTCOME. 256 00:12:39,040 --> 00:12:40,760 WE HAVE TO DECIDE IF THE HLA 257 00:12:40,760 --> 00:12:43,160 ANTIBODY PRESENT AND IF SO WE 258 00:12:43,160 --> 00:12:45,720 HAVE TO RISK ASSESS. 259 00:12:45,720 --> 00:12:50,320 IS THIS AN ANTIBODY WHERE OUR 260 00:12:50,320 --> 00:12:53,360 SURGERY TEAM CAN DO ACROSS IS 261 00:12:53,360 --> 00:12:59,880 THIS AN INJURIOUS ANTIBODY AND 262 00:12:59,880 --> 00:13:00,960 ALL IN A SPECIFIC CONTEXT 263 00:13:00,960 --> 00:13:03,600 MANNER. 264 00:13:03,600 --> 00:13:08,120 SO THE DEVELOPMENT OF LUMINEX 265 00:13:08,120 --> 00:13:09,600 BEAD PLATFORMS WAS A BOON TO THE 266 00:13:09,600 --> 00:13:11,760 HLA LABORATORY. 267 00:13:11,760 --> 00:13:14,240 AS MENTIONED THERE ARE TENS OF 268 00:13:14,240 --> 00:13:17,880 THOUSANDS OF HLA VARIANTS. 269 00:13:17,880 --> 00:13:20,720 THE LUMINEX ALLOWS US TO TEST A 270 00:13:20,720 --> 00:13:22,880 DROP OF SERUM ACROSS PROTEINS. 271 00:13:22,880 --> 00:13:24,840 THE PLATFORM IS A SET OF BEADS, 272 00:13:24,840 --> 00:13:27,400 100 OR 500 SET IN WHICH EACH 273 00:13:27,400 --> 00:13:29,520 BEAD IS INFUSED WITH TWO 274 00:13:29,520 --> 00:13:34,120 DIFFERENT RATIOS OF RED 275 00:13:34,120 --> 00:13:36,040 FLUORESCENT DIE SO EACH BEAD HAS 276 00:13:36,040 --> 00:13:38,400 ITS UNIQUE FOOTPRINT AND 277 00:13:38,400 --> 00:13:40,200 INCUBATE THESE BEADS WITH A DROP 278 00:13:40,200 --> 00:13:41,800 OF PATIENT SIERRA AND CAN 279 00:13:41,800 --> 00:13:44,040 DETERMINE IF IT MAKES AN 280 00:13:44,040 --> 00:13:45,880 ANTIBODY TO A PARTICULAR 281 00:13:45,880 --> 00:13:46,160 MOLECULE. 282 00:13:46,160 --> 00:13:47,960 THEY'RE PASSED THROUGH AN 283 00:13:47,960 --> 00:13:49,280 INSTRUMENT TO DETERMINE WHAT 284 00:13:49,280 --> 00:13:51,600 BEAD IS PASSING BY COATED WITH 285 00:13:51,600 --> 00:13:54,400 HLA 1, FOR INSTANCE, THE SECOND 286 00:13:54,400 --> 00:13:55,280 LASER DETERMINES IF THERE'S AN 287 00:13:55,280 --> 00:13:56,920 ANTIBODY BOUND TO THE BEAD. 288 00:13:56,920 --> 00:13:58,480 THROUGH THE LARGE BEAD SETS WE 289 00:13:58,480 --> 00:14:02,120 CAN DO A DEEP INTERROGATION OF 290 00:14:02,120 --> 00:14:03,240 WHAT ANTIBODY PATIENTS ARE 291 00:14:03,240 --> 00:14:05,360 FORMING AND WHAT EPITOPES 292 00:14:05,360 --> 00:14:08,600 THEY'RE REACTING TO. 293 00:14:08,600 --> 00:14:10,960 SO THE NEXT SLIDE IS A READ OUT 294 00:14:10,960 --> 00:14:14,000 FROM THESE ASSAYS AND ON THE Y 295 00:14:14,000 --> 00:14:16,760 AXIS IS A FLUORESCENT INTENSITY 296 00:14:16,760 --> 00:14:19,800 WHICH IS SEMI PROPORTIONAL TO 297 00:14:19,800 --> 00:14:24,760 THE AMOUNT OF ANTIBODY IN THE 298 00:14:24,760 --> 00:14:27,200 SERA AND THERE'S BEADS AND THIS 299 00:14:27,200 --> 00:14:30,640 IS A 100 BEAD SET AND THE HLA 300 00:14:30,640 --> 00:14:31,640 MOLECULES CODED ON THE BEAD. 301 00:14:31,640 --> 00:14:33,280 EVEN WOULD TRAINING ALL OF YOU 302 00:14:33,280 --> 00:14:38,040 CAN SEE THIS PATIENT IN FACT 303 00:14:38,040 --> 00:14:42,600 MAKES HIGHER LEVEL MMFI ANTIBODY 304 00:14:42,600 --> 00:14:45,280 MOLECULES WITH LOWER REACTIVITY 305 00:14:45,280 --> 00:14:46,680 TO THE THESE MOLECULES HERE. 306 00:14:46,680 --> 00:14:50,720 AS NANCY ALLUDED TO WHEN WE 307 00:14:50,720 --> 00:14:52,360 ANALYZE HLA ANTIBODY WE'RE 308 00:14:52,360 --> 00:14:57,760 LOOKING AT UNDILUTED SERA WHICH 309 00:14:57,760 --> 00:15:00,760 POSES PROBLEMS AND THERE ARE 310 00:15:00,760 --> 00:15:08,120 SEROLOGICAL TESTS AND TITERS ARE 311 00:15:08,120 --> 00:15:09,920 DILUTED AND WE HAVE THE 312 00:15:09,920 --> 00:15:11,480 BACKGROUND ACTIVITY IN THE SERA. 313 00:15:11,480 --> 00:15:14,960 SO WE USE PATTERN ANALYSIS TO 314 00:15:14,960 --> 00:15:16,520 MAKE SURE WE'RE CALLING REAL 315 00:15:16,520 --> 00:15:17,800 ANTIBODY AND NOT DELVING INTO 316 00:15:17,800 --> 00:15:19,280 BACKGROUND. 317 00:15:19,280 --> 00:15:21,840 THE CIRCLED TOP LINE WITH THE 318 00:15:21,840 --> 00:15:25,280 DR479 AND 1 ARE PART OF THE SAME 319 00:15:25,280 --> 00:15:27,440 CROSS-KRAEKTIVE GROUP. 320 00:15:27,440 --> 00:15:30,760 THEY EVOLVE FROM ONE ANOTHER AND 321 00:15:30,760 --> 00:15:34,320 THEREFORE SHARE IMMUNODOMINANT 322 00:15:34,320 --> 00:15:34,800 EPITOPES. 323 00:15:34,800 --> 00:15:36,640 SO WE CONVEY THE ANTIBODIES TO 324 00:15:36,640 --> 00:15:39,160 BOTH THE PATIENTS AND THE 325 00:15:39,160 --> 00:15:40,320 CLINICIANS THROUGH SOMETHING 326 00:15:40,320 --> 00:15:41,240 CALLED PANEL REACTIVE ANTIBODY. 327 00:15:41,240 --> 00:15:43,280 THIS IS A THROW BACK TO THE DAYS 328 00:15:43,280 --> 00:15:47,000 WHEN WE USED TO DO CELL PANELS 329 00:15:47,000 --> 00:15:48,400 TO DETECT HLA ANTIBODIES. 330 00:15:48,400 --> 00:15:52,160 NOW WE USE OUR BEAD PANELS AND 331 00:15:52,160 --> 00:15:56,760 USE THE ALLELE FREQUENCY IN OUR 332 00:15:56,760 --> 00:15:57,400 DECEASED DONOR POPULATION TO 333 00:15:57,400 --> 00:15:58,600 COUNT THE FREQUENCY IN WHICH 334 00:15:58,600 --> 00:16:02,640 THIS ANTIGEN EXISTS IN THE DONOR 335 00:16:02,640 --> 00:16:03,160 POOL. 336 00:16:03,160 --> 00:16:04,080 IN THE PATIENT ON THE PREVIOUS 337 00:16:04,080 --> 00:16:08,280 SLIDE HAS MULTIPLE DQ AND AL 338 00:16:08,280 --> 00:16:13,120 ALLELES AND DR AND THIS WOULD 339 00:16:13,120 --> 00:16:18,360 HAVE A CPRA OF 89% OUT OF EVERY 340 00:16:18,360 --> 00:16:21,920 100 DECEASED DONOR OFFERS. 341 00:16:21,920 --> 00:16:24,760 IMMEDIATELY THIS PATIENT RULES 342 00:16:24,760 --> 00:16:30,240 OUT 90% OF DONORS. 343 00:16:30,240 --> 00:16:39,840 THIS IS THE SCOPE OF THE 344 00:16:39,840 --> 00:16:40,560 PROBLEM. 345 00:16:40,560 --> 00:16:42,560 30% OF THE SENSITIZED PATIENTS 346 00:16:42,560 --> 00:16:44,200 ARE IN THE HIGHLY SENSITIZED 347 00:16:44,200 --> 00:16:46,320 CATEGORY WITH A CPRA OF GREATER 348 00:16:46,320 --> 00:16:46,960 THAN 80%. 349 00:16:46,960 --> 00:16:51,480 THERE'S BEEN A GROWTH IN THE 350 00:16:51,480 --> 00:16:53,960 NUMBER OF HLA SENSITIZED 351 00:16:53,960 --> 00:16:57,960 PATIENTS IN PART DUE TO OUR 352 00:16:57,960 --> 00:16:59,400 DIAGNOSTICS AND TRANSPLANTATION 353 00:16:59,400 --> 00:17:03,800 OF KIDNEY, HEART AND LUNG AND 354 00:17:03,800 --> 00:17:05,480 DEVICES AND STRATEGIES TO BRIDGE 355 00:17:05,480 --> 00:17:08,680 PATIENTS TO TRANSPLANT SUCH AS 356 00:17:08,680 --> 00:17:12,760 IMPLANTING LEFT VENTRICULAR 357 00:17:12,760 --> 00:17:13,720 ASSIST DEVICES WHERE THEY GET A 358 00:17:13,720 --> 00:17:15,720 LOT OF BLOOD TRANSFUSIONS. 359 00:17:15,720 --> 00:17:18,480 SO AS WITH YOU SPOKEN BRIEFLY 360 00:17:18,480 --> 00:17:24,760 THIS MORNING, HOW DO WE 361 00:17:24,760 --> 00:17:30,720 CIRCUMVENT HLA ANTIBODIES WE CAN 362 00:17:30,720 --> 00:17:33,840 DO A KIDNEY PAIR DONATION WHERE 363 00:17:33,840 --> 00:17:37,080 WE SWAP DONORS BETWEEN 364 00:17:37,080 --> 00:17:37,400 RECIPIENTS. 365 00:17:37,400 --> 00:17:39,840 THE INSTITUTION OF KPD IN THE 366 00:17:39,840 --> 00:17:42,000 U.S. AND I WOULD SAY THE 367 00:17:42,000 --> 00:17:49,120 LEGALIZATION OF KPD WAS REALLY 368 00:17:49,120 --> 00:17:51,720 BROUGHT FOURTH BY THE LEADERSHIP 369 00:17:51,720 --> 00:17:54,600 OF DR. MONTGOMERY TO MAKE IT A 370 00:17:54,600 --> 00:17:55,280 VIABLE MODALITY. 371 00:17:55,280 --> 00:17:59,280 PRIOR TO 2007 IT WAS ACTUALLY 372 00:17:59,280 --> 00:18:01,280 ILLEGAL TO SWAP LIVING DONOR 373 00:18:01,280 --> 00:18:03,040 KIDNEYS BECAUSE IT WAS ILLEGAL 374 00:18:03,040 --> 00:18:05,920 TO BUY OR BARTER FOR ORGANS SO 375 00:18:05,920 --> 00:18:11,280 IT HAS TO BE SHOWN TO BE ETHICAL 376 00:18:11,280 --> 00:18:12,760 AND ABLE TO BE DONE 377 00:18:12,760 --> 00:18:13,200 LOGISTICALLY. 378 00:18:13,200 --> 00:18:15,000 FOR PATIENTS WITHOUT A LIVE 379 00:18:15,000 --> 00:18:16,760 DONOR, THEY'RE GOING TO WAIT ON 380 00:18:16,760 --> 00:18:19,280 THE DECEASED DONOR KIDNEY LIST. 381 00:18:19,280 --> 00:18:21,920 IN 2014 BUT STARTING MANY YEARS 382 00:18:21,920 --> 00:18:23,680 PRIOR, A NEW EFFORT WAS MADE IN 383 00:18:23,680 --> 00:18:27,720 THE DECEASED DONOR KIDNEY 384 00:18:27,720 --> 00:18:28,760 ALLOCATION SYSTEM TO PROVIDE 385 00:18:28,760 --> 00:18:32,080 MORE EQUITY TO THE POPULATION. 386 00:18:32,080 --> 00:18:33,280 PARTICULARLY THE HLA SENSITIZED 387 00:18:33,280 --> 00:18:34,720 PATIENTS WHO WERE TRANSPLANTED 388 00:18:34,720 --> 00:18:36,720 AT VERY LOW RATES AND HAD A VERY 389 00:18:36,720 --> 00:18:43,680 HIGH MORTALITY ON THE WAIT LIST. 390 00:18:43,680 --> 00:18:45,600 AND WE GAVE THEM EXTRA 391 00:18:45,600 --> 00:18:47,520 ALLOCATION POINTS DEPENDING ON 392 00:18:47,520 --> 00:18:49,480 THEIR CPRA. 393 00:18:49,480 --> 00:18:52,040 THE HIGHER THE CPRA THE MORE 394 00:18:52,040 --> 00:18:53,720 POINTS AND BUMPED THEM TO THE 395 00:18:53,720 --> 00:18:54,600 TOP OF THE LIST. 396 00:18:54,600 --> 00:18:55,840 ANOTHER POINT THAT WAS EQUALLY 397 00:18:55,840 --> 00:19:01,280 AS CRITICAL WAS THE IDEA THAT 398 00:19:01,280 --> 00:19:04,200 ORGANS BECAUSE THEY'RE OF SHORT 399 00:19:04,200 --> 00:19:05,760 SUPPLY SHOULD BE CONSIDERED A 400 00:19:05,760 --> 00:19:07,920 NATIONAL RESOURCE SO IF WE 401 00:19:07,920 --> 00:19:10,640 PROCURE AN ORGAN OR KIDNEY AT 402 00:19:10,640 --> 00:19:12,840 DUKE, IT'S NOT DUKE'S KIDNEY TO 403 00:19:12,840 --> 00:19:15,240 GO TO DUKE'S PATIENT BUT SHARED 404 00:19:15,240 --> 00:19:17,440 TO ACHIEVE THE MOST EQUITABLE 405 00:19:17,440 --> 00:19:21,240 AND LIFE-SAVING USE OF THAT 406 00:19:21,240 --> 00:19:21,800 KIDNEY. 407 00:19:21,800 --> 00:19:24,760 REGIONAL AND NATIONAL ORGAN 408 00:19:24,760 --> 00:19:28,600 SHARING WAS MANDATED. 409 00:19:28,600 --> 00:19:31,400 IT WAS LAUNCHED IN 2014 AND THE 410 00:19:31,400 --> 00:19:36,760 HIGHLY SENSITIZED PATIENT THE 411 00:19:36,760 --> 00:19:40,760 BROWN LINE WENT UP DRAMATICALLY 412 00:19:40,760 --> 00:19:44,040 AND THAT YEAR WE GOT A LOT OF 413 00:19:44,040 --> 00:19:45,040 SENSITIZED PATIENTS TRANSPLANTED 414 00:19:45,040 --> 00:19:47,200 AND WE OPENED UP THE DONOR POOL 415 00:19:47,200 --> 00:19:49,280 SO THEY COULD FIND THEIR NEEDLE 416 00:19:49,280 --> 00:19:51,440 IN THE HAYSTACK AND WE 417 00:19:51,440 --> 00:19:52,440 TRANSPLANTED A LOT OF PATIENTS. 418 00:19:52,440 --> 00:19:53,760 HOWEVER, MORE DETAILED ANALYSIS 419 00:19:53,760 --> 00:19:57,680 OF THE DATA HAS SHOWN US THAT 420 00:19:57,680 --> 00:19:59,080 THERE ARE STILL THE MOST HIGHLY 421 00:19:59,080 --> 00:20:05,920 SENSITIZED THE 99.9% THAT ARE 422 00:20:05,920 --> 00:20:07,320 STILL DISADVANTAGED AND NOT 423 00:20:07,320 --> 00:20:08,760 RECEIVING DONOR OFFERS. 424 00:20:08,760 --> 00:20:11,160 THE OTHER LIMITING FACTOR IN 425 00:20:11,160 --> 00:20:12,760 CLINICAL TRANSPLANTATION IS THE 426 00:20:12,760 --> 00:20:17,560 LIMITED ORGAN SURVIVAL TIME. 427 00:20:17,560 --> 00:20:20,400 I LIFTED THIS FIGURE OUT OF A 428 00:20:20,400 --> 00:20:24,520 MEDICAL JOURNAL OF ECONOMICS 429 00:20:24,520 --> 00:20:25,800 REVIEW AND IT SHOWS THE LIFE 430 00:20:25,800 --> 00:20:27,560 SPAN OF TRANSPLANTED ORGANS IN 431 00:20:27,560 --> 00:20:29,480 THE U.S. AND I INSERTED THE 432 00:20:29,480 --> 00:20:30,880 DOTTED RED LINE TO SHOW THE HALF 433 00:20:30,880 --> 00:20:31,800 LIFE OF THESE ORGANS. 434 00:20:31,800 --> 00:20:35,160 FOR KIDNEY, LIVER AND HEART THE 435 00:20:35,160 --> 00:20:37,680 HALF LIFE IS ABOUT 15 YEARS. 436 00:20:37,680 --> 00:20:40,520 MUCH SHORTER FOR LUNG DOWN 437 00:20:40,520 --> 00:20:42,360 TOWARDS LIKE 7 YEARS HALF LIFE. 438 00:20:42,360 --> 00:20:51,480 THIS LOSS OF ORGANS IS DUE TOALO 439 00:20:51,480 --> 00:20:53,520 GRAPH REJECTION AND IT'S A 440 00:20:53,520 --> 00:20:55,000 FOREIGN INVADER. 441 00:20:55,000 --> 00:20:57,040 SO I'M GOING TO RUN THROUGH AND 442 00:20:57,040 --> 00:21:00,680 THIS IS WHERE I'M STILL TAKING 443 00:21:00,680 --> 00:21:03,760 THIS VERY HIGH 30,000 FOOT VIEW 444 00:21:03,760 --> 00:21:06,040 BUT THIS PORTION OF THE TALK I 445 00:21:06,040 --> 00:21:08,160 GIVE TO TRANSPLANT FELLOWS TO 446 00:21:08,160 --> 00:21:11,040 TRY TO MAKE THEM THINK HARDER OF 447 00:21:11,040 --> 00:21:13,240 IMMUNOLOGY IN THE TRANSPLANT 448 00:21:13,240 --> 00:21:13,480 CLINIC. 449 00:21:13,480 --> 00:21:16,360 SO REJECTION BEGINS WITH 450 00:21:16,360 --> 00:21:18,040 ACTIVATION OF HLA SPECIFIC T 451 00:21:18,040 --> 00:21:18,480 CELLS. 452 00:21:18,480 --> 00:21:21,320 MANY MAY KNOW YOUR T CELLS ARE 453 00:21:21,320 --> 00:21:24,240 POSITIVELY SELECTED ON HLA 454 00:21:24,240 --> 00:21:25,280 MOLECULES SO YOU'RE T CELL 455 00:21:25,280 --> 00:21:27,120 REPERTOIRE HAS BEEN SELECTED TO 456 00:21:27,120 --> 00:21:28,160 BIND HLA WELL. 457 00:21:28,160 --> 00:21:31,080 THIS DOES NOT BODE WELL WHEN 458 00:21:31,080 --> 00:21:32,000 YOU'RE TRYING TO HIDE AN HLA 459 00:21:32,000 --> 00:21:33,640 MISS MATCH ORGAN IN A TRANSPLANT 460 00:21:33,640 --> 00:21:34,480 PATIENT. 461 00:21:34,480 --> 00:21:38,080 IT'S ESTIMATED UP TO 10% OF YOUR 462 00:21:38,080 --> 00:21:38,920 T CELL REPERTOIRE WILL RECOGNIZE 463 00:21:38,920 --> 00:21:42,360 AND BE ABLE TO BIND AND BECOME 464 00:21:42,360 --> 00:21:43,880 ACTIVATED TO FOREIGN HLA THROUGH 465 00:21:43,880 --> 00:21:46,120 THE DIRECT PATHWAY BY DIRECTLY 466 00:21:46,120 --> 00:21:47,360 RECOGNIZING OR THROUGH THE 467 00:21:47,360 --> 00:21:50,560 INDIRECT PATHWAY WHEN IT'S 468 00:21:50,560 --> 00:21:52,480 CHOPPED INTO THE LITTLE RED 469 00:21:52,480 --> 00:21:54,320 PEPTIDES LOADED IN THE 470 00:21:54,320 --> 00:21:55,840 RECIPIENT'S HLA. 471 00:21:55,840 --> 00:21:59,600 HLA IS AN INCREDIBLY ABUNDANT 472 00:21:59,600 --> 00:22:01,280 ANTIGEN EXPRESSED AT A HIGH 473 00:22:01,280 --> 00:22:04,200 LEVEL ON ALL NUCLEATED CELLS AND 474 00:22:04,200 --> 00:22:07,280 A BIG BOLUS OF ANTIGEN WHEN WE 475 00:22:07,280 --> 00:22:09,920 PUT IN THE ORGAN AND IT'S 476 00:22:09,920 --> 00:22:14,800 EXTREMELY IMMUNOGENIC. 477 00:22:14,800 --> 00:22:16,760 TRYING TO KEEP A T CELL FROM 478 00:22:16,760 --> 00:22:20,760 BEING ACTIVATED BY FOREIGN HLA 479 00:22:20,760 --> 00:22:27,760 IS ACTUALLY BEYOND REALITY. 480 00:22:27,760 --> 00:22:30,280 SO OUR PATIENT WITHSTAND LIFE 481 00:22:30,280 --> 00:22:30,960 LONG IMMUNOSUPPRESSION AND IT'S 482 00:22:30,960 --> 00:22:34,640 VERY MUCH TARGETED TO SUPPRESS T 483 00:22:34,640 --> 00:22:35,560 CELL ACTIVATION NOT B CELL BUT 484 00:22:35,560 --> 00:22:43,120 JUST T CELL ACTIVATION. 485 00:22:43,120 --> 00:22:45,400 AND IF WE'RE SUCCESSFUL AND SOME 486 00:22:45,400 --> 00:22:46,680 T CELLS BECOME ACTIVATED AND 487 00:22:46,680 --> 00:22:49,280 SLIP THROUGH THEY'LL LOOK FOR 488 00:22:49,280 --> 00:22:52,760 THEIR COGNATE B CELL BECAUSE 489 00:22:52,760 --> 00:22:54,280 THEY'LL ALSO RECOGNIZE FOREIGN 490 00:22:54,280 --> 00:22:56,160 HLA AND BRING IT IN TO THEIR B 491 00:22:56,160 --> 00:23:00,160 CELL RECEPTOR, PROCESS AND WHEN 492 00:23:00,160 --> 00:23:03,000 WE GET THE HLA SPECIFIC T CELL 493 00:23:03,000 --> 00:23:06,600 AND B CELL WE CAN CREATE GER 494 00:23:06,600 --> 00:23:10,440 GERMINAL CENTERS WHICH CREATE 495 00:23:10,440 --> 00:23:12,440 ANTIBODIES AND PLASMA CELLS ARE 496 00:23:12,440 --> 00:23:13,920 A VERY INTERESTING AREA OF 497 00:23:13,920 --> 00:23:15,720 SCIENCE RIGHT NOW. 498 00:23:15,720 --> 00:23:18,560 WE'RE COLLABORATING WITH EMORY 499 00:23:18,560 --> 00:23:20,880 TO REALLY UNDERSTAND PLASMA CELL 500 00:23:20,880 --> 00:23:26,080 SUBSETS AND NICHES. 501 00:23:26,080 --> 00:23:36,600 THEY'RE LONG LIVED ONES THEY WE 502 00:23:40,480 --> 00:23:44,640 TREAT THEM WITH INHIBITOR AND 503 00:23:44,640 --> 00:23:47,720 DEPLETING ANTIBODIES CB38 AND 504 00:23:47,720 --> 00:23:51,680 STILL THESE SURVIVE OR PART OF 505 00:23:51,680 --> 00:23:52,240 THEM SURVIVE. 506 00:23:52,240 --> 00:23:54,680 SO EVOLUTION HAS DONE A GOOD JOB 507 00:23:54,680 --> 00:23:57,920 AT TUCKING AWAY PLASMA CELLS AND 508 00:23:57,920 --> 00:24:01,200 MAKING THEM SURVIVE FOR THE LONG 509 00:24:01,200 --> 00:24:04,200 HAUL BUT ONCE IT OCCURS AND WE 510 00:24:04,200 --> 00:24:06,520 GET PLASMA CELLS IN THE 511 00:24:06,520 --> 00:24:08,400 TRANSPLANT ARENA WE ARE HELD 512 00:24:08,400 --> 00:24:11,280 HOSTAGE AND DON'T HAVE CURRENT 513 00:24:11,280 --> 00:24:13,080 THERAPEUTICS TO FIGHT THE HLA 514 00:24:13,080 --> 00:24:13,400 ANTIBODIES. 515 00:24:13,400 --> 00:24:18,400 SO IF AN IMAGE IS WORTH A 516 00:24:18,400 --> 00:24:20,040 THOUSAND WORDS A VIDEO WOULD BE 517 00:24:20,040 --> 00:24:21,440 WORTH A THOUSAND IMAGES. 518 00:24:21,440 --> 00:24:23,680 IF YOU GO AHEAD AND START THE 519 00:24:23,680 --> 00:24:26,760 VIDEO -- THIS IS REALLY A MOVIE 520 00:24:26,760 --> 00:24:28,120 CREATED BY MARK JENKINS AT 521 00:24:28,120 --> 00:24:30,760 UNIVERSITY OF MINNESOTA AND 522 00:24:30,760 --> 00:24:32,440 SIMULATES THE FIRST 50 HOURS OF 523 00:24:32,440 --> 00:24:33,720 THE IMMUNE RESPONSE. 524 00:24:33,720 --> 00:24:35,360 I USE THIS IN MY TEACHING 525 00:24:35,360 --> 00:24:36,200 LECTURES WITH THE TRANSPLANT 526 00:24:36,200 --> 00:24:37,760 FELLOWS BECAUSE I WANT TO GET A 527 00:24:37,760 --> 00:24:42,360 FEW POINTS ACROSS. 528 00:24:42,360 --> 00:24:52,640 WE START HERE -- 529 00:25:07,320 --> 00:25:12,760 >> DOWN HERE IS THE T CELL AND 530 00:25:12,760 --> 00:25:16,600 THESE PURPLE ARE COATED WITH HLA 531 00:25:16,600 --> 00:25:18,800 PRESENTING TO T CELLS WHICH ARE 532 00:25:18,800 --> 00:25:29,240 MONITORING AND PROBING. 533 00:25:31,360 --> 00:25:41,800 THIS IS TO WAKE EVERYBODY UP. 534 00:25:48,240 --> 00:25:52,760 WELL, IT'S SPECTACULAR. 535 00:25:52,760 --> 00:25:54,080 I ENCOURAGE TO LOOK AT THE 536 00:25:54,080 --> 00:25:54,440 VIDEO. 537 00:25:54,440 --> 00:26:00,080 IT'S NOT A TRANSPLANT BUT 538 00:26:00,080 --> 00:26:02,040 INJECTING INTO A LIVE MOUSE AND 539 00:26:02,040 --> 00:26:07,280 IT SHOWS THE GREEN T CELL WOULD 540 00:26:07,280 --> 00:26:15,160 BE PROBING THESE DENDRITIC CELL 541 00:26:15,160 --> 00:26:17,320 AND YOU GET A CALCIUM FLUX IN 542 00:26:17,320 --> 00:26:18,000 THE T CELL. 543 00:26:18,000 --> 00:26:20,760 AS SOON AS THE T CELL GETS 544 00:26:20,760 --> 00:26:23,520 ACTIVATED IT STARTS DIVIDING AND 545 00:26:23,520 --> 00:26:24,560 YOU SEE THE GREEN CELLS APPEAR 546 00:26:24,560 --> 00:26:27,960 IN FRONT OF YOU AND AS SOON AS 547 00:26:27,960 --> 00:26:28,800 THEY'RE ACTIVATED THEY MOVE 548 00:26:28,800 --> 00:26:30,360 TOWARDS THE B CELL BORDER AND 549 00:26:30,360 --> 00:26:31,640 ACTIVATE THE B CELL AND THERE'S 550 00:26:31,640 --> 00:26:34,440 A WHOLE LOT OF SPARKS TO THEM 551 00:26:34,440 --> 00:26:36,080 WHEN WE GET MAJOR FLEX WITHIN 552 00:26:36,080 --> 00:26:37,760 THE B CELL AND REASON I SHOW 553 00:26:37,760 --> 00:26:40,440 THIS TO THE TRANSPLANT FELLOWS 554 00:26:40,440 --> 00:26:42,720 IS BECAUSE IN CLINICAL 555 00:26:42,720 --> 00:26:43,920 TRANSPLANTATION WE THINK OF T 556 00:26:43,920 --> 00:26:46,400 CELL REJECTION IN ONE CAMP AND B 557 00:26:46,400 --> 00:26:49,080 CELL REJECTION IN ANOTHER CAMP 558 00:26:49,080 --> 00:26:52,160 BUT THEY'RE ALL PART OF AN ANY 559 00:26:52,160 --> 00:26:53,240 ADAPTIVE IMMUNE RESPONSE AND IF 560 00:26:53,240 --> 00:26:56,320 A PATIENT HAS REPEATED T CELL 561 00:26:56,320 --> 00:27:00,400 REJECTIONS HE MAY HAVE ALSO 562 00:27:00,400 --> 00:27:01,200 ACTIVATED B CELLS IN THE PROCESS 563 00:27:01,200 --> 00:27:06,280 AND WE SHOULD BE MONITORING FOR 564 00:27:06,280 --> 00:27:07,600 HLA ANTIBODIES PERHAPS MORE 565 00:27:07,600 --> 00:27:08,760 VIGILANTLY AFTER T CELL 566 00:27:08,760 --> 00:27:09,040 REJECTION. 567 00:27:09,040 --> 00:27:11,000 IT'S MY IDEA TO SHOW THEM IF 568 00:27:11,000 --> 00:27:12,600 THEY IMAGINE THIS VIDEO IS THE 569 00:27:12,600 --> 00:27:16,240 FIRST 50 HOURS AFTER A SIMPLE 570 00:27:16,240 --> 00:27:17,720 ANTIGEN INJECTION, IMAGINE THE 571 00:27:17,720 --> 00:27:19,280 FIRST 50 HOURS IN A TRANSPLANT 572 00:27:19,280 --> 00:27:20,320 PATIENT WHEN THEY GO TO THE 573 00:27:20,320 --> 00:27:23,880 BEACH AND FORGET THEIR MEDS AND 574 00:27:23,880 --> 00:27:26,240 GO FOR 48 HOURS WITH LITERALLY 575 00:27:26,240 --> 00:27:31,200 NO MEDICATION HOW WE CAN GET 576 00:27:31,200 --> 00:27:36,760 BREAKTHROUGH OF ALLO IMMUNE 577 00:27:36,760 --> 00:27:43,000 RESPONSE. 578 00:27:43,000 --> 00:27:45,280 WHY DO WE CARE ABOUT HLA 579 00:27:45,280 --> 00:27:47,080 ANTIBODY PRODUCTION? 580 00:27:47,080 --> 00:27:49,360 THEY'RE ACTIVATORS OF COMPLIMENT 581 00:27:49,360 --> 00:27:51,520 WITH THE TRANSPLANTED ALLO 582 00:27:51,520 --> 00:27:52,120 GRAPH. 583 00:27:52,120 --> 00:27:54,200 THIS IS FROM SCIENCE MAGAZINE IN 584 00:27:54,200 --> 00:27:59,360 2014 WHICH SHOWED YOU HAVE TO 585 00:27:59,360 --> 00:28:02,840 GET CLOSE PROXIMITY AND WHY IS 586 00:28:02,840 --> 00:28:06,000 HLA COMPLEMENT A GOOD ACTIVATOR? 587 00:28:06,000 --> 00:28:08,240 IT'S HIGHLY EXPRESSED ON CELL 588 00:28:08,240 --> 00:28:11,320 SURFACES AND A STRONG 589 00:28:11,320 --> 00:28:12,760 IMMUNOGENIC AND THERE ARE 590 00:28:12,760 --> 00:28:18,440 NUMEROUS EPITOPES AND IT'S EASY 591 00:28:18,440 --> 00:28:25,280 TO GET JUXTAPOSE TO THE SUB 592 00:28:25,280 --> 00:28:26,800 CLASS WHICH ARE EXCELLENT 593 00:28:26,800 --> 00:28:27,320 COMPLEMENT ACTIVATORS. 594 00:28:27,320 --> 00:28:31,720 THIS IS A KIDNEY BIOPSY LOOKING 595 00:28:31,720 --> 00:28:33,840 AT THE SPLIT PRODUCT DEPOSITED 596 00:28:33,840 --> 00:28:35,040 ON THE VASCULAR TISSUE. 597 00:28:35,040 --> 00:28:39,200 YOU CAN SEE THIS TYPE OF 598 00:28:39,200 --> 00:28:41,480 COMPLEMENT ACTIVATION WILL 599 00:28:41,480 --> 00:28:46,640 RESULT IN ALLO GRAPH FAILURE AND 600 00:28:46,640 --> 00:28:48,800 LOSS IF WE DON'T INTERVENE WITH 601 00:28:48,800 --> 00:28:54,280 THERAPEUTICS. 602 00:28:54,280 --> 00:28:58,320 THE BIGGEST FEAR WE HAVE IS THE 603 00:28:58,320 --> 00:28:59,480 ROLE OF HLA ANTIBODY AND 604 00:28:59,480 --> 00:29:00,600 INCREASE ANTIBODY MEDIATED 605 00:29:00,600 --> 00:29:01,880 REJECTION. 606 00:29:01,880 --> 00:29:05,200 THIS IS A SILENT INDULLENT 607 00:29:05,200 --> 00:29:08,400 INJURY THAT LIKELY HAPPENS WHEN 608 00:29:08,400 --> 00:29:12,680 THE HLA TITER IS LOW OR DIRECTED 609 00:29:12,680 --> 00:29:15,520 TOWARD ANTIGENS WITH LOWER 610 00:29:15,520 --> 00:29:17,280 EXPRESSION WHEN THINGS ARE CALM 611 00:29:17,280 --> 00:29:18,440 IN THE ALLO GRAPH. 612 00:29:18,440 --> 00:29:22,040 I THINK OF THIS AKIN TO WOUND 613 00:29:22,040 --> 00:29:24,760 HEALING WHERE YOU HAVE ANTIBODY 614 00:29:24,760 --> 00:29:28,000 BINDING AND SMOOTH MUSCLE CELL 615 00:29:28,000 --> 00:29:34,760 PROLIFERATION YOU GET TRANSPLANT 616 00:29:34,760 --> 00:29:38,040 VASCULEOPATHY AND IN THE KIDNEY 617 00:29:38,040 --> 00:29:40,760 WE GET MEMBRANE DUPLICATION 618 00:29:40,760 --> 00:29:51,240 RESULTING IN A NON-FUNCTIONAL 619 00:29:51,520 --> 00:29:55,040 GLOMERULUS AND WHY IT'S NOT 620 00:29:55,040 --> 00:29:57,720 ACHIEVED ITS LONG-TERM GOAL AND 621 00:29:57,720 --> 00:30:02,320 ANTIBODIES TO THE DQ ARE MOST 622 00:30:02,320 --> 00:30:06,400 STRONGLY ASSOCIATED WITH THIS 623 00:30:06,400 --> 00:30:06,800 REJECTION. 624 00:30:06,800 --> 00:30:08,400 SO THE HLA COMMUNITY IS FOCUSSED 625 00:30:08,400 --> 00:30:13,560 ON HOW CAN WE BE BETTER AT DONOR 626 00:30:13,560 --> 00:30:13,800 SELECTION. 627 00:30:13,800 --> 00:30:16,600 AS NANCY MENTIONED WE'RE LOOKING 628 00:30:16,600 --> 00:30:18,040 AT HLA MOLECULAR MATCHING. 629 00:30:18,040 --> 00:30:22,320 THIS IS AN IMAGE FROM A PAPER BY 630 00:30:22,320 --> 00:30:26,240 CHRIS WEAVE AND PETER NICKERSON 631 00:30:26,240 --> 00:30:28,760 LOOKING AT THEM AT TWO ANTIGEN 632 00:30:28,760 --> 00:30:32,520 BUT WE'RE UNDERSTANDING BETTER 633 00:30:32,520 --> 00:30:36,400 THE PARTICULAR MOTIF THAT ARE 634 00:30:36,400 --> 00:30:37,760 PARTICULARLY IMO GENIC. 635 00:30:37,760 --> 00:30:43,280 IN YELLOW ARE EPETS WE CAN 636 00:30:43,280 --> 00:30:47,320 IDENTIFY AS THE EPICENTER OF 637 00:30:47,320 --> 00:30:47,760 ANTIBODY EPITOPES. 638 00:30:47,760 --> 00:30:50,360 WE'RE ABLE TO DEFINE THEM 639 00:30:50,360 --> 00:30:52,000 THROUGH MOLECULAR TYPING OF THE 640 00:30:52,000 --> 00:30:53,800 DONORS AND ABLE TO CHARACTERIZE 641 00:30:53,800 --> 00:30:56,760 ANTIBODIES THROUGH THESE EPLETS 642 00:30:56,760 --> 00:31:01,960 IN OUR ANALYSIS SOFTWARE. 643 00:31:01,960 --> 00:31:05,880 WHILE WE WON'T BE ABLE TO MATCH 644 00:31:05,880 --> 00:31:07,840 HLA IN RECIPIENT PAIRS BUT WHICH 645 00:31:07,840 --> 00:31:11,000 IS MOST IMMUNOGENIC AND AVOID 646 00:31:11,000 --> 00:31:14,640 THOSE MISMATCHES AS A HAPPY 647 00:31:14,640 --> 00:31:15,120 MEDIUM. 648 00:31:15,120 --> 00:31:17,280 I OFTEN GET ASKED WHAT'S THE 649 00:31:17,280 --> 00:31:17,800 WORSE? 650 00:31:17,800 --> 00:31:20,000 I THINK THAT'S THE MOST OFTEN 651 00:31:20,000 --> 00:31:23,400 ASKED QUESTION AND I SAY IT 652 00:31:23,400 --> 00:31:25,080 TOTALLY DEPENDS ON THE GENOTYPE 653 00:31:25,080 --> 00:31:27,320 OF THE RECIPIENT. 654 00:31:27,320 --> 00:31:31,280 IT'S NOT A SIMPLE THING THIS 655 00:31:31,280 --> 00:31:34,240 AMINO ACID IS PARTICULARLY 656 00:31:34,240 --> 00:31:34,560 IMMUNOGENIC. 657 00:31:34,560 --> 00:31:40,960 IT DEPENDS ON THE PATIENT TYPE. 658 00:31:40,960 --> 00:31:42,880 EFFIE AND I ARE POOLING DATA 659 00:31:42,880 --> 00:31:44,600 FROM AROUND THE WORLD TO GET 660 00:31:44,600 --> 00:31:45,720 GREATER DIVERSITY AND 661 00:31:45,720 --> 00:31:48,760 UNDERSTANDING OF THE EPLETS AND 662 00:31:48,760 --> 00:31:49,240 THEIR IMMUNOGENICITY. 663 00:31:49,240 --> 00:31:50,800 TO END, KNOWING I WAS SPEAKING 664 00:31:50,800 --> 00:31:54,280 IN A SESSION WITH EFFIE I HAD TO 665 00:31:54,280 --> 00:31:56,880 SLIP IN A SLIDE ON STEM CELL 666 00:31:56,880 --> 00:31:59,520 TRANSPLANTATION AND THE ROLE OF 667 00:31:59,520 --> 00:32:01,240 ANTIBODIES IN STEM CELL 668 00:32:01,240 --> 00:32:04,040 TRANSPLANTATION AS THE GROWTH IN 669 00:32:04,040 --> 00:32:05,840 THE NUMBER OF HLA MISMATCH 670 00:32:05,840 --> 00:32:07,280 TRANSPLANTS HAPPEN WE ARE 671 00:32:07,280 --> 00:32:09,080 UNDERSTANDING THE ROLE OF HLA 672 00:32:09,080 --> 00:32:09,400 ANTIBODIES. 673 00:32:09,400 --> 00:32:12,320 THIS IS DATA WHEN I WAS AT JOHNS 674 00:32:12,320 --> 00:32:13,560 HOPKINS SHOWING ON THE FAR RIGHT 675 00:32:13,560 --> 00:32:16,680 APPROXIMATELY ALL CANDIDATES 676 00:32:16,680 --> 00:32:20,720 ABOUT 14% HAD DONOR-SPECIFIC HLA 677 00:32:20,720 --> 00:32:22,480 DONOR BODIES TO THEIR INTENDED 678 00:32:22,480 --> 00:32:23,040 STEM CELL DONOR. 679 00:32:23,040 --> 00:32:28,720 THIS WAS HIGHER IN FEMALES AND 680 00:32:28,720 --> 00:32:32,520 HIGHER YET IN MULTI-PAIR 681 00:32:32,520 --> 00:32:33,520 FEMALES. 682 00:32:33,520 --> 00:32:35,040 THE MISS MATCHED STEM CELL 683 00:32:35,040 --> 00:32:40,440 TRANSPLANT GREG AS ARE CELLULAR 684 00:32:40,440 --> 00:32:42,080 THERAPIES AND TREGS ARE BEING 685 00:32:42,080 --> 00:32:44,320 USED AND GROWING EXPEDITIOUSLY 686 00:32:44,320 --> 00:32:47,680 BUT ALLO OFF THE SHELF THERAPIES 687 00:32:47,680 --> 00:32:48,760 ARE ALSO GROWING IN INTEREST NOT 688 00:32:48,760 --> 00:32:52,160 ONLY FOR ONCOLOGY BUT IN 689 00:32:52,160 --> 00:32:52,760 AUTOIMMUNITY AND INFECTIOUS 690 00:32:52,760 --> 00:32:57,560 DISEASE. 691 00:32:57,560 --> 00:32:59,960 AS WE LOOK AT THE HLA DIVERSITY 692 00:32:59,960 --> 00:33:01,880 ESPECIALLY IN OUR NON-WHITE 693 00:33:01,880 --> 00:33:03,360 PATIENTS IT'S IMPORTANT TO 694 00:33:03,360 --> 00:33:05,760 REMEMBER HLA ANTIBODIES DO PLAY 695 00:33:05,760 --> 00:33:07,880 A ROLE IN THE EFFICIENCY AND 696 00:33:07,880 --> 00:33:09,160 EFFICACY OF THESE THERAPIES. 697 00:33:09,160 --> 00:33:13,280 THEY'RE ASSOCIATED WITH REDUCED 698 00:33:13,280 --> 00:33:15,960 STEM CELL ENGRAFTMENT AND 699 00:33:15,960 --> 00:33:19,040 ANTIBODY TESTING IS CENTRAL IN 700 00:33:19,040 --> 00:33:24,240 THE SETTING OF THERAPIES AND I'D 701 00:33:24,240 --> 00:33:25,600 LIKE TO THANK THE RESEARCH GROUP 702 00:33:25,600 --> 00:33:28,840 AT DUKE AND MY HLA LAB. 703 00:33:28,840 --> 00:33:39,200 THANK YOU VERY MUCH. 704 00:33:53,680 --> 00:33:55,280 >> TWO QUESTIONS. 705 00:33:55,280 --> 00:34:01,000 ONE, WHY YOU DON'T USE DILUTED 706 00:34:01,000 --> 00:34:03,120 SERUM AND TWO, IF THERE'S ANY 707 00:34:03,120 --> 00:34:05,720 REASON TO THINK A SHARED EPLET 708 00:34:05,720 --> 00:34:10,200 BETWEEN DONOR AND RECIPIENT CAN 709 00:34:10,200 --> 00:34:16,480 TRIGGER A TOLEROGENIC RESPONSE. 710 00:34:16,480 --> 00:34:19,200 >> A SHARED EPITOPE BETWEEN 711 00:34:19,200 --> 00:34:21,120 RECIPIENT AND DONOR? 712 00:34:21,120 --> 00:34:24,000 THERE'S A LOT OF SHARED EPITOPES 713 00:34:24,000 --> 00:34:25,280 BETWEEN THEM. 714 00:34:25,280 --> 00:34:28,320 HLA EVOLVED FROM GENE 715 00:34:28,320 --> 00:34:32,400 DUPLICATION AND CONVERSION SO 716 00:34:32,400 --> 00:34:36,120 RECIPIENT AND DONOR SHARE AN 717 00:34:36,120 --> 00:34:38,720 ENORMOUS AMOUNT OF AMINO ACID 718 00:34:38,720 --> 00:34:39,000 LINKS. 719 00:34:39,000 --> 00:34:41,040 OUR SYSTEM CAN DETECT -- 720 00:34:41,040 --> 00:34:48,400 >> THAT PROBABLY OUTWEIGHS ANY 721 00:34:48,400 --> 00:34:49,280 MATCHING EFFECT. 722 00:34:49,280 --> 00:34:55,280 AND WHY DON'T WE DILUTE, WE DO, 723 00:34:55,280 --> 00:34:57,680 THE LUMINEX ASSAYS MAX OUT 724 00:34:57,680 --> 00:34:59,520 EASILY AND WE DETERMINE THE 725 00:34:59,520 --> 00:35:04,160 TITER OF HLA ANTIBODIES BUT 726 00:35:04,160 --> 00:35:07,160 ANTIBODY DETECTED ARE KNOWN TO 727 00:35:07,160 --> 00:35:08,680 HAVE DETRIMENTAL AFFECTS AT THE 728 00:35:08,680 --> 00:35:12,440 TIME OF TRANSPLANT AND THOSE 729 00:35:12,440 --> 00:35:14,560 DETECTED OVER 5,000 TO 5 730 00:35:14,560 --> 00:35:16,200 CORRELATE TO A POSITIVE 731 00:35:16,200 --> 00:35:18,840 CROSS-MATCH IS A 732 00:35:18,840 --> 00:35:20,720 CONTRAINDICATION TO TRANSPLANT 733 00:35:20,720 --> 00:35:24,040 WITHOUT ADDITIONAL AUGMENTED 734 00:35:24,040 --> 00:35:24,440 IMMUNOEXPRESSION. 735 00:35:24,440 --> 00:35:34,720 IT'S TEDETECTED AT LOW LEVEL AR 736 00:35:34,720 --> 00:35:35,520 USED WITH LOW SERUM BUT IT'S A 737 00:35:35,520 --> 00:35:36,240 PAIN. 738 00:35:36,240 --> 00:35:38,320 >> HAVE A QUESTION ABOUT THE 739 00:35:38,320 --> 00:35:38,920 PLASMA CELL. 740 00:35:38,920 --> 00:35:43,080 FIRST, DO YOU KNOW IF THERE'S A 741 00:35:43,080 --> 00:35:45,120 DIFFERENCE BETWEEN LONG LIVED 742 00:35:45,120 --> 00:35:47,000 AND SHORT LIVED PLASMA CELL IN 743 00:35:47,000 --> 00:35:47,560 THIS PROCESS? 744 00:35:47,560 --> 00:35:52,760 AND MY SECOND QUESTION IS YOU 745 00:35:52,760 --> 00:35:55,600 MENTIONED CLINICAL TRIALS FOR 746 00:35:55,600 --> 00:35:59,320 DEPLETING CANCER CELLS WOULD IT 747 00:35:59,320 --> 00:36:00,280 BE CONSIDERED TO BE LIFE LONG 748 00:36:00,280 --> 00:36:01,640 WHICH WOULD PROBABLY NOT BE 749 00:36:01,640 --> 00:36:06,600 PRACTICAL BECAUSE A PATIENT 750 00:36:06,600 --> 00:36:10,520 WOULD BE VERY SUSCEPTIBLE TO 751 00:36:10,520 --> 00:36:12,760 INFECTION AND IT'S AT A CRITICAL 752 00:36:12,760 --> 00:36:18,960 TIME IT WOULD BE APPLIED. 753 00:36:18,960 --> 00:36:24,760 >> WHEN WE FIRST START THE 754 00:36:24,760 --> 00:36:26,080 CLINICAL TRIALS I WAS NERVOUS 755 00:36:26,080 --> 00:36:28,800 MAYBE IT WOULD WORK TOO MUCH AND 756 00:36:28,800 --> 00:36:30,640 WE WERE IN THE COVID PANDEMIC 757 00:36:30,640 --> 00:36:33,800 FOR INSTANCE HOWEVER, IT WAS EYE 758 00:36:33,800 --> 00:36:35,600 OPENING HOW RESILIENT THE PLASMA 759 00:36:35,600 --> 00:36:38,320 CELL COMPARTMENT WAS. 760 00:36:38,320 --> 00:36:47,160 WE'RE WORK WITH A BIOLOGIST AT 761 00:36:47,160 --> 00:36:48,960 EMORY AND FINDING HLA ANTIBODIES 762 00:36:48,960 --> 00:36:53,640 RESIDE IN ALL THE PLASMA CELL 763 00:36:53,640 --> 00:36:56,640 SUBSETS LESS MATURE AND MORE 764 00:36:56,640 --> 00:36:59,800 MATURE LONG LIVED AND LOOKING 765 00:36:59,800 --> 00:37:04,400 WITH THE PATHOGEN LUMINEX PANEL 766 00:37:04,400 --> 00:37:05,560 WHETHER PROTECTED AND HLA 767 00:37:05,560 --> 00:37:07,920 IMMUNITY ARE FOUND IN THE SAME 768 00:37:07,920 --> 00:37:08,760 COMPARTMENTS AND FREQUENCY AND 769 00:37:08,760 --> 00:37:15,160 THAT. 770 00:37:15,160 --> 00:37:17,080 WE HAVEN'T DEPLETED TREMENDOUSLY 771 00:37:17,080 --> 00:37:19,280 THE PLASMA CELL DEPARTMENT. 772 00:37:19,280 --> 00:37:20,720 IT'S QUITE RESILIENT. 773 00:37:20,720 --> 00:37:27,320 THAT'S GOOD FOR OUR SPECIES BUT 774 00:37:27,320 --> 00:37:30,560 WE DON'T HAVE TO GET RID OF ALL 775 00:37:30,560 --> 00:37:31,600 THE PLASMA CELLS JUST KNOCK A 776 00:37:31,600 --> 00:37:39,000 HOLE IN IT AND GET THE 99% 777 00:37:39,000 --> 00:37:40,960 PEOPLE TO EVEN 90% AND THAT 778 00:37:40,960 --> 00:37:43,200 WOULD OPEN UP THE FLOODGATES FOR 779 00:37:43,200 --> 00:37:43,440 THEM. 780 00:37:43,440 --> 00:37:44,760 >> THE OTHER ANSWER TO THAT 781 00:37:44,760 --> 00:37:47,320 QUESTION IS WE KNOW THE IMMUNE 782 00:37:47,320 --> 00:37:52,720 SYSTEM HAS TREMENDOUS AMOUNT OF 783 00:37:52,720 --> 00:37:55,240 DUPLICATION AND I THINK WE SAW 784 00:37:55,240 --> 00:37:58,960 IN COVID T CELLS WERE QUITE 785 00:37:58,960 --> 00:38:00,560 IMPORTANT AND WE'RE HITTING T 786 00:38:00,560 --> 00:38:03,480 CELLS HERE AS WELL BUT IT'S 787 00:38:03,480 --> 00:38:08,760 SURPRISING WHEN YOU USE VERY 788 00:38:08,760 --> 00:38:11,640 EFFECTIVE COMPONENT YOU DON'T 789 00:38:11,640 --> 00:38:12,360 CRIPPLE THAT PATIENT. 790 00:38:12,360 --> 00:38:13,480 THEY STILL SEAL TO BE ABLE TO DO 791 00:38:13,480 --> 00:38:22,960 PRETTY WELL. 792 00:38:22,960 --> 00:38:26,440 >> THERE'S PROBABLY NO AREA IN 793 00:38:26,440 --> 00:38:30,240 OUR DIVISION WHERE WE COUNT ON 794 00:38:30,240 --> 00:38:31,560 PRIMATES AND WONDERING YOU CAN 795 00:38:31,560 --> 00:38:35,040 COMMENT ON THE COMPLEXITIES OF 796 00:38:35,040 --> 00:38:40,760 THE RHESUS AND MHC AND HOW WE 797 00:38:40,760 --> 00:38:42,520 CAN ADDRESS SOME OF THOSE 798 00:38:42,520 --> 00:38:44,080 CHALLENGES AS PRECLINICAL MODELS 799 00:38:44,080 --> 00:38:46,360 FOR THE TOPIC YOU ARE TALKING 800 00:38:46,360 --> 00:38:48,160 ABOUT TODAY. 801 00:38:48,160 --> 00:38:55,040 >> SO THE ADAPT CLINICAL TRIAL 802 00:38:55,040 --> 00:38:56,720 TO BLOCK PLASMA CELL 803 00:38:56,720 --> 00:38:59,240 REPOPULATION WAS BASED ON 804 00:38:59,240 --> 00:38:59,880 NON-HUMAN PRIMATE MODEL. 805 00:38:59,880 --> 00:39:02,280 CERTAINLY NON-HUMAN PRIMATE 806 00:39:02,280 --> 00:39:04,520 ALLOWS US TO USE THERAPEUTICS 807 00:39:04,520 --> 00:39:07,280 THAT WE'RE USING IN HUMAN AND 808 00:39:07,280 --> 00:39:08,320 THEY INFORM US VASTLY OVER MOUSE 809 00:39:08,320 --> 00:39:12,000 MODELS. 810 00:39:12,000 --> 00:39:14,760 YET THEIR MHC IS DIFFERENT. 811 00:39:14,760 --> 00:39:19,280 THEY'RE MISSING SOME OF THE 812 00:39:19,280 --> 00:39:22,240 MOLECULES WE HAVE. 813 00:39:22,240 --> 00:39:24,760 AT LEAST UNLIKE MOUSE STRAINS 814 00:39:24,760 --> 00:39:27,280 WHICH ARE CONGENIC AND HAVE LACK 815 00:39:27,280 --> 00:39:30,080 OF DIVERSITY WITHIN THE MHC 816 00:39:30,080 --> 00:39:30,480 REGION. 817 00:39:30,480 --> 00:39:34,160 AT LEAST THE PRIMATES ARE A BIT 818 00:39:34,160 --> 00:39:35,200 MORE OUTBRED. 819 00:39:35,200 --> 00:39:40,760 SO WHEN WE MISMATCH BETWEEN THE 820 00:39:40,760 --> 00:39:42,960 MONKEYS WE'RE GETTING A MORE 821 00:39:42,960 --> 00:39:46,400 DIVERSE ALLO-IMMUNE RESPONSE. 822 00:39:46,400 --> 00:39:47,680 THEY'RE MORE PERTINENT AND 823 00:39:47,680 --> 00:39:53,280 USEFUL BECAUSE WE CAN USE HUMAN 824 00:39:53,280 --> 00:40:00,040 DRUGS IN THEM WE'RE LOOKING INTO 825 00:40:00,040 --> 00:40:02,280 CORRELATIONS WITH HOMOLOGY. 826 00:40:02,280 --> 00:40:05,840 THERE'S HOMOLOGY BETWEEN HOUSE, 827 00:40:05,840 --> 00:40:07,360 HUMAN AND NON-HUMAN PRIMATE 828 00:40:07,360 --> 00:40:09,640 THAT'S HOW IMPORTANT HLA IS TO 829 00:40:09,640 --> 00:40:11,200 THE ADAPTIVE IMMUNE SYSTEM. 830 00:40:11,200 --> 00:40:15,960 IN FACT, IN SOME OF THE XENO 831 00:40:15,960 --> 00:40:18,600 EXPERIMENTS WHERE THEY PUT A PIG 832 00:40:18,600 --> 00:40:20,480 ORGAN INTO A NON-HUMAN PRIMATE 833 00:40:20,480 --> 00:40:23,640 WE RAN THE SERA AND I SAID 834 00:40:23,640 --> 00:40:29,320 THAT'S A VW6 ANTIBODY AND IT'S A 835 00:40:29,320 --> 00:40:30,560 CRITICAL MOTIF. 836 00:40:30,560 --> 00:40:32,760 IT'S PRESENT IN PIG, PRESENT IN 837 00:40:32,760 --> 00:40:33,400 NON-HUMAN PRIMATE AND PRESENT IN 838 00:40:33,400 --> 00:40:36,480 HUMAN. 839 00:40:36,480 --> 00:40:39,360 SO THERE'S CERTAIN MHC PROTEEF 840 00:40:39,360 --> 00:40:40,640 THAT ARE CRITICAL IN OUR 841 00:40:40,640 --> 00:40:41,720 RESPONSE TO PATHOGENS. 842 00:40:41,720 --> 00:40:46,480 WE ARE NOW LOOKING AT THAT TYPE 843 00:40:46,480 --> 00:40:47,200 OF HOMOLOGY BETWEEN NON-HUMAN 844 00:40:47,200 --> 00:40:49,000 PRIMATE AND HUMAN. 845 00:40:49,000 --> 00:40:52,280 WHETHER IT WILL BE USEFUL IN 846 00:40:52,280 --> 00:40:53,560 DETERMINING IMMUNOGENICITY I 847 00:40:53,560 --> 00:40:56,760 THINK WE'RE BETTER OFF MINING 848 00:40:56,760 --> 00:41:00,120 OUR LUMINEX DATA FOR 849 00:41:00,120 --> 00:41:00,760 UNDERSTANDING IMMUNOGENICITY 850 00:41:00,760 --> 00:41:09,400 WITHIN HUMANS. 851 00:41:09,400 --> 00:41:14,240 YOU MENTIONED THE LUMINEX ASSAY 852 00:41:14,240 --> 00:41:15,680 WHICH SOUNDS USEFUL CLINICALLY 853 00:41:15,680 --> 00:41:18,960 AND MENTIONED WHOLE GENOME 854 00:41:18,960 --> 00:41:21,080 SEQUENCING EARLIER DOES THAT ADD 855 00:41:21,080 --> 00:41:22,240 ANYTHING TO THE ANTIBODY BASED 856 00:41:22,240 --> 00:41:24,240 RISK S YOU DO? 857 00:41:24,240 --> 00:41:26,600 >> ABSOLUTELY. 858 00:41:26,600 --> 00:41:28,720 WE DO DEEP SEQUENCING THROUGH 859 00:41:28,720 --> 00:41:30,600 THE HLA GENES TO DEFINE WHAT 860 00:41:30,600 --> 00:41:34,360 EPLETS ARE PRESENT IN THE DONOR 861 00:41:34,360 --> 00:41:36,680 AND LOOK FOR THAT IN THE LUMINEX 862 00:41:36,680 --> 00:41:38,440 ASSAY AND WE HAVE SOFTWARE TO 863 00:41:38,440 --> 00:41:40,360 TELL US THE ANTIBODY HITS ARE 864 00:41:40,360 --> 00:41:42,960 LIKELY DIRECTS AT THESE EPLETS. 865 00:41:42,960 --> 00:41:45,320 UNFORTUNATELY OUR SOFTWARE WE 866 00:41:45,320 --> 00:41:47,200 DON'T KNOW WHAT'S THEORETICAL 867 00:41:47,200 --> 00:41:48,520 AND WHAT IS MEANINGFUL EPLET. 868 00:41:48,520 --> 00:41:51,600 WE'RE WORKING ON TRYING TO DO 869 00:41:51,600 --> 00:41:56,200 MORE MINING OF SERA AND IT'S BIG 870 00:41:56,200 --> 00:41:56,800 DATA. 871 00:41:56,800 --> 00:42:01,240 WE GENERATE 100 DATA POINTS WITH 872 00:42:01,240 --> 00:42:03,440 EVERY SINGLE SERA WE TEST AND WE 873 00:42:03,440 --> 00:42:05,440 TEST 30,000 A YEAR. 874 00:42:05,440 --> 00:42:07,440 IN ONE LAB WE GENERATE A LOT OF 875 00:42:07,440 --> 00:42:08,480 DATA. 876 00:42:08,480 --> 00:42:10,960 WHEN WE COMBINE IT WITH DEEP 877 00:42:10,960 --> 00:42:13,080 SEQUENCING SO THE ALLELE LEVEL 878 00:42:13,080 --> 00:42:16,800 OF THE HLA WE CAN INTERROGATE IT 879 00:42:16,800 --> 00:42:20,880 PRETTY WELL. 880 00:42:20,880 --> 00:42:24,880 WE HAVE THE DATA WE JUST NEED TO 881 00:42:24,880 --> 00:42:34,200 MINE IT. 882 00:42:34,200 --> 00:42:37,840 >> THANK YOU, VERY MUCH, NANCY. 883 00:42:37,840 --> 00:42:41,440 WE'VE HAD A LONG STANDING 884 00:42:41,440 --> 00:42:43,760 INTEREST OF HLA IN BLOOD AND 885 00:42:43,760 --> 00:42:44,480 MARROW TRANSPLANTATION AND I'LL 886 00:42:44,480 --> 00:42:45,600 TAKE A DIFFERENT APPROACH AND 887 00:42:45,600 --> 00:42:48,120 TAKE IT FROM THE GENOMIC 888 00:42:48,120 --> 00:42:49,080 STANDPOINT AND I'LL SHARE WITH 889 00:42:49,080 --> 00:42:52,720 YOU TWO MODELS IN WHICH WE 890 00:42:52,720 --> 00:42:54,120 DEVELOPED TOOLS CURRENTLY BEING 891 00:42:54,120 --> 00:42:59,080 USED BY TRANSPLANT CENTERS 892 00:42:59,080 --> 00:43:00,160 WORLDWIDE. 893 00:43:00,160 --> 00:43:02,040 THE LANDSCAPE UNRYE MARKABLY 894 00:43:02,040 --> 00:43:05,240 OVER THE LAST FOUR -- 895 00:43:05,240 --> 00:43:07,960 UNREMARKABLY IN THE BLUE 896 00:43:07,960 --> 00:43:10,720 REPRESENTS MATCH DONORS THE 897 00:43:10,720 --> 00:43:11,520 PREFERRED STEM CELL SOURCES. 898 00:43:11,520 --> 00:43:13,880 AND THAT IS BECAUSE THEY WERE 899 00:43:13,880 --> 00:43:17,480 ASSOCIATED WITH LOW RISK OF 900 00:43:17,480 --> 00:43:19,520 GRAPH REJECTION AND GBHD AND 901 00:43:19,520 --> 00:43:24,000 WITH THE UNRELATED DONOR 902 00:43:24,000 --> 00:43:29,160 REGISTRIES WORLDWIDE YOU SEE THE 903 00:43:29,160 --> 00:43:31,040 ORANGE LINE COME UP HERE WHICH 904 00:43:31,040 --> 00:43:33,240 REPRESENTS UNRELATED DONOR 905 00:43:33,240 --> 00:43:36,760 TRANSPLANTS AND IN 2010 THE 906 00:43:36,760 --> 00:43:37,880 UNRELATED DONOR TRANSPLANT 907 00:43:37,880 --> 00:43:39,400 EXPERIENCE NEARLY ECLIPSED THE 908 00:43:39,400 --> 00:43:43,400 MATCH RELATED TRANSPLANT AND THE 909 00:43:43,400 --> 00:43:47,480 GREEN CURVE WAS MADE POSSIBLE 910 00:43:47,480 --> 00:43:49,880 BECAUSE RESEARCH AND THROUGH 911 00:43:49,880 --> 00:43:54,680 SUPPORTIVE CARE AND PROPHYLAXIS 912 00:43:54,680 --> 00:43:56,960 SO IN 2020 IT ECLIPSED MATCH 913 00:43:56,960 --> 00:43:57,200 RELATED. 914 00:43:57,200 --> 00:44:00,320 NUMBER ONE UNRELATED. 915 00:44:00,320 --> 00:44:01,840 NUMBER TWO [INDISCERNIBLE] AND 916 00:44:01,840 --> 00:44:05,720 THE NEXT SLIDE THE GROWTH OF 917 00:44:05,720 --> 00:44:07,280 UNRELATED DONOR REGISTRIES 918 00:44:07,280 --> 00:44:09,560 SINGULARLY HELPED US ACHIEVE. 919 00:44:09,560 --> 00:44:15,120 THE NEXT SLIDE IS THE WNDA 920 00:44:15,120 --> 00:44:16,760 REGISTERED SUPPORT 1.4 MILLION 921 00:44:16,760 --> 00:44:20,760 REGISTERED UNRELATED DONORS 922 00:44:20,760 --> 00:44:21,160 WORLDWIDE. 923 00:44:21,160 --> 00:44:23,280 A TRUE HUMANITARIAN EFFORT. 924 00:44:23,280 --> 00:44:24,520 THE NEXT SLIDE SHOWS YOU THERE 925 00:44:24,520 --> 00:44:27,880 IS SOMETHING ELSE THAT IS 926 00:44:27,880 --> 00:44:28,800 INCREASING. 927 00:44:28,800 --> 00:44:33,240 THE NUMBER OF HLA ALLELES. 928 00:44:33,240 --> 00:44:36,760 WHEN WE BEGAN THE PROJECT AND WE 929 00:44:36,760 --> 00:44:39,440 STARTED 964 AND ARE TODAY IN THE 930 00:44:39,440 --> 00:44:46,240 MONTH OF JULY, 37,619. 931 00:44:46,240 --> 00:44:49,280 THAT POSES MAJOR ISSUES FOR US 932 00:44:49,280 --> 00:44:50,840 IN TRANSPLANTATION BECAUSE WE 933 00:44:50,840 --> 00:44:55,120 HAVE TO MATCH AS PRECISELY AS WE 934 00:44:55,120 --> 00:44:57,360 POSSIBLY CAN AND TALK FREQUENTLY 935 00:44:57,360 --> 00:44:59,960 ABOUT BLOOD AND MARROW 936 00:44:59,960 --> 00:45:00,640 TRANSPLANTATION. 937 00:45:00,640 --> 00:45:04,120 THE FIRST 02 IS SEROLOGICAL 938 00:45:04,120 --> 00:45:07,160 ANTIGEN SPECIFICITY AND THE 939 00:45:07,160 --> 00:45:10,720 SECOND FIELD SHOWS THE UNIQUE 940 00:45:10,720 --> 00:45:11,320 ALLELE. 941 00:45:11,320 --> 00:45:12,600 YOU'LL HEAR ABOUT NEXT GEN 942 00:45:12,600 --> 00:45:16,760 SEQUENCING WHICH DOES ALLOW US 943 00:45:16,760 --> 00:45:20,400 TO GET TO THE THIRD FIELD AND 944 00:45:20,400 --> 00:45:25,040 THIS NON-CODING REGION 945 00:45:25,040 --> 00:45:25,360 POLYMORPHISMS. 946 00:45:25,360 --> 00:45:26,360 THERE'S PRELIMINARY DATA THAT 947 00:45:26,360 --> 00:45:28,760 SHOW US THERE MIGHT BE BENEFIT 948 00:45:28,760 --> 00:45:30,080 WITH ULTRA HIGH RESOLUTION 949 00:45:30,080 --> 00:45:32,680 TYPING BUT FOR THE TIME BEING 950 00:45:32,680 --> 00:45:34,880 WE'RE STILL AT TWO FIELD. 951 00:45:34,880 --> 00:45:36,760 THE NEXT SLIDE SHOWS YOU WHEN 952 00:45:36,760 --> 00:45:39,720 WE'RE ABLE TO SUCCESSFULLY 953 00:45:39,720 --> 00:45:43,120 IDENTIFY FIVE LOCUS, TEN ALLELE 954 00:45:43,120 --> 00:45:45,600 AND PATIENTS IN THE RED GROUP 955 00:45:45,600 --> 00:45:50,600 ENJOYED SUPERIOR SURVIVAL. 956 00:45:50,600 --> 00:45:54,760 SO WE IN THE IHWG HAVE BEEN 957 00:45:54,760 --> 00:45:55,520 INTERESTING IN UNDERSTANDING 958 00:45:55,520 --> 00:45:57,560 WHEN YOU CAN'T IDENTIFY A MATCH 959 00:45:57,560 --> 00:46:00,480 HOW DO YOU POSSIBLY FIGURE OUT 960 00:46:00,480 --> 00:46:02,920 WHICH MISMATCHES ARE BETTER THAN 961 00:46:02,920 --> 00:46:03,160 OTHERS. 962 00:46:03,160 --> 00:46:07,080 THESE CURVES SHOW THE ADDITIVE 963 00:46:07,080 --> 00:46:09,640 EFFECT OF ONE, TWO, THREE OR 964 00:46:09,640 --> 00:46:11,240 MORE MISMATCHES. 965 00:46:11,240 --> 00:46:12,760 I'LL SHOW DATA OF THE GREEN 966 00:46:12,760 --> 00:46:15,240 CURVE AND SINGLE LOCUS MISS 967 00:46:15,240 --> 00:46:15,480 MATCHES. 968 00:46:15,480 --> 00:46:23,320 BY FAR THE MOST RISKY HLA A AND 969 00:46:23,320 --> 00:46:25,640 B LEADING TO HIGH MORTALITY. 970 00:46:25,640 --> 00:46:28,280 WE WERE VERY INTRIGUED WITH 971 00:46:28,280 --> 00:46:28,640 HLA-B. 972 00:46:28,640 --> 00:46:32,760 AS YOU ALL KNOW IT'S THE MOST 973 00:46:32,760 --> 00:46:36,560 POLYMORPHIC LOCUS IN THE HUMAN 974 00:46:36,560 --> 00:46:37,680 GENOME AND CAUSES MUCH ANGST 975 00:46:37,680 --> 00:46:42,320 WHEN WE TRY TO MATCH SO WE CARRY 976 00:46:42,320 --> 00:46:46,880 OFTEN TWO LOCUS MISS MATCHED 977 00:46:46,880 --> 00:46:48,760 DONORS. 978 00:46:48,760 --> 00:46:50,200 WE WERE INTERESTED IN FOCUSSING 979 00:46:50,200 --> 00:46:53,920 ON HLA-B AND THERE'S TWO MOLE 980 00:46:53,920 --> 00:46:56,000 MODELS TODAY ONE FOR HLA-B AND 981 00:46:56,000 --> 00:46:59,000 WE'RE LEARNING ABOUT NON-CODING 982 00:46:59,000 --> 00:47:00,240 REGION VARIATION AND IN THE LAST 983 00:47:00,240 --> 00:47:02,480 HALF OF THE TALK IN TERMS OF 984 00:47:02,480 --> 00:47:03,920 HLA-DP AND EXPRESSION. 985 00:47:03,920 --> 00:47:05,840 THE NEXT SLIDE GIVES A SENSE OF 986 00:47:05,840 --> 00:47:08,760 THE ORGANIZATION OF HLA-B AND 987 00:47:08,760 --> 00:47:11,720 THE LEADER IS A SHORT AMINO ACID 988 00:47:11,720 --> 00:47:16,280 PEPTIDE ENCODED BY XO1 AND 989 00:47:16,280 --> 00:47:17,800 ESSENTIALLY SHOWS POLYMORPHISM 990 00:47:17,800 --> 00:47:22,320 AT A SINGLE NUCLEOTIDE 991 00:47:22,320 --> 00:47:24,240 POLYMORPHISM THE MINUS 21 992 00:47:24,240 --> 00:47:24,760 POSITION. 993 00:47:24,760 --> 00:47:29,160 THIS SNIP GIVES RISE TO PEPTIDES 994 00:47:29,160 --> 00:47:31,200 AT THE SECOND POSITION. 995 00:47:31,200 --> 00:47:32,800 HLA A AND C ARE INVARIANT AT 996 00:47:32,800 --> 00:47:42,360 THIS PARTICULAR SNIP. 997 00:47:42,360 --> 00:47:46,800 THOUGH THE SNIP RESIDES IT HAS 998 00:47:46,800 --> 00:47:48,760 PROFOUND CONSEQUENCES HOW IT 999 00:47:48,760 --> 00:47:51,800 GETS TO THE SURFACE AND CAN 1000 00:47:51,800 --> 00:47:53,400 ENGAGE WITH RECEPTORS. 1001 00:47:53,400 --> 00:47:58,960 THE B LOCUS IS THE ONLY ONE THAT 1002 00:47:58,960 --> 00:48:03,160 GIVES T LEADERS AND THE TT HOMO 1003 00:48:03,160 --> 00:48:07,320 ZYGOTES AND FOR HLA A, B AND C 1004 00:48:07,320 --> 00:48:09,640 HAVE LEADERS ASSOCIATED WITH 1005 00:48:09,640 --> 00:48:09,960 EXPRESSION. 1006 00:48:09,960 --> 00:48:16,640 IN MY LAB WE'RE EXPLORING THE T 1007 00:48:16,640 --> 00:48:17,920 CELL BIOLOGY FOR THE LEADER AND 1008 00:48:17,920 --> 00:48:23,800 IT'S A STORY FOR ANOTHER DAY. 1009 00:48:23,800 --> 00:48:29,400 HLA-B THE MOST POLYMORPHIC GENE 1010 00:48:29,400 --> 00:48:31,120 9386 ALLELES. 1011 00:48:31,120 --> 00:48:32,760 WE NEEDED TO UNDERSTAND THE 1012 00:48:32,760 --> 00:48:34,520 ORGANIZATION OF THESE ALLELES. 1013 00:48:34,520 --> 00:48:40,680 IN THE NEXT SLIDE WE LOOKED AT A 1014 00:48:40,680 --> 00:48:43,840 THOUSAND NUCLEOTIDES OF CODING 1015 00:48:43,840 --> 00:48:44,440 AND DISCOVERED TWO TYPES. 1016 00:48:44,440 --> 00:48:49,040 THE FIRST IN BLUE AND THE SECOND 1017 00:48:49,040 --> 00:48:56,720 IN RED. 1018 00:48:56,720 --> 00:49:03,200 WE ESTIMATE THEY'RE AT LEAST 8 1019 00:49:03,200 --> 00:49:12,760 MILLION YEARS OLD ALL THE ALLO 1020 00:49:12,760 --> 00:49:15,480 TYPES HERE WE THOUGHT IT WAS A 1021 00:49:15,480 --> 00:49:17,840 GREAT OPPORTUNITY TO LEARN AND 1022 00:49:17,840 --> 00:49:19,760 WE HYPOTHESIZED IF THE PATIENT 1023 00:49:19,760 --> 00:49:24,120 AND DONOR BOTH WERE IN THE T OR 1024 00:49:24,120 --> 00:49:25,400 M CLADE THEY'RE CALLED A LEADER 1025 00:49:25,400 --> 00:49:30,280 MATCH BECAUSE THEY COME FROM THE 1026 00:49:30,280 --> 00:49:32,200 SAME AND LESS MISMATCHES WHERE 1027 00:49:32,200 --> 00:49:36,720 ONE CAME FROM THE T AND THE 1028 00:49:36,720 --> 00:49:38,840 OTHER CAME FROM THE M. 1029 00:49:38,840 --> 00:49:44,640 WE CALL THOSE LEADER MISMATCH. 1030 00:49:44,640 --> 00:49:52,160 YOU CAN SEE ONE PIECE OF 1031 00:49:52,160 --> 00:49:53,800 INFORMATION WE'RE EXCITED TO SEE 1032 00:49:53,800 --> 00:49:58,920 WAS THE NEXT SLIDE THAT ON THE 1033 00:49:58,920 --> 00:50:02,440 MATCH TYPE THAT M CLADE WAS 1034 00:50:02,440 --> 00:50:06,080 ACTUALLY DRIVING THIS SO IT DID 1035 00:50:06,080 --> 00:50:08,040 NOT REQUIRE THE HLA MISMATCHING 1036 00:50:08,040 --> 00:50:08,920 TO HAVE AN EFFECT. 1037 00:50:08,920 --> 00:50:12,760 IT'S ONE OF THE MODELS WHERE THE 1038 00:50:12,760 --> 00:50:20,760 MATCH AND THE MISMATCH HAP 1039 00:50:20,760 --> 00:50:23,480 HAPLOTYPES SHOWED THIS OUTCOME 1040 00:50:23,480 --> 00:50:27,120 AND THE THIS SHOWS THE STUDY WE 1041 00:50:27,120 --> 00:50:29,840 DID 10,000 TRANSPLANTS ALL B 1042 00:50:29,840 --> 00:50:40,600 MATCHED SO THE PATIENTS WITH MM 1043 00:50:40,600 --> 00:50:41,400 HAS HIGHER FATALITY. 1044 00:50:41,400 --> 00:50:45,640 THESE RELATIONSHIPS DO HOLD TRUE 1045 00:50:45,640 --> 00:50:47,320 IN MATCH, MISMATCH AND IN THE 1046 00:50:47,320 --> 00:50:48,760 FOLLOWING SLIDE WE WERE ABLE TO 1047 00:50:48,760 --> 00:50:52,400 CONFIRM THE IMPORTANCE OF THE 1048 00:50:52,400 --> 00:50:56,760 LEADER MATCHING WITH HAPLO 1049 00:50:56,760 --> 00:50:59,640 IDENTICAL TRANSPLANTATION. 1050 00:50:59,640 --> 00:51:01,160 RECEIVING A TRANSPLANT FROM THE 1051 00:51:01,160 --> 00:51:03,120 PARENT, CHILD OR SIBLING AND 1052 00:51:03,120 --> 00:51:06,080 BARELY MISS MATCH FOR THE OTHER 1053 00:51:06,080 --> 00:51:06,480 TYPE. 1054 00:51:06,480 --> 00:51:09,880 B MISMATCHES WHO ARE LEADER 1055 00:51:09,880 --> 00:51:11,360 MATCH ENJOY SUPERIOR SURVIVAL 1056 00:51:11,360 --> 00:51:13,320 COMPARED TO B MISMATCHES THAT 1057 00:51:13,320 --> 00:51:15,240 ARE LEADER MISMATCHED IN THE 1058 00:51:15,240 --> 00:51:15,800 CURVE. 1059 00:51:15,800 --> 00:51:18,160 I'M PARTICULARLY EXCITED BY 1060 00:51:18,160 --> 00:51:20,360 THESE DATA BECAUSE UP UNTIL NOW 1061 00:51:20,360 --> 00:51:21,880 WE ACTUALLY NEVER HAD ANY 1062 00:51:21,880 --> 00:51:23,040 CRITERIA TO BE ABLE TO HELP 1063 00:51:23,040 --> 00:51:26,000 CHOOSE BETWEEN A PARENT, A 1064 00:51:26,000 --> 00:51:29,800 SIBLING OR A CHILD SO IT'S 1065 00:51:29,800 --> 00:51:30,360 REALLY IMPORTANT. 1066 00:51:30,360 --> 00:51:31,600 THE NEXT SLIDE SHOWS WHEN YOU 1067 00:51:31,600 --> 00:51:33,440 START TO THINK ABOUT TOOLS HOW 1068 00:51:33,440 --> 00:51:35,120 WILL YOU GET THE INFORMATION ON 1069 00:51:35,120 --> 00:51:37,880 CLADS AND HOW WILL YOU GET THE 1070 00:51:37,880 --> 00:51:40,800 INFORMATION IN HAPLO TOGETHER TO 1071 00:51:40,800 --> 00:51:42,360 BE ABLE TO INFORM PATIENT RISK 1072 00:51:42,360 --> 00:51:43,280 PRIOR TO TRANSPLANT AND HELP 1073 00:51:43,280 --> 00:51:48,840 SELECT A BETTER DONOR? 1074 00:51:48,840 --> 00:51:52,120 IMAGINE WE HAVE HIGH-RISK TYPING 1075 00:51:52,120 --> 00:51:53,920 IN ULTRA HIGH RESOLUTION WE HAVE 1076 00:51:53,920 --> 00:51:56,840 TO REDUCE THE TYPE TO A LEADER 1077 00:51:56,840 --> 00:52:00,480 MM, TT OR MT IN THE TYPE IN THE 1078 00:52:00,480 --> 00:52:02,320 PATIENT AND HAVE TO BE THE SAME 1079 00:52:02,320 --> 00:52:03,520 IN THE DONOR. 1080 00:52:03,520 --> 00:52:05,680 WHAT THE BIOLOGICAL MODEL HAVE 1081 00:52:05,680 --> 00:52:07,320 TOLD US IT'S FAR SUPERIOR TO 1082 00:52:07,320 --> 00:52:10,240 SELECT A LEADER MATCH DONOR 1083 00:52:10,240 --> 00:52:12,720 OPPOSED TO LEADER MISS MATCHED 1084 00:52:12,720 --> 00:52:16,720 DONOR AND YOU'LL SEE IN THE T 1085 00:52:16,720 --> 00:52:19,320 CONE PATIENT WHO'S ARE 1086 00:52:19,320 --> 00:52:21,320 HETEROZYGOUS HAVE UP TO FOUR 1087 00:52:21,320 --> 00:52:23,000 DIFFERENT DONORS BUT THE 1088 00:52:23,000 --> 00:52:25,960 PREFERRED DONOR IS THE TOP ONE 1089 00:52:25,960 --> 00:52:29,400 WHO IS LEADER MATCHED AND THE 1090 00:52:29,400 --> 00:52:32,800 SHARE HAPLO TYPE SHOULD REDUCE 1091 00:52:32,800 --> 00:52:41,360 THE RISK. 1092 00:52:41,360 --> 00:52:43,320 WE HAD TO THINK ABOUT THE DATA 1093 00:52:43,320 --> 00:52:45,400 IN WHICH WE'D BUILD THE 1094 00:52:45,400 --> 00:52:47,240 INFERENCE OF SEQUENCE TO THE 1095 00:52:47,240 --> 00:52:50,480 ALLELE NAME TO THE GENOTYPE. 1096 00:52:50,480 --> 00:52:52,120 THERE ARE TWO SOFTWARE PACKAGES 1097 00:52:52,120 --> 00:52:54,360 I'D LIKE TO INVITE YOU TO THE 1098 00:52:54,360 --> 00:52:55,320 LEFT SIDE OF THE SCREEN AND 1099 00:52:55,320 --> 00:52:57,280 PLEASE TRY OUT THE PROGRAM THAT 1100 00:52:57,280 --> 00:53:02,440 WAS DESIGN BY DR. STEVEN MARSH 1101 00:53:02,440 --> 00:53:05,880 AND COLLEAGUES AT THE ANTHONY 1102 00:53:05,880 --> 00:53:06,800 NOLAN RESEARCH INSTITUTE IN 1103 00:53:06,800 --> 00:53:09,160 LONDON I WAS INVOLVED IN THE 1104 00:53:09,160 --> 00:53:10,440 TOOL ON THE RIGHT AND WE'LL SHOW 1105 00:53:10,440 --> 00:53:12,120 YOU HOW WE BUILT THE TOOL FROM 1106 00:53:12,120 --> 00:53:14,200 THE POPULATION-BASED STUDIES. 1107 00:53:14,200 --> 00:53:15,520 WE FELT VERY STRONG IF YOU'RE 1108 00:53:15,520 --> 00:53:18,920 GOING TO ROLL OUT A TOOL FOR 1109 00:53:18,920 --> 00:53:20,480 CLINICAL PRACTICE YOU HAVE TO 1110 00:53:20,480 --> 00:53:22,640 HAVE RIGOR AT MULTIPLE LEVELS. 1111 00:53:22,640 --> 00:53:26,040 SO THE THREE MAJOR POINTS OF 1112 00:53:26,040 --> 00:53:28,480 RIGOR ARE ON TOP WE DEMANDED WE 1113 00:53:28,480 --> 00:53:32,760 HAVE TO KNOW THE BREADTH AND THE 1114 00:53:32,760 --> 00:53:42,160 EXTENT OF THE HLA-ALLELES AND 1115 00:53:42,160 --> 00:53:44,600 THE TOOL HAS TO BE ABLE TO 1116 00:53:44,600 --> 00:53:48,560 HANDLE RARE ALLELES AND THE 1117 00:53:48,560 --> 00:53:51,240 INFORMATIVE OF DIVERSE RACE AND 1118 00:53:51,240 --> 00:53:52,880 ETHNICITIES TO BE IMPACTFUL FOR 1119 00:53:52,880 --> 00:53:54,880 ANY PATIENT WHO NEEDS A TRANS 1120 00:53:54,880 --> 00:53:55,280 PLANT. 1121 00:53:55,280 --> 00:53:56,760 RECOGNIZING LABORATORIES HAVE 1122 00:53:56,760 --> 00:53:57,840 DIFFERENT METHODS AVAILABLE TO 1123 00:53:57,840 --> 00:54:00,520 THEM, A TOOL HAS TO BE ABLE TO 1124 00:54:00,520 --> 00:54:02,040 HANDLE ANYTHING FROM FIRST FIELD 1125 00:54:02,040 --> 00:54:04,760 SEROLOGICAL EQUIVALENT TO NEXT 1126 00:54:04,760 --> 00:54:07,160 GEN ULTRA, ULTRA HIGH RESOLUTION 1127 00:54:07,160 --> 00:54:08,640 TYPING AND OF COURSE IF YOU'RE 1128 00:54:08,640 --> 00:54:11,080 TOOL IS USER FRIENDLY IT'S MORE 1129 00:54:11,080 --> 00:54:13,400 APT TO BE USED BY PEOPLE. 1130 00:54:13,400 --> 00:54:15,320 SO THE NEXT SLIDE SHOWS YOU HOW 1131 00:54:15,320 --> 00:54:16,400 WE BUILT THE TOOL IN THE FIRST 1132 00:54:16,400 --> 00:54:19,640 BULLET POINT FOR RIGOR IS HOW DO 1133 00:54:19,640 --> 00:54:22,880 WE KNOW THE P2 IS ALWAYS GOING 1134 00:54:22,880 --> 00:54:25,320 TO BE IN THE BIND WE EXAMINED 1135 00:54:25,320 --> 00:54:28,680 NEXT GEN SEQUENCING IN 1.1 1136 00:54:28,680 --> 00:54:30,040 MILLION AMERICAN DONORS FROM THE 1137 00:54:30,040 --> 00:54:32,720 BE THE MATCH REGISTRY AND FOUND 1138 00:54:32,720 --> 00:54:36,000 OVER 99.9% LEADERS EITHER HAD AN 1139 00:54:36,000 --> 00:54:37,720 M OR A T. 1140 00:54:37,720 --> 00:54:41,760 WE DID SEE POLYMORPHISM AT P2, 1141 00:54:41,760 --> 00:54:44,160 OTHER POLYMORPHISMS WE DID SEE 1142 00:54:44,160 --> 00:54:47,160 THEM AT SOME OTHER POSITIONS YOU 1143 00:54:47,160 --> 00:54:48,800 CAN SEE FROM THE ACCOUNTS 1144 00:54:48,800 --> 00:54:50,720 THEY'RE VANISHINGLY SMALL. 1145 00:54:50,720 --> 00:54:52,600 THIS REALLY INCREASED OUR 1146 00:54:52,600 --> 00:54:54,480 CONFIDENCE THAT IF YOU HAVE A 1147 00:54:54,480 --> 00:54:56,400 NEW ALLELE AND A PATIENT WHO IS 1148 00:54:56,400 --> 00:54:59,160 REFERRED FOR TRANSPLANTATION, 1149 00:54:59,160 --> 00:55:04,120 YOU CAN ALMOST GUARANTEE THE P2 1150 00:55:04,120 --> 00:55:05,120 POSITION WAS GOING TO BE 1151 00:55:05,120 --> 00:55:05,480 [INDISCERNIBLE]. 1152 00:55:05,480 --> 00:55:06,920 NEXT SLIDE SHOWS THE RIGOR FOR 1153 00:55:06,920 --> 00:55:08,720 ASKING HOW DO YOU KNOW ALL THE 1154 00:55:08,720 --> 00:55:10,520 ALLELES WITHIN THE GIVEN ANTIGEN 1155 00:55:10,520 --> 00:55:12,520 FAMILY WILL ALWAYS HAVE THE SAME 1156 00:55:12,520 --> 00:55:12,760 LEADER? 1157 00:55:12,760 --> 00:55:14,280 WE PUT THIS TO THE TEST. 1158 00:55:14,280 --> 00:55:16,760 THE QUESTION IS, THESE SEVEN IS 1159 00:55:16,760 --> 00:55:23,600 A MEMBER OF THE M CLADE AND DO 1160 00:55:23,600 --> 00:55:29,040 ALL SEVEN HAVE ALL -- ALLELES 1161 00:55:29,040 --> 00:55:33,000 AND THEY DID NOT HAVE IT AND THE 1162 00:55:33,000 --> 00:55:35,880 B27 A MEMBER OF THE T CLADE WE 1163 00:55:35,880 --> 00:55:37,600 HAD THUS FAR FOUND ANY EXAMPLE 1164 00:55:37,600 --> 00:55:40,520 OF A B27 THAT'S NOT. 1165 00:55:40,520 --> 00:55:42,560 THIS ALSO GIVES ONE CONFIDENCE 1166 00:55:42,560 --> 00:55:44,520 THAT EVEN IF YOU ONLY HAVE 1167 00:55:44,520 --> 00:55:46,560 FIRST-FIELD TYPING AS YOU HAVE 1168 00:55:46,560 --> 00:55:48,080 IN KIDNEY AND SOMETIMES SOLID 1169 00:55:48,080 --> 00:55:51,280 ORGAN, YOU CAN LITERALLY TAKE 1170 00:55:51,280 --> 00:55:52,640 FIRST-FIELD TYPING AND MAP IT 1171 00:55:52,640 --> 00:55:55,040 BACK TO THE PARENT ANTIGEN AND 1172 00:55:55,040 --> 00:55:56,760 BE SURE HAVE YOU THE P2 CORRECT. 1173 00:55:56,760 --> 00:55:59,840 IN THE NEXT SLIDE WE HAVE THE 1174 00:55:59,840 --> 00:56:01,600 ALL-IMPORTANT POPULATION STUDIES 1175 00:56:01,600 --> 00:56:07,280 THAT SHOWS US THAT IT'S 1176 00:56:07,280 --> 00:56:09,720 IMPORTANT TO KNOW 1177 00:56:09,720 --> 00:56:10,520 POPULATION-BASED FREQUENCIES. 1178 00:56:10,520 --> 00:56:13,320 IN 8 MILLION OF THE U.S. DONORS 1179 00:56:13,320 --> 00:56:15,520 WE COLLAPSED THE TYPING AND YOU 1180 00:56:15,520 --> 00:56:19,040 CAN SEE PROFOUND DIFFERENCES IN 1181 00:56:19,040 --> 00:56:22,160 THE FREQUENCIES OF THESE LEADER 1182 00:56:22,160 --> 00:56:22,440 GENOTYPES. 1183 00:56:22,440 --> 00:56:24,600 DONORS WHO SELF-DESCRIBE AS 1184 00:56:24,600 --> 00:56:28,600 ASIAN OR PACIFIC ISLANDER ARE 1185 00:56:28,600 --> 00:56:31,280 MOST OFTEN GOING TO HAVE THE TT 1186 00:56:31,280 --> 00:56:34,240 TYPE AND THIS IS IMPORTANT FOR 1187 00:56:34,240 --> 00:56:36,760 SPECIALISTS AND CENTERS TO PLAN 1188 00:56:36,760 --> 00:56:39,280 YOUR APPROACH TO DO THE DONOR 1189 00:56:39,280 --> 00:56:40,480 SEARCH AND WHAT TO MATCH FOR AND 1190 00:56:40,480 --> 00:56:43,360 WHAT ARE THE LIKELY GROUPS TO 1191 00:56:43,360 --> 00:56:48,760 FIND THAT MATCH. 1192 00:56:48,760 --> 00:56:54,960 NEXT SLIDE SHOWS WE HAVE TO HAVE 1193 00:56:54,960 --> 00:56:57,120 THE OUTPUT MET AND USER FRIENDLY 1194 00:56:57,120 --> 00:57:00,280 NO MATTER THE SETTING OR 1195 00:57:00,280 --> 00:57:02,520 CLINICAL TRAINING. 1196 00:57:02,520 --> 00:57:05,000 THE OUTPUT IS FROM HLA ALLELE TO 1197 00:57:05,000 --> 00:57:07,720 A LEADER TYPE IN THE PATIENT AND 1198 00:57:07,720 --> 00:57:09,440 LEADER TYPE IN THE DONOR. 1199 00:57:09,440 --> 00:57:11,480 FOR OUR TOOL THE USER CAN ENTER 1200 00:57:11,480 --> 00:57:15,200 IN ANY OF THE NUMBER OF DONORS, 1201 00:57:15,200 --> 00:57:16,600 ONE OR 10 DONORS. 1202 00:57:16,600 --> 00:57:19,320 WHAT THE TOOL DOES IS MAKES 1203 00:57:19,320 --> 00:57:29,040 EIGHT PAIRWISE COMPARISON AND 1204 00:57:29,040 --> 00:57:32,200 MATCH OR MISS MATCH AND TELLS 1205 00:57:32,200 --> 00:57:36,760 YOU IS THE MATCH HAPLO TYPE AN M 1206 00:57:36,760 --> 00:57:42,080 OR T AND THE MOST IMPORTANT 1207 00:57:42,080 --> 00:57:44,320 OUTPUT, IT RANKS FOR THE USER. 1208 00:57:44,320 --> 00:57:47,480 IT TELLS YOU THIS IS THE MOST 1209 00:57:47,480 --> 00:57:49,880 FAVORABLE DONOR BECAUSE THEY'RE 1210 00:57:49,880 --> 00:57:51,240 LEADER MATCHED AND SHARE THAT T 1211 00:57:51,240 --> 00:57:52,720 THEN IF YOU GO DOWN THE RANK 1212 00:57:52,720 --> 00:57:55,320 ORDER IT TELLS THE TRANSPLANT 1213 00:57:55,320 --> 00:57:57,640 CENTERS TRY IF POSSIBLE TO AVOID 1214 00:57:57,640 --> 00:58:04,080 THAT VERY RISKY DONOR. 1215 00:58:04,080 --> 00:58:06,680 Q 1216 00:58:06,680 --> 00:58:08,640 WE LAUNCH THE TOOL IN 2021. 1217 00:58:08,640 --> 00:58:10,840 WE HAVE ABOUT 1800 UNIQUE USERS. 1218 00:58:10,840 --> 00:58:12,480 THIS SHOWS THE DAILY USAGE OF 1219 00:58:12,480 --> 00:58:15,520 THE PROGRAM AND EVERY TIME WE 1220 00:58:15,520 --> 00:58:19,280 HAVE A BIG SPIKE IT CORRELATES 1221 00:58:19,280 --> 00:58:20,720 TO A TRAINING PROGRAM WE DID 1222 00:58:20,720 --> 00:58:22,360 WHICH TELLS YOU THE IMPORTANCE 1223 00:58:22,360 --> 00:58:24,000 OF EDUCATION AND TRAINING. 1224 00:58:24,000 --> 00:58:27,040 SO I'M HOPING THAT WHEN WE PLOT 1225 00:58:27,040 --> 00:58:29,760 THIS NEXT AFTER TODAY WE WILL 1226 00:58:29,760 --> 00:58:31,800 SEE ANOTHER SPIKE, SEPTEMBER OF 1227 00:58:31,800 --> 00:58:42,240 2023 SO PLEASE GO TO THE 1228 00:58:46,240 --> 00:58:46,640 BLEADER.NMDP.org. 1229 00:58:46,640 --> 00:58:47,760 WE'D LIKE KNOW HOW TO IMPROVE 1230 00:58:47,760 --> 00:58:48,800 THE TOOL. 1231 00:58:48,800 --> 00:58:50,840 THE USERS COME FROM 55 DIFFERENT 1232 00:58:50,840 --> 00:58:51,400 COUNTRIES. 1233 00:58:51,400 --> 00:58:54,120 WE COLLABORATE WITH THE WORLD 1234 00:58:54,120 --> 00:58:55,280 MARROW DONOR ASSOCIATION AND 1235 00:58:55,280 --> 00:58:57,280 PROFESSIONAL SOCIETIES TO HAVE 1236 00:58:57,280 --> 00:58:58,880 EDUCATIONAL SESSIONS AND 1237 00:58:58,880 --> 00:59:00,720 TRAINING PROVIDERS AT ALL STAGES 1238 00:59:00,720 --> 00:59:03,520 OF THEIR TRAINING. 1239 00:59:03,520 --> 00:59:05,680 THE NEXT SLIDE I'D LIKE TO TURN 1240 00:59:05,680 --> 00:59:08,360 TO THE SECOND EXAMPLE IN THE 1241 00:59:08,360 --> 00:59:08,960 LAST FEW MINUTES. 1242 00:59:08,960 --> 00:59:11,000 HLA DP. 1243 00:59:11,000 --> 00:59:14,000 THIS IS A FASCINATING LOCUS AND 1244 00:59:14,000 --> 00:59:16,360 NOT WHAT WE EXPECTED. 1245 00:59:16,360 --> 00:59:19,440 WE CAN APPRECIATE POLYMORPHISMS 1246 00:59:19,440 --> 00:59:24,760 OUTSIDE THE ANTIGEN RECOGNITION 1247 00:59:24,760 --> 00:59:26,600 DOMAIN AND THE LEVEL OF 1248 00:59:26,600 --> 00:59:29,320 EXPRESSION IS ONE 1249 00:59:29,320 --> 00:59:29,680 CHARACTERISTIC. 1250 00:59:29,680 --> 00:59:35,040 WHAT MY LAB DID WAS WE WERE VERY 1251 00:59:35,040 --> 00:59:39,360 INTERESTED IN DISCOVERING 1252 00:59:39,360 --> 00:59:43,360 DETERMINATES WITHIN THE MHC AND 1253 00:59:43,360 --> 00:59:47,040 RAN A SEARCH AND DID A COHORT 1254 00:59:47,040 --> 00:59:50,600 ANALYSIS AND VALIDATED TWO SNIPS 1255 00:59:50,600 --> 00:59:53,160 OUT OF 1,200 SNIPS. 1256 00:59:53,160 --> 00:59:55,000 THE NEXT SLIDE SHOWS THE SNIP OF 1257 00:59:55,000 --> 00:59:56,760 INTEREST FOR US WAS AN 1258 00:59:56,760 --> 01:00:00,520 ASSOCIATION MARKER ON THE RIGHT 1259 01:00:00,520 --> 01:00:06,960 SIDE, THE RS2281389. 1260 01:00:06,960 --> 01:00:08,240 IF THE PATIENT GENOTYPE WAS 1261 01:00:08,240 --> 01:00:10,520 DIFFERENT THAN THE DONOR THAT 1262 01:00:10,520 --> 01:00:16,760 WAS ASSOCIATED WITH HIGH RISK OF 1263 01:00:16,760 --> 01:00:22,200 ACUTE MARKER AND THE INDEX 1264 01:00:22,200 --> 01:00:27,840 MARKER WAS THE RS9277534 IN RED 1265 01:00:27,840 --> 01:00:29,640 WHERE THERE WAS 100% LINK. 1266 01:00:29,640 --> 01:00:31,680 THE ASSOCIATION MARKER WAS A 1267 01:00:31,680 --> 01:00:32,120 TAG. 1268 01:00:32,120 --> 01:00:37,400 IN FACT HAPLO TYPES GO ALL THE 1269 01:00:37,400 --> 01:00:42,320 WAY IT EXON 2 THAT YEP CODES THE 1270 01:00:42,320 --> 01:00:44,120 ALL PERSON PEPTIDE BINDING 1271 01:00:44,120 --> 01:00:44,760 GROUP. 1272 01:00:44,760 --> 01:00:47,320 WE HYPOTHESIZED IF THE 1273 01:00:47,320 --> 01:00:49,200 ASSOCIATION WAS TELLING US 1274 01:00:49,200 --> 01:00:51,280 SOMETHING ABOUT SNIP MISS 1275 01:00:51,280 --> 01:00:54,840 MATCHING AND WAS 100% LD WITH 1276 01:00:54,840 --> 01:00:57,000 HIGH OR LOW EXPRESSION AND IN 1277 01:00:57,000 --> 01:00:59,160 ASSOCIATION WITH THE PEPTIDE 1278 01:00:59,160 --> 01:01:00,720 BINDING AND THE FIRST ORDER OF 1279 01:01:00,720 --> 01:01:02,360 BUSINESS IS TO PROVE HAVE YOU 1280 01:01:02,360 --> 01:01:03,840 DIFFERENTIAL EXPRESSION 1281 01:01:03,840 --> 01:01:08,760 ACCORDING TO YOUR PROIMRY ETR 1282 01:01:08,760 --> 01:01:12,120 SHOWN ON THE RIGHT SIDE. 1283 01:01:12,120 --> 01:01:16,720 THE A ALLELE IS ASSOCIATED WITH 1284 01:01:16,720 --> 01:01:19,200 LOWER DP EXPRESSION AS MEASURED 1285 01:01:19,200 --> 01:01:21,520 BY QUANTITATIVE DPCR AND LED TO 1286 01:01:21,520 --> 01:01:23,600 THE HYPOTHESIS THAT SHOWS WHEN 1287 01:01:23,600 --> 01:01:27,480 YOU HAVE A MISMATCH IT'S THE'S 1288 01:01:27,480 --> 01:01:34,040 MISS MACHINED DP THAT PROVIDES A 1289 01:01:34,040 --> 01:01:36,320 VISIBLE TARGET FOR THE RESPONSE 1290 01:01:36,320 --> 01:01:41,520 SHOULD BE HIGHER THAN EXPRESSED 1291 01:01:41,520 --> 01:01:43,840 AT LOW LEVELS. 1292 01:01:43,840 --> 01:01:48,200 WE FOUND RISK OF GBHD ONE FOLD 1293 01:01:48,200 --> 01:01:52,240 HIGHER WHEN I THE DP MISS 1294 01:01:52,240 --> 01:01:54,880 MISMATCH IS HIGH. 1295 01:01:54,880 --> 01:01:58,160 WE VALIDATED THIS IN A VERY 1296 01:01:58,160 --> 01:02:00,520 LARGE POPULATION OF UNRELATED 1297 01:02:00,520 --> 01:02:01,880 TRANSPLANTS RELATIVE TO LOW 1298 01:02:01,880 --> 01:02:02,200 EXPRESSION. 1299 01:02:02,200 --> 01:02:06,160 WE NOW QUANTIFIED A 36% HIGHER 1300 01:02:06,160 --> 01:02:14,000 RISK OF GBHD FOR HIGH EXPRESSION 1301 01:02:14,000 --> 01:02:14,560 MISMATCHES. 1302 01:02:14,560 --> 01:02:18,920 THERE ARE OTHER MODELS AND THIS 1303 01:02:18,920 --> 01:02:23,240 SHOWS HOW WE RELATE IT. 1304 01:02:23,240 --> 01:02:27,480 PATIENTS INHERENT TOO LOW OR ONE 1305 01:02:27,480 --> 01:02:28,560 HIGH HAPLO TYPE. 1306 01:02:28,560 --> 01:02:30,080 THE FAVORABLE DONOR IS THE 1307 01:02:30,080 --> 01:02:33,480 PERSON MISMATCHED FOR ONLY ONE 1308 01:02:33,480 --> 01:02:33,880 DP. 1309 01:02:33,880 --> 01:02:42,320 WE WANT TO AVOID DOUBLE DP 1310 01:02:42,320 --> 01:02:42,640 MISMATCHES. 1311 01:02:42,640 --> 01:02:43,280 PATIEN 1312 01:02:43,280 --> 01:02:46,200 PATIENTS WE TRIED TO FORGO THE 1313 01:02:46,200 --> 01:02:47,960 MISS MATCH AT THE LOW EXPRESSION 1314 01:02:47,960 --> 01:02:51,320 AND THAT SHOULD LOWER AND DRIVE 1315 01:02:51,320 --> 01:02:57,480 DOWN THE RATES OF GBHD FOR US. 1316 01:02:57,480 --> 01:03:00,760 THERE'S ANOTHER MODEL OF 1317 01:03:00,760 --> 01:03:07,320 REACTIVITY ON ABBREVIATED CDE 1318 01:03:07,320 --> 01:03:12,760 FOCUSSED ON EXON TWO. 1319 01:03:12,760 --> 01:03:17,840 THIS HAS THE MODEL AND IT'S 1320 01:03:17,840 --> 01:03:20,720 ASKING HOW IT'S IMPACTING PEP 1321 01:03:20,720 --> 01:03:24,040 SIDE REPERTOIRE AND RECOGNITION 1322 01:03:24,040 --> 01:03:24,480 OF T CELL. 1323 01:03:24,480 --> 01:03:29,560 THIS TCE MODEL WAS DEVELOPED AND 1324 01:03:29,560 --> 01:03:36,200 USED ALLO REACTIVE CLONES FROM A 1325 01:03:36,200 --> 01:03:39,120 PATIENT WHO FAILED TO ENGRAPH 1326 01:03:39,120 --> 01:03:43,280 AND IDENTIFIED THREE GROUPS OF 1327 01:03:43,280 --> 01:03:47,160 ALLO TYPES THAT HAVE VERY 1328 01:03:47,160 --> 01:03:50,000 DIFFERENT ABILITY TO STIMULATE 1329 01:03:50,000 --> 01:03:52,240 AND THE TCE PERMISSIVE IS A 1330 01:03:52,240 --> 01:03:55,040 MISMATCH FOR THE PATIENTS AND 1331 01:03:55,040 --> 01:03:58,760 DONOR MISMATCHES COME FROM THE 1332 01:03:58,760 --> 01:04:00,120 SAME GROUP. 1333 01:04:00,120 --> 01:04:03,320 TCE NON-PERMISSIVE MISMATCH IS 1334 01:04:03,320 --> 01:04:05,240 WHEN THE MISMATCHES COME FROM 1335 01:04:05,240 --> 01:04:05,960 DIFFERENT GROUPS. 1336 01:04:05,960 --> 01:04:08,760 THE TCE MODEL HAS BEEN AROUND 1337 01:04:08,760 --> 01:04:12,760 LONGER AND BEEN USED BY 1338 01:04:12,760 --> 01:04:13,280 TRANSPLANT CENTERS TO SELECT 1339 01:04:14,720 --> 01:04:20,560 DP MISMATCHED DONORS. 1340 01:04:20,560 --> 01:04:22,800 IN THIS SLIDE SHOWS THE WORK WE 1341 01:04:22,800 --> 01:04:25,680 AND OTHERS HAVE DONE IN THE 1342 01:04:25,680 --> 01:04:27,280 COMMUNITY TO BE ABLE TO 1343 01:04:27,280 --> 01:04:29,560 UNDERSTAND HOW YOU JUXTA POSE 1344 01:04:29,560 --> 01:04:32,320 THE EXPRESSION MODEL WITH THE 1345 01:04:32,320 --> 01:04:32,720 ISOTOPE MODEL. 1346 01:04:32,720 --> 01:04:35,120 WITH LOW EXPRESSION MISMATCHES 1347 01:04:35,120 --> 01:04:38,680 ARE VERY UNIFORM AND USUALLY TCE 1348 01:04:38,680 --> 01:04:43,680 PERMISSIVE, WE HAVE A LOT OF 1349 01:04:43,680 --> 01:04:46,400 HETEROGENEITY AMONG 1350 01:04:46,400 --> 01:04:46,760 NON-PERMISSIVE. 1351 01:04:46,760 --> 01:04:49,520 THE KEY TO THE MODELS IS EXON 1352 01:04:49,520 --> 01:04:49,720 THREE. 1353 01:04:49,720 --> 01:04:52,200 IT'S BEEN IGNORED FOR A LONG 1354 01:04:52,200 --> 01:04:52,400 TIME. 1355 01:04:52,400 --> 01:04:55,200 WE COLLABORATED WITH THE GERMAN 1356 01:04:55,200 --> 01:05:02,680 REGISTRY DKMS AND THEY SEQUENCED 1357 01:05:02,680 --> 01:05:04,800 32,000 GERMAN DONORS 1358 01:05:04,800 --> 01:05:10,200 CONSECUTIVELY RECRUIT AND FOUND 1359 01:05:10,200 --> 01:05:13,600 A SEVEN-SNIP HAP HAPLO TYPE IN 1360 01:05:13,600 --> 01:05:16,160 100% WITH THE LOW AND HIGH 1361 01:05:16,160 --> 01:05:16,760 VARIANTS. 1362 01:05:16,760 --> 01:05:20,280 THIS ALLOWED US TO USE EXON 1363 01:05:20,280 --> 01:05:21,240 THREE TO THE FULL CAPACITY AND 1364 01:05:21,240 --> 01:05:24,760 NOT HAVE TO SPECIFICALLY TARGET 1365 01:05:24,760 --> 01:05:29,440 THE UTR REGION. 1366 01:05:29,440 --> 01:05:30,640 IT SHOWS THE REQUIREMENT IN 1367 01:05:30,640 --> 01:05:33,520 PLACE FOR DEVELOPING A TOOL TO 1368 01:05:33,520 --> 01:05:34,600 TRANSLATE THE DP EXPRESSION 1369 01:05:34,600 --> 01:05:36,200 MODEL TO THE CLINIC. 1370 01:05:36,200 --> 01:05:39,880 AGAIN LIKE THE B READER WE 1371 01:05:39,880 --> 01:05:41,240 REQUIRED RIGOR IN THREE 1372 01:05:41,240 --> 01:05:44,600 DIFFERENT AREAS AND HAD TO 1373 01:05:44,600 --> 01:05:46,640 CATALOG LOW AND HIGH EXPRESSION 1374 01:05:46,640 --> 01:05:47,040 DP ALLELES. 1375 01:05:47,040 --> 01:05:51,360 THE TOOL HAS TO BE PICK UP ON 1376 01:05:51,360 --> 01:05:54,600 THE RARE ALLELE AND OF COURSE IT 1377 01:05:54,600 --> 01:05:56,520 HAS TO BE INFORMATIVE FOR 1378 01:05:56,520 --> 01:06:04,760 INDIVIDUALS OF ALL RACES AND 1379 01:06:04,760 --> 01:06:05,120 ON 1380 01:06:05,120 --> 01:06:06,400 ETHNICITIES AND WE HAVE SAMPLE 1381 01:06:06,400 --> 01:06:09,440 WERE ONLY TYPE FOR EXON 2 USING 1382 01:06:09,440 --> 01:06:11,960 PROBES AND LIMITED PANELS OF 1383 01:06:11,960 --> 01:06:12,880 PROBES FOR CERTAIN REGIONS ALL 1384 01:06:12,880 --> 01:06:16,280 THE WAY TO LABORATORIES USING 1385 01:06:16,280 --> 01:06:18,280 NEXT GEN SEQUENCING AND GET EXON 1386 01:06:18,280 --> 01:06:20,760 2 TO UTR. 1387 01:06:20,760 --> 01:06:27,000 I'LL SHOW YOU IN THE NEXT SLIDE 1388 01:06:27,000 --> 01:06:30,160 I'D LIKE YOU TO SHOW YOU THE 1389 01:06:30,160 --> 01:06:31,960 TOOL WE CALL EX-PAT. 1390 01:06:31,960 --> 01:06:35,520 IT WAS BUILD ON THROW DIFFERENT 1391 01:06:35,520 --> 01:06:35,760 COHORTS. 1392 01:06:35,760 --> 01:06:39,080 DATA SET 1 WE USED WHOLE GENOME 1393 01:06:39,080 --> 01:06:42,560 SEQUENCING FROM UNRELATED DONORS 1394 01:06:42,560 --> 01:06:46,720 IN U.S. REGISTRY, PHASED TWO AND 1395 01:06:46,720 --> 01:06:49,760 THREE TO LINK THE HYPERVARIABLE 1396 01:06:49,760 --> 01:06:53,880 REGIONS TO THE HAPLO TYPE. 1397 01:06:53,880 --> 01:06:57,720 DATA SET 2 DONORS IN CORD BLOOD 1398 01:06:57,720 --> 01:06:59,680 UNITS TO GET LINKAGE BETWEEN THE 1399 01:06:59,680 --> 01:07:04,680 HAPLO TYPE AND THE MARKER AND 1400 01:07:04,680 --> 01:07:09,200 FINALLY COHORT 3 TO SIMULATE NEW 1401 01:07:09,200 --> 01:07:12,880 DP SEARCH ALGORITHMS. 1402 01:07:12,880 --> 01:07:16,040 THE BOTTOM LINE IS EXON THREE 1403 01:07:16,040 --> 01:07:20,720 HOLD THE KEY TO UNDERSTANDING 1404 01:07:20,720 --> 01:07:23,480 REACTIVITY IN DP. 1405 01:07:23,480 --> 01:07:24,760 AFRICAN AMERICANS HAVE THE MOST 1406 01:07:24,760 --> 01:07:27,280 DIVERSE SEQUENCES AND ASIAN 1407 01:07:27,280 --> 01:07:30,400 AMERICANS HAVE THE LEAST DIVERSE 1408 01:07:30,400 --> 01:07:30,680 SEQUENCES. 1409 01:07:30,680 --> 01:07:32,600 WHAT EXON 3 PROVIDES A SITUATION 1410 01:07:32,600 --> 01:07:36,400 WHERE YOU CAN HAVE A DP MOLECULE 1411 01:07:36,400 --> 01:07:40,640 WITH IDENTICAL PEPTIDE BINDING 1412 01:07:40,640 --> 01:07:41,480 GROOVE POLYMORPHISMS BUT 1413 01:07:41,480 --> 01:07:42,120 SOMETIMES EXPRESSED HIGH AND 1414 01:07:42,120 --> 01:07:43,280 SOMETIMES LOW. 1415 01:07:43,280 --> 01:07:50,240 THAT IS A SOURCE OF DISCORDANT 1416 01:07:50,240 --> 01:07:55,520 ALLELES WITH THE ISOTOPE AND 1417 01:07:55,520 --> 01:07:56,280 MODEL. 1418 01:07:56,280 --> 01:07:57,920 THE NEXT SLIDE THOSE EX PAT 1419 01:07:57,920 --> 01:08:01,320 ABILITY FOR THE USER TO PUT 1420 01:08:01,320 --> 01:08:04,200 EVERYTHING FROM LOW TO HIGH DP 1421 01:08:04,200 --> 01:08:04,760 TYPING. 1422 01:08:04,760 --> 01:08:09,320 EX-PAT HAS LEARNED AND TRAINED 1423 01:08:09,320 --> 01:08:14,040 TO THE EXON THREE POLYMORPHISMS 1424 01:08:14,040 --> 01:08:16,920 AND THE OUTPUT WILL DEPEND ON 1425 01:08:16,920 --> 01:08:20,000 WHAT THE USER'S GOAL IS. 1426 01:08:20,000 --> 01:08:21,680 IF YOU WANT TO USE T CELL 1427 01:08:21,680 --> 01:08:26,080 EPITOPE YOU HAVE THE OPTION OF 1428 01:08:26,080 --> 01:08:27,400 ONLY DOING T CELL EPITOPE AND IF 1429 01:08:27,400 --> 01:08:31,720 YOU WANT TO SEE HOW THE TOOLS 1430 01:08:31,720 --> 01:08:35,320 STACK UP YOU CAN DO BOTH. 1431 01:08:35,320 --> 01:08:37,320 HERE YOU HAVE AN OUTPUT WHERE 1432 01:08:37,320 --> 01:08:39,040 THE FAVORABLE DONOR IS FAVORABLE 1433 01:08:39,040 --> 01:08:41,280 FROM BOTH EXPRESSION AND TCE AND 1434 01:08:41,280 --> 01:08:43,240 THE UNFAVORABLE DONOR TO AVOID 1435 01:08:43,240 --> 01:08:47,440 IS THE ONE ON THE BOTTOM, NUMBER 1436 01:08:47,440 --> 01:08:49,640 4, UNFAVORABLE EXPRESSION AND A 1437 01:08:49,640 --> 01:08:51,840 TCE NON-PERMISSIVE AND THE 1438 01:08:51,840 --> 01:08:53,080 INTERMEDIATE GROUP OF DONORS. 1439 01:08:53,080 --> 01:08:56,560 THIS OUTPUT WE FEEL IS INTUITIVE 1440 01:08:56,560 --> 01:08:58,480 AND REALLY HELPS SEARCH 1441 01:08:58,480 --> 01:08:59,160 COORDINATORS AND TRANSPLANT 1442 01:08:59,160 --> 01:09:02,800 PHYSICIAN AND NURSES TO GET A 1443 01:09:02,800 --> 01:09:04,400 BETTER HANDLE ON THE DONORS 1444 01:09:04,400 --> 01:09:06,840 THEY'D LIKE TO MOVE TO THE NEXT 1445 01:09:06,840 --> 01:09:10,840 STEP FOR CONFIRMATORY TYPING AND 1446 01:09:10,840 --> 01:09:11,160 SCHEDULING. 1447 01:09:11,160 --> 01:09:14,880 THE NEXT SLIDE SHOWS WE JUST 1448 01:09:14,880 --> 01:09:16,600 ROLLED OUT EX-PAT LAT OVER A 1449 01:09:16,600 --> 01:09:17,600 MONTH AGO. 1450 01:09:17,600 --> 01:09:20,760 I'LL INVITE YOU TO THE URL AND 1451 01:09:20,760 --> 01:09:24,720 GIVE IT A TRY AND HOW YOU'RE 1452 01:09:24,720 --> 01:09:27,240 ABLE TO USE IT. 1453 01:09:27,240 --> 01:09:29,720 AND PRELIMINARY USERS IN THE 1454 01:09:29,720 --> 01:09:31,760 LAST MONTH TRYING THE TOOL 1455 01:09:31,760 --> 01:09:38,520 GIVING US FEEDBACK IS WORE AT AN 1456 01:09:38,520 --> 01:09:39,120 EARLY STAGE. 1457 01:09:39,120 --> 01:09:41,680 WE CAN LEARN A LOT IN THE 1458 01:09:41,680 --> 01:09:42,520 RESEARCH LABORATORY AND DO 1459 01:09:42,520 --> 01:09:44,040 POPULATION STUDIES BUT AT THE 1460 01:09:44,040 --> 01:09:46,920 END OF THE DAY WHAT TRANSPLANT 1461 01:09:46,920 --> 01:09:48,240 PROGRAMS NEED SAY HIGHLY 1462 01:09:48,240 --> 01:09:48,920 EFFICIENT ACCURATE WAY TO PICK 1463 01:09:48,920 --> 01:09:53,640 THOSE DONORS. 1464 01:09:53,640 --> 01:09:59,200 SO THEY BEGAN PROSPECTIVE DP1 1465 01:09:59,200 --> 01:10:03,400 TYPING ACHIEVING 100% TYPING IN 1466 01:10:03,400 --> 01:10:06,880 2015 AND SO AS OF TODAY 2.8 1467 01:10:06,880 --> 01:10:10,520 MILLION UNRELATED U.S. DONORS 1468 01:10:10,520 --> 01:10:12,920 HAVE BEEN FULLY SEQUENCED FOR 1469 01:10:12,920 --> 01:10:14,360 DP1 AND THE NEXT SLIDE SHOWS YOU 1470 01:10:14,360 --> 01:10:17,360 WHAT A PROFOUND IMPACT THAT 1471 01:10:17,360 --> 01:10:19,320 INFORMATION HAS. 1472 01:10:19,320 --> 01:10:24,760 WE HAVE BEEN FOR FIVE GENETIC 1473 01:10:24,760 --> 01:10:30,320 LOCI FOR A LONG TIME AND WHEN WE 1474 01:10:30,320 --> 01:10:35,680 ASSESSED THEM ONLY 20% TO 25% 1475 01:10:35,680 --> 01:10:39,080 WERE MATCHED AT THAT LOCUS AND 1476 01:10:39,080 --> 01:10:41,720 WITH 2.8 MILLION U.S. DONORS AND 1477 01:10:41,720 --> 01:10:45,520 MANY MORE FROM EUROPE ALREADY 1478 01:10:45,520 --> 01:10:47,360 HAVING THE DP TYPING IN THE 1479 01:10:47,360 --> 01:10:50,880 SYSTEM YOU CAN CONDUCT EFFECTIVE 1480 01:10:50,880 --> 01:10:55,320 SEARCHS AND DRIVE UP THE RATE 1481 01:10:55,320 --> 01:10:56,480 TREMENDOUSLY. 1482 01:10:56,480 --> 01:10:59,880 SO THE BLUE BARS ARE THE SIX 1483 01:10:59,880 --> 01:11:02,400 LOCUS MATCHES EXQUISITELY WELL 1484 01:11:02,400 --> 01:11:04,720 MATCHED. 1485 01:11:04,720 --> 01:11:10,280 WE'RE TRYING VERY HARD TO PICK A 1486 01:11:10,280 --> 01:11:10,880 SINGLE DP LOW EXPRESSION IN THE 1487 01:11:10,880 --> 01:11:11,120 ORANGE. 1488 01:11:11,120 --> 01:11:13,080 WE'RE TRYING TO DRIVE DOWN THE 1489 01:11:13,080 --> 01:11:14,040 RATE OF HIGH EXPRESSION 1490 01:11:14,040 --> 01:11:19,120 MISMATCHES IN THE GRAY AND YOU 1491 01:11:19,120 --> 01:11:23,120 CAN SEE OUR EFFORT PAID OFF EVEN 1492 01:11:23,120 --> 01:11:25,400 WITH THE CHALLENGES OF THE 1493 01:11:25,400 --> 01:11:25,960 PANDEMIC. 1494 01:11:25,960 --> 01:11:29,480 LAST YEAR IN TOTAL 80% OF THE 1495 01:11:29,480 --> 01:11:32,760 TRANSPLANTS WERE WELL MATCHED OR 1496 01:11:32,760 --> 01:11:33,640 FAVORABLE IN DP MISMATCHES. 1497 01:11:33,640 --> 01:11:35,440 THAT'S WHY THIS IS SO IMPORTANT. 1498 01:11:35,440 --> 01:11:37,320 YOU LEARN SOMETHING IN THE LAB 1499 01:11:37,320 --> 01:11:39,160 AND DO THESE POPULATION STUDIES, 1500 01:11:39,160 --> 01:11:41,360 YOU WORK WITH COLLEAGUES TO BE 1501 01:11:41,360 --> 01:11:46,680 ABLE TO DEPLOY IT AND THEN THE 1502 01:11:46,680 --> 01:11:52,360 FINALLY PRODUCT AND OFFER IT TO 1503 01:11:52,360 --> 01:11:52,760 PATIENTS. 1504 01:11:52,760 --> 01:11:55,320 I'VE GIVEN YOU TWO TOOLS, AND WE 1505 01:11:55,320 --> 01:12:01,400 HAVE A NUMBER IN THE WORKS AND 1506 01:12:01,400 --> 01:12:02,600 WE'LL BE MOVING TOWARDS A 1507 01:12:02,600 --> 01:12:06,480 COMPLETE MODEL WHERE INSTEAD OF 1508 01:12:06,480 --> 01:12:08,120 INDIVIDUAL TOOLS IN DIFFERENT 1509 01:12:08,120 --> 01:12:10,400 PLACES WE'D LIKE IT ALL IN ONE 1510 01:12:10,400 --> 01:12:11,760 PLACE BECAUSE THE PATIENT 1511 01:12:11,760 --> 01:12:13,200 PRESENTS AS ONE PERSON WITH TWO 1512 01:12:13,200 --> 01:12:17,800 HAPLO TYPES SO YOU NEED TO PUT 1513 01:12:17,800 --> 01:12:20,160 TOGETHER ALL THE TOOLS SO 1514 01:12:20,160 --> 01:12:21,840 CLINICIANS CAN CHOOSE FOR EACH 1515 01:12:21,840 --> 01:12:22,920 INDIVIDUAL PATIENT 1516 01:12:22,920 --> 01:12:24,560 CHARACTERISTIC AND THIS WAY I 1517 01:12:24,560 --> 01:12:26,160 THINK WE'RE TRYING TO INCREASE 1518 01:12:26,160 --> 01:12:29,840 THE AVAILABILITY OF 1519 01:12:29,840 --> 01:12:30,800 TRANSPLANTATION TO ALL PATIENTS 1520 01:12:30,800 --> 01:12:32,400 EVEN IF A PATIENT DOES NOT HAVE 1521 01:12:32,400 --> 01:12:36,400 A MATCH OUR SINCERE HOPE IS WE 1522 01:12:36,400 --> 01:12:40,520 CAN BRING THEM TO A SAFE 1523 01:12:40,520 --> 01:12:41,520 CURATIVE TRANSPLANT WITH A 1524 01:12:41,520 --> 01:12:42,120 MATCH. 1525 01:12:42,120 --> 01:12:45,240 I'D LIKE TO THANK MY COLLEAGUES 1526 01:12:45,240 --> 01:12:46,960 WITHIN THE WORKING GROUP 1527 01:12:46,960 --> 01:12:48,560 INDIVIDUAL INVESTIGATORS, 1528 01:12:48,560 --> 01:12:50,720 TRANSPLANT CENTERS AND DONOR 1529 01:12:50,720 --> 01:12:56,720 REGISTRIES AND THE FINAL SLIDE 1530 01:12:56,720 --> 01:13:00,760 WOULD LIKE TO THANK THE BIO 1531 01:13:00,760 --> 01:13:04,760 INFORMATICS TEAM IN INDIANAPOLIS 1532 01:13:04,760 --> 01:13:07,360 WHO PESPEARHEADED THE DEVELOPME 1533 01:13:07,360 --> 01:13:08,720 AND ACKNOWLEDGE COLLEAGUES IN 1534 01:13:08,720 --> 01:13:12,280 THE BONE MARROW ASSOCIATION AND 1535 01:13:12,280 --> 01:13:13,160 PROFESSIONAL SOCIETY. 1536 01:13:13,160 --> 01:13:15,080 THEY'VE PLAYED AN AN IMPORTANT 1537 01:13:15,080 --> 01:13:16,760 ROLE IN EDUCATION AND PROVIDING 1538 01:13:16,760 --> 01:13:19,160 THE FORUMS TO BE ABLE TO HOLD 1539 01:13:19,160 --> 01:13:23,400 TEACHING AND EDUCATIONAL 1540 01:13:23,400 --> 01:13:24,400 SESSIONS TO REACH THOSE 1541 01:13:24,400 --> 01:13:25,360 COLLEAGUES ACROSS THE GLOBE IN 1542 01:13:25,360 --> 01:13:28,520 55 COUNTRIES AND WE'RE GRATEFUL 1543 01:13:28,520 --> 01:13:31,360 FOR THE FUNDING TO MAKE IT 1544 01:13:31,360 --> 01:13:31,640 POSSIBLE. 1545 01:13:31,640 --> 01:13:41,960 THANKS VERY MUCH. 1546 01:14:10,960 --> 01:14:13,120 >> WE HAVE NEW DATA IN THE LAB 1547 01:14:13,120 --> 01:14:15,640 WHERE WE'RE TRYING TO DISSECT 1548 01:14:15,640 --> 01:14:17,600 OUT THE GRAPH VERSUS HOST VERSUS 1549 01:14:17,600 --> 01:14:18,520 LEUKEMIA EFFECT. 1550 01:14:18,520 --> 01:14:24,760 I THINK IT'S GOING CHANGE OUR 1551 01:14:24,760 --> 01:14:28,240 PERCEPTION OF WHAT IT IS. 1552 01:14:28,240 --> 01:14:31,160 IN INDIVIDUALS WITH GBHD THEY 1553 01:14:31,160 --> 01:14:33,160 TEND TO HAVE A LOWER OVER ALL 1554 01:14:33,160 --> 01:14:34,680 RATE BUT NOT NECESSARILY SO AND 1555 01:14:34,680 --> 01:14:36,760 HAVE NEVER BEEN ABLE TO EXPLAIN 1556 01:14:36,760 --> 01:14:41,160 WHY SOME PATIENTS RELAPSE WITH 1557 01:14:41,160 --> 01:14:42,080 GBHD AND OTHERS NEVER DEVELOP IT 1558 01:14:42,080 --> 01:14:47,680 OR RELAPSE AND PEOPLE WITH 1559 01:14:47,680 --> 01:14:52,800 CLASSIC THE CLASSIC AND WE HAVE 1560 01:14:52,800 --> 01:14:54,480 SEEN A CLASS. 1561 01:14:54,480 --> 01:14:59,600 SO 12 OF 12 MATCHES ABSOLUTELY 1562 01:14:59,600 --> 01:15:02,040 HAVE LOWER GBHD LEADING TO 1563 01:15:02,040 --> 01:15:04,520 MORTALITY AND THEIR RELAPSE IS 1564 01:15:04,520 --> 01:15:05,840 HIGHER SO IT'S A BALANCE. 1565 01:15:05,840 --> 01:15:08,120 AT THE END OF THE DAY IT'S ABOUT 1566 01:15:08,120 --> 01:15:10,520 SAFETY AND BEING ABLE TO CARRY A 1567 01:15:10,520 --> 01:15:11,640 PATIENT THROUGH SAFELY IN THE 1568 01:15:11,640 --> 01:15:14,080 FIRST 100 DAYS OF THE TRANSPLANT 1569 01:15:14,080 --> 01:15:20,720 SO FOR NOW, WE BELIEVE THERE ARE 1570 01:15:20,720 --> 01:15:22,200 BENEFITS FOR MATCHING BECAUSE 1571 01:15:22,200 --> 01:15:26,280 THERE'S PROLONGATION OF 1572 01:15:26,280 --> 01:15:27,720 IMMUNOEXPRESSION AND VIRAL, 1573 01:15:27,720 --> 01:15:29,520 BACTERIAL, FUNGAL INFECTIONS 1574 01:15:29,520 --> 01:15:32,320 THESE PATIENTS EXPERIENCE WITH 1575 01:15:32,320 --> 01:15:39,280 PROLONGED IMMUNOSUPPRESSION. 1576 01:15:39,280 --> 01:15:49,600 IT'S AN ACTIVE AREA. 1577 01:16:00,080 --> 01:16:00,720 >> GOOD AFTERNOON. 1578 01:16:00,720 --> 01:16:03,760 THANK YOU VERY MUCH FOR THIS 1579 01:16:03,760 --> 01:16:08,720 OPPORTUNITY TO BE HERE AND WITH 1580 01:16:08,720 --> 01:16:09,200 YOU TODAY. 1581 01:16:09,200 --> 01:16:13,000 THIS IS A MESSY TOPIC. 1582 01:16:13,000 --> 01:16:14,720 IT INVOLVES A LOT. 1583 01:16:14,720 --> 01:16:20,520 ABOUT 30 YEARS OF WORK IN THIS 1584 01:16:20,520 --> 01:16:24,760 FIELD I'LL DO MY BEST TO HIT 1585 01:16:24,760 --> 01:16:27,720 SOME OF THE HIGH POINTS. 1586 01:16:27,720 --> 01:16:30,160 SO THESE ARE MY DISCLOSURES. 1587 01:16:30,160 --> 01:16:32,280 YOU'LL SEE A FAIR NUMBER OF 1588 01:16:32,280 --> 01:16:33,000 RELEVANT CONFLICTS. 1589 01:16:33,000 --> 01:16:36,240 I'VE BEEN IN THIS SPACE FOR A 1590 01:16:36,240 --> 01:16:42,080 LONG TIME AND ABOUT 80% OF THE 1591 01:16:42,080 --> 01:16:43,480 CLINICAL TRIALS I'LL TALK ABOUT 1592 01:16:43,480 --> 01:16:47,360 HAVE BEEN SPONSORED BY 1593 01:16:47,360 --> 01:16:48,760 PHARMA-AND THERE'S A NEW DRUG 1594 01:16:48,760 --> 01:16:52,760 WHERE THERE'S A LOT OF PATIENTS 1595 01:16:52,760 --> 01:16:55,560 AND EXPERIENCE SO THAT IS JUST 1596 01:16:55,560 --> 01:16:58,800 HOW IT IS. 1597 01:16:58,800 --> 01:17:02,760 SO THIS IS WHAT HYPER REJECTION 1598 01:17:02,760 --> 01:17:04,760 LOOKS LIKE. 1599 01:17:04,760 --> 01:17:06,080 HYPERACUTE REJECTION IS A 1600 01:17:06,080 --> 01:17:06,520 TERMINAL EVENT. 1601 01:17:06,520 --> 01:17:08,640 THERE'S NOTHING YOU CAN DO TO 1602 01:17:08,640 --> 01:17:10,840 SAVE THIS KIDNEY. 1603 01:17:10,840 --> 01:17:13,360 THIS IS CAUSED BY PREFORMED 1604 01:17:13,360 --> 01:17:16,280 ANTIBODY TO PROTEINS LIKE HLA 1605 01:17:16,280 --> 01:17:18,320 THAT ARE PLENTIFUL IN THEIR 1606 01:17:18,320 --> 01:17:24,280 EXPRESSION OR CARBOHYDRATES LIKE 1607 01:17:24,280 --> 01:17:25,960 GROUP ANTIGENS OR XENO ANTIGENS 1608 01:17:25,960 --> 01:17:28,160 AND HIGH TITER ANTIBODY AND YOU 1609 01:17:28,160 --> 01:17:29,800 GET THIS CASCADE OF INJURY THAT 1610 01:17:29,800 --> 01:17:31,360 UNFOLDS IN FRONT OF YOUR EYES 1611 01:17:31,360 --> 01:17:32,800 OVER A MATTER OF MINUTES, 1612 01:17:32,800 --> 01:17:40,400 BELIEVE IT OR NOT. 1613 01:17:40,400 --> 01:17:50,920 SO THIS MAN, PAUL TERASAKI GAVE 1614 01:17:54,920 --> 01:17:58,080 US A WAY TO LOOK AT THIS AND 1615 01:17:58,080 --> 01:17:59,440 BEFORE THAT IT WASN'T UNUSUAL 1616 01:17:59,440 --> 01:18:02,280 FOR A KIDNEY TO TURN BACK ON THE 1617 01:18:02,280 --> 01:18:02,480 TABLE. 1618 01:18:02,480 --> 01:18:05,560 MIX THE SERUM FROM THE RECIPIENT 1619 01:18:05,560 --> 01:18:10,320 FROM THE DONOR CELLS AND SO THIS 1620 01:18:10,320 --> 01:18:12,760 BASICALLY WAS THE END OF 1621 01:18:12,760 --> 01:18:15,240 HYPERACUTE REJECTION BUT IT WAS 1622 01:18:15,240 --> 01:18:17,440 THE BEGINS OF A NEW PROBLEM. 1623 01:18:17,440 --> 01:18:21,280 THE UNINTENDED CONSEQUENCE WAS 1624 01:18:21,280 --> 01:18:25,800 WE NOW WERE ABLE TO DEFINE A 1625 01:18:25,800 --> 01:18:29,920 GROUP OF PATIENTS WHO HAD GREAT 1626 01:18:29,920 --> 01:18:32,080 DIFFICULTY FINDING A MATCH AND 1627 01:18:32,080 --> 01:18:34,160 WERE BASICALLY BEING WAREHOUSED 1628 01:18:34,160 --> 01:18:36,160 ON A TRANSPLANT LIST. 1629 01:18:36,160 --> 01:18:38,040 SO JUST TO GET A SENSE FOR THE 1630 01:18:38,040 --> 01:18:43,360 NATURE AND SCOPE OF THE PROBLEM, 1631 01:18:43,360 --> 01:18:47,200 WE KNOW THAT EXPOSURE TO ANOTHER 1632 01:18:47,200 --> 01:18:48,240 PERSON'S TISSUE THROUGH A NUMBER 1633 01:18:48,240 --> 01:18:54,240 OF WAYS THAT CAN HAPPEN CAN LEAD 1634 01:18:54,240 --> 01:18:57,280 TO ANTI-HLA ANTIBODIES. 1635 01:18:57,280 --> 01:19:00,880 ABOUT 25% TO 30% OF THE PATIENTS 1636 01:19:00,880 --> 01:19:04,480 ON THE TRANSPLANT LIST ARE 1637 01:19:04,480 --> 01:19:06,200 HIGHLY SENSITIZED. 1638 01:19:06,200 --> 01:19:09,360 THIS IS A BIG PUBLIC HEALTH 1639 01:19:09,360 --> 01:19:10,920 PROBLEM WHEN HAVE YOU OVER 1640 01:19:10,920 --> 01:19:12,760 100,000 PEOPLE ON THE LIST. 1641 01:19:12,760 --> 01:19:18,560 IT WAS THE WORK THAT ANNETTE 1642 01:19:18,560 --> 01:19:20,720 THAT ALLOWED US TO BEGIN TO 1643 01:19:20,720 --> 01:19:21,640 INNOVATE AND APPROACH THE 1644 01:19:21,640 --> 01:19:22,040 PROBLEM. 1645 01:19:22,040 --> 01:19:25,880 AS YOU SAW IN BOTH OF THE 1646 01:19:25,880 --> 01:19:28,360 PREVIOUS TALKS BACK IN THE '90s 1647 01:19:28,360 --> 01:19:31,360 WERE LIKE MEDIEVAL TIMES BECAUSE 1648 01:19:31,360 --> 01:19:33,040 WE COULDN'T FOLLOW HLA ANTIBODY. 1649 01:19:33,040 --> 01:19:40,760 ALL THESE ALLELES WEREN'T 1650 01:19:40,760 --> 01:19:43,360 IDENTIFIED. 1651 01:19:43,360 --> 01:19:49,800 SO IN ORDER TO TREAT IT YOU HAVE 1652 01:19:49,800 --> 01:19:51,200 TO TRACK IT IN THERAPY. 1653 01:19:51,200 --> 01:19:53,240 THIS IS ONE OF THE FIRST 1654 01:19:53,240 --> 01:19:54,200 ATTEMPTS TO DO THAT. 1655 01:19:54,200 --> 01:19:59,880 THIS IS A WAY OF REMOVING 1656 01:19:59,880 --> 01:20:04,120 ANTIBODY BEFORE TRANSPLANT IN 1657 01:20:04,120 --> 01:20:07,720 PATIENTS YOU KNOW ARE SENSITIZED 1658 01:20:07,720 --> 01:20:12,760 AND IT INVOLVES AN INITIATE WAY 1659 01:20:12,760 --> 01:20:15,280 OF REMOVING IGG. 1660 01:20:15,280 --> 01:20:18,640 PLASMAPHERESIS REMOVES IT FROM 1661 01:20:18,640 --> 01:20:20,000 THE VASCULAR COMPARTMENT AND YOU 1662 01:20:20,000 --> 01:20:21,000 HAVE TO WAIT FOR A CERTAIN 1663 01:20:21,000 --> 01:20:23,840 PERIOD OF TIME AND THE OPTIMAL 1664 01:20:23,840 --> 01:20:27,040 PERIOD IS 48 HOURS UNTIL I 1665 01:20:27,040 --> 01:20:33,120 RECALCULIBRATES WITH THE 1666 01:20:33,120 --> 01:20:34,560 INTERSTITIUM AND THE ONLY WAY TO 1667 01:20:34,560 --> 01:20:37,360 DO THIS IS KNOWING WHEN THE 1668 01:20:37,360 --> 01:20:40,720 TRANSPLANT WILL OCCUR WORKING 1669 01:20:40,720 --> 01:20:44,120 BACKWARD BUT WITH DECEASED 1670 01:20:44,120 --> 01:20:45,040 DONATION IT'S IMPOSSIBLE AND 1671 01:20:45,040 --> 01:20:47,440 COULD BE DONE IN THE SETTING OF 1672 01:20:47,440 --> 01:20:51,960 A LIVING DONOR. 1673 01:20:51,960 --> 01:20:53,600 BASICALLY IT INVOLVED THIS AND 1674 01:20:53,600 --> 01:20:58,960 ADDING BACK COOL IGG FOR 1675 01:20:58,960 --> 01:21:01,360 PATIENTS AT RISK OF LOW FORM 1676 01:21:01,360 --> 01:21:02,040 ANTIBODIES EXPRESSING THE 1677 01:21:02,040 --> 01:21:03,680 REBOUND OF THE ANTIBODIES 1678 01:21:03,680 --> 01:21:05,360 BECAUSE YOU'RE NOT DOING 1679 01:21:05,360 --> 01:21:09,480 ANYTHING ABOUT THE PLASMA CELLS. 1680 01:21:09,480 --> 01:21:11,080 THEY'RE SOLUBLE PRODUCTS YOU'RE 1681 01:21:11,080 --> 01:21:12,760 REMOVING AND DO THIS WITH 1682 01:21:12,760 --> 01:21:15,120 IMMUNOEXPRESSION AND TREATMENTS 1683 01:21:15,120 --> 01:21:16,720 AFTERWARD AND YOU COULD GET 1684 01:21:16,720 --> 01:21:21,920 PATIENTS TRANSPLANTED WHO HAD 1685 01:21:21,920 --> 01:21:23,040 PREFORMED ANTIBODY AT RISK FOR 1686 01:21:23,040 --> 01:21:26,520 HYPER ACUTE REJECTION. 1687 01:21:26,520 --> 01:21:31,360 NOW, YOU CAN IMAGINE IT'S 1688 01:21:31,360 --> 01:21:35,760 DIFFICULT TO DEMONSTRATE 1689 01:21:35,760 --> 01:21:36,840 EFFICACY BECAUSE THERE'S NOT A 1690 01:21:36,840 --> 01:21:38,240 GOOD PARITY. 1691 01:21:38,240 --> 01:21:39,000 YOU'RE NOT GOING TO TAKE A 1692 01:21:39,000 --> 01:21:41,440 PATIENT YOU KNOW IS AT RISK FOR 1693 01:21:41,440 --> 01:21:42,680 HYPERACUTE REJECTION AND HAVE 1694 01:21:42,680 --> 01:21:46,000 THEM AS YOUR PLACEBO GROUP. 1695 01:21:46,000 --> 01:21:48,880 SO THIS HAS PLAGUED THIS FIELD. 1696 01:21:48,880 --> 01:21:52,760 YOU'LL SEE THIS THROUGHOUT THE 1697 01:21:52,760 --> 01:21:56,080 STOREY I TELL. 1698 01:21:56,080 --> 01:21:58,880 ON THE PANEL ON THE LEFT IS A 1699 01:21:58,880 --> 01:22:00,400 COHORT OF PATIENTS WE 1700 01:22:00,400 --> 01:22:03,800 DESENSITIZED AND TRANSPLANTED 1701 01:22:03,800 --> 01:22:06,280 ACROSS A POSITIVE CROSS MATCH 1702 01:22:06,280 --> 01:22:08,080 OVER A PERIOD OF EIGHT YEARS AT 1703 01:22:08,080 --> 01:22:09,800 JOHNS HOPKINS. 1704 01:22:09,800 --> 01:22:12,360 IT'S A SINGLE CENTER. 1705 01:22:12,360 --> 01:22:13,360 BASICALLY WHAT WE DID WAS AS 1706 01:22:13,360 --> 01:22:18,160 EACH OF THE PATIENTS WAS 1707 01:22:18,160 --> 01:22:20,400 TRANSPLANTED WE FOUND FIVE 1708 01:22:20,400 --> 01:22:23,480 CONTROLS USING AN ITERATIVE 1709 01:22:23,480 --> 01:22:26,160 EXPANDED RADIUS MATCHING FROM 1710 01:22:26,160 --> 01:22:30,680 THE WAITING LIST SIMILAR TO EACH 1711 01:22:30,680 --> 01:22:32,160 OF THE PATIENTS ACROSS 11 1712 01:22:32,160 --> 01:22:33,680 VARIABLES KNOWN TO BE IMPORTANT 1713 01:22:33,680 --> 01:22:36,520 FOR ALLO GRAPH SURVIVAL SO THESE 1714 01:22:36,520 --> 01:22:37,600 WERE MATCH CONTROL. 1715 01:22:37,600 --> 01:22:40,080 THE LINE ON THE TOP ARE REAL 1716 01:22:40,080 --> 01:22:44,720 PATIENTS WHO WE TREATED AND 1717 01:22:44,720 --> 01:22:45,040 TRANSPLANTED. 1718 01:22:45,040 --> 01:22:47,680 YOU CAN SEE AS WE WATCH TO SEE 1719 01:22:47,680 --> 01:22:49,120 WHAT HAPPENS TO THE PATIENTS 1720 01:22:49,120 --> 01:22:50,720 OVER EIGHT YEARS AND THEIR MATCH 1721 01:22:50,720 --> 01:22:54,320 CONTROLS, THAT 80% OF THOSE 1722 01:22:54,320 --> 01:22:56,320 PATIENTS WERE STILL ALIVE AFTER 1723 01:22:56,320 --> 01:22:57,480 EIGHT YEARS. 1724 01:22:57,480 --> 01:23:00,880 WHEREAS THE PATIENTS WHO STAYED 1725 01:23:00,880 --> 01:23:03,880 ON THE WAITING LIST WAITING FOR 1726 01:23:03,880 --> 01:23:08,680 A COMPATIBLE ORGAN HAD A LOWER 1727 01:23:08,680 --> 01:23:09,360 SURVIVAL RATE. 1728 01:23:09,360 --> 01:23:11,200 IN FACT IF YOU LOOK AT THE TOP 1729 01:23:11,200 --> 01:23:14,600 LINE AND NEXT LINE DOWN, IT 1730 01:23:14,600 --> 01:23:18,040 REPRESENTS 26% OF THE PATIENTS 1731 01:23:18,040 --> 01:23:19,280 ACTUALLY GETTING A TRANSPLANT IN 1732 01:23:19,280 --> 01:23:20,760 THE SECOND GROUP BECAUSE MOST 1733 01:23:20,760 --> 01:23:24,720 THE PATIENTS NEVER GOT A 1734 01:23:24,720 --> 01:23:25,280 TRANSPLANT. 1735 01:23:25,280 --> 01:23:27,920 SO IF YOU TAKE THE PATIENTS WHO 1736 01:23:27,920 --> 01:23:30,120 REMAINED ON THE LIST AND STAYED 1737 01:23:30,120 --> 01:23:32,120 ON DIALYSIS THE WHOLE TIME, 1738 01:23:32,120 --> 01:23:34,160 THEIR SURVIVAL RATE AT THE END 1739 01:23:34,160 --> 01:23:35,920 OF EIGHT YEARS, A VAST MAJORITY 1740 01:23:35,920 --> 01:23:37,360 WAS ONLY 30%. 1741 01:23:37,360 --> 01:23:40,680 THAT'S WORSE THAN MOST CANCERS. 1742 01:23:40,680 --> 01:23:43,440 WITH WERE ABLE TO DUPLICATE THIS 1743 01:23:43,440 --> 01:23:45,760 IN A MULTI-CENTER THE TRIAL SET 1744 01:23:45,760 --> 01:23:51,240 UP THE SAME WAY, 22 DIFFERENT 1745 01:23:51,240 --> 01:23:53,600 CENTERS TO SHOW IT WASN'T JUST 1746 01:23:53,600 --> 01:23:54,280 SOMETHING WE WERE DOING. 1747 01:23:54,280 --> 01:23:59,440 NOW, THE OTHER COMPETING 1748 01:23:59,440 --> 01:24:02,240 APPROACH WAS PIONEERED BY STAN 1749 01:24:02,240 --> 01:24:06,760 JORDAN AT CEDARS AND INVOLVED 1750 01:24:06,760 --> 01:24:08,640 GIVING HIGH DOSE IVFG. 1751 01:24:08,640 --> 01:24:13,120 MANY IN THE ROOM PROBABLY USE 1752 01:24:13,120 --> 01:24:14,720 HIGH DOSE IVIG. 1753 01:24:14,720 --> 01:24:15,800 THERE'S SO MANY POTENTIAL 1754 01:24:15,800 --> 01:24:19,200 MECHANISMS OF HOW IT WORKS BUT 1755 01:24:19,200 --> 01:24:24,720 IT REALLY DIDN'T LOWER PREFORMED 1756 01:24:24,720 --> 01:24:35,280 ANTIBODY IN A MEASURABLE WAY AND 1757 01:24:35,280 --> 01:24:38,840 RITUXIMAB AND THEY WERE ABLE TO 1758 01:24:38,840 --> 01:24:43,360 GET 80% OF THE PATIENTS THEY 1759 01:24:43,360 --> 01:24:46,600 TREATED TRANSPLANTED WITH A 95% 1760 01:24:46,600 --> 01:24:48,240 SURVIVAL. 1761 01:24:48,240 --> 01:24:49,040 THE COMBINATION WORKED BETTER 1762 01:24:49,040 --> 01:24:51,800 THAN IVIG ALONE. 1763 01:24:51,800 --> 01:24:54,800 NOW, IT'S THE ONLY APPROACH THAT 1764 01:24:54,800 --> 01:24:59,720 HAS EVER BEEN TESTED IN A 1765 01:24:59,720 --> 01:25:00,720 RANDOMIZED PLACEBO CONTROLLED 1766 01:25:00,720 --> 01:25:03,680 TRIAL THE GO2 STUDY FROM WAY 1767 01:25:03,680 --> 01:25:07,720 BACK IN THE LATE 1990s, EARLY 1768 01:25:07,720 --> 01:25:10,680 2000s AND DOESN'T WORK THAT 1769 01:25:10,680 --> 01:25:11,520 WELL. 1770 01:25:11,520 --> 01:25:15,160 THE ADDITION OF RITUXIMAB HELPS 1771 01:25:15,160 --> 01:25:18,120 AND BRINGS UP THE ISSUE OF END 1772 01:25:18,120 --> 01:25:19,960 POINTS AND IS TRANSPLANT RATE A 1773 01:25:19,960 --> 01:25:21,320 REASONABLE END POINT? 1774 01:25:21,320 --> 01:25:24,760 WE BASICALLY DUPLICATED THE IVIG 1775 01:25:24,760 --> 01:25:28,240 ALONE STUDY WITH A GROUP OF 1776 01:25:28,240 --> 01:25:31,040 PATIENTS AND IT DID INCREASE THE 1777 01:25:31,040 --> 01:25:33,320 TRANSPLANT RATE BUT EVERY ONE OF 1778 01:25:33,320 --> 01:25:34,480 THE PATIENTS THAT GOT 1779 01:25:34,480 --> 01:25:35,520 TRANSPLANTED WOULD HAVE BEEN 1780 01:25:35,520 --> 01:25:37,920 ELIGIBLE FOR THAT ORGAN PRIOR TO 1781 01:25:37,920 --> 01:25:40,720 RECEIVING ANY IVIG AND IT WAS 1782 01:25:40,720 --> 01:25:42,840 JUST ABOUT CROSS-MATCHING THEM 1783 01:25:42,840 --> 01:25:44,120 AGAINST EVERY ORGAN AVAILABLE 1784 01:25:44,120 --> 01:25:46,200 AND HAVING THEM READY FOR 1785 01:25:46,200 --> 01:25:47,840 TRANSPLANT THAT INCREASED THEIR 1786 01:25:47,840 --> 01:25:48,360 TRANSPLANT RATE. 1787 01:25:48,360 --> 01:25:50,600 YOU CAN SEE CHOOSING YOUR END 1788 01:25:50,600 --> 01:25:56,120 POINT IS A REALLY IMPORTANT 1789 01:25:56,120 --> 01:25:56,920 THING AND IT'S KIND OF DIFFICULT 1790 01:25:56,920 --> 01:26:03,400 IN THIS SPACE. 1791 01:26:03,400 --> 01:26:10,720 SO IN 1998, THIS WOMAN, JOYCE 1792 01:26:10,720 --> 01:26:12,720 ROUSH PRESENTED AT HOPKINS AND 1793 01:26:12,720 --> 01:26:23,120 SHE WAS THE OG OF AL ALTRUISTIC 1794 01:26:23,120 --> 01:26:24,960 DONORS AND WANTED TO GIVE HER 1795 01:26:24,960 --> 01:26:27,000 ORGAN AND THERE WERE NO 1796 01:26:27,000 --> 01:26:28,720 ALLOCATION STRATEGIES FOR WHAT 1797 01:26:28,720 --> 01:26:30,480 TO DO WITH THIS NEW SOURCE OF 1798 01:26:30,480 --> 01:26:30,720 ORGANS. 1799 01:26:30,720 --> 01:26:33,880 SO WE DECIDED AND I CAN PUT HER 1800 01:26:33,880 --> 01:26:35,400 PICTURE UP HERE BECAUSE SHE DID 1801 01:26:35,400 --> 01:26:37,640 IT IN A PUBLIC WAY AND WAS 1802 01:26:37,640 --> 01:26:42,000 TRYING TO CREATE A REVOLUTION 1803 01:26:42,000 --> 01:26:46,160 AND BROUGHT A PUBLICIST WITH HER 1804 01:26:46,160 --> 01:26:48,040 AND WE GAVE THE KIDNEY TO A 1805 01:26:48,040 --> 01:26:50,640 CHILD BECAUSE THEY'RE MOST 1806 01:26:50,640 --> 01:26:51,960 IMPACTED BY TRANSPLANTATION. 1807 01:26:51,960 --> 01:26:54,600 THE NEXT DAY WAS IN THE NEWS AND 1808 01:26:54,600 --> 01:26:57,480 50 PEOPLE SAID WE WANT TO EXTEND 1809 01:26:57,480 --> 01:26:58,040 THE SAME. 1810 01:26:58,040 --> 01:27:01,320 AND IN A YEAR AND A HALF WE 1811 01:27:01,320 --> 01:27:02,080 TRANSPLANTED ALL THE CHILDREN ON 1812 01:27:02,080 --> 01:27:04,240 OUR LIST SO THE QUESTION IS WHAT 1813 01:27:04,240 --> 01:27:06,480 DO WE DO WITH THE ORGANS? 1814 01:27:06,480 --> 01:27:08,360 THERE WAS A MOMENT WHERE WE 1815 01:27:08,360 --> 01:27:09,880 DECIDED TO GIVE THE ALTRUISTIC 1816 01:27:09,880 --> 01:27:12,960 OR NON-DIRECTED DONORS TO 1817 01:27:12,960 --> 01:27:14,680 SOMEBODY WHO HAD AN INCOMPATIBLE 1818 01:27:14,680 --> 01:27:16,320 DONOR AND THAT PERSON WOULD GIVE 1819 01:27:16,320 --> 01:27:18,640 TO THE PERSON AT THE TOP OF THE 1820 01:27:18,640 --> 01:27:22,600 LIST OF THEIR BLOOD GROUP. 1821 01:27:22,600 --> 01:27:26,600 THIS STARTED OF WHAT WE CALLED A 1822 01:27:26,600 --> 01:27:28,160 DOMINO DONATION BUT IT WAS JUST 1823 01:27:28,160 --> 01:27:32,760 A CHAIN OF TRANSPLANTS. 1824 01:27:32,760 --> 01:27:35,200 WE STARTED DOING THIS NOW NOT 1825 01:27:35,200 --> 01:27:37,280 JUST WITHIN OUR OWN INSTITUTION 1826 01:27:37,280 --> 01:27:39,480 BUT BETWEEN INSTITUTIONS AND 1827 01:27:39,480 --> 01:27:40,760 ALLOWED IT TO DEVELOP OVER A 1828 01:27:40,760 --> 01:27:44,720 PERIOD OF TIME TO CRET LONGER 1829 01:27:44,720 --> 01:27:47,880 CHAINS, KIDNEYS WOULD BE FLOWN 1830 01:27:47,880 --> 01:27:49,720 FROM ONE CENTER TO THE OTHER AND 1831 01:27:49,720 --> 01:27:52,440 YOU DIDN'T HAVE TO SHIP THE 1832 01:27:52,440 --> 01:27:54,640 DONOR, YOU COULD SHIP THE 1833 01:27:54,640 --> 01:27:54,880 KIDNEY. 1834 01:27:54,880 --> 01:27:59,720 THIS HAD A HUGE IMPACT BUT 1835 01:27:59,720 --> 01:28:01,360 NOTFUL IT BECAME A NATIONAL. 1836 01:28:01,360 --> 01:28:05,280 WHEN WE WERE DOING IT THE IMPACT 1837 01:28:05,280 --> 01:28:08,640 WAS PRETTY SMALL BUT PEOPLE WILL 1838 01:28:08,640 --> 01:28:15,400 GET TRANS PLANTED THROUGH 1839 01:28:15,400 --> 01:28:16,760 KIDNEY-PAIR DONATION WHO WOULD 1840 01:28:16,760 --> 01:28:24,720 NOT HAVE OTHERWISE BEEN 1841 01:28:24,720 --> 01:28:30,320 TRANSPLANTED. 1842 01:28:30,320 --> 01:28:32,880 OVERNIGHT 2014 THE NEW KIDNEY 1843 01:28:32,880 --> 01:28:36,720 ALLOCATION SYSTEM IS NOW IN 1844 01:28:36,720 --> 01:28:37,360 CLINICAL PRACTICE. 1845 01:28:37,360 --> 01:28:42,520 AND AS MENTIONED ON THE LEFT OF 1846 01:28:42,520 --> 01:28:44,240 THE SCREEN YOU CAN SEE 1847 01:28:44,240 --> 01:28:46,520 ALLOCATION POINTS WERE GIVEN TO 1848 01:28:46,520 --> 01:28:54,920 PATIENTS AT THE HIGH END OF THE 1849 01:28:54,920 --> 01:29:01,360 CPR STARTING AT 98% CPRA THEY 1850 01:29:01,360 --> 01:29:03,840 GOT AN EXPONENTIAL NUMBER OF 1851 01:29:03,840 --> 01:29:04,280 POINTS. 1852 01:29:04,280 --> 01:29:07,280 PATIENTS WHO WERE 99.5 AND ABOVE 1853 01:29:07,280 --> 01:29:08,920 WERE CALLED 100%. 1854 01:29:08,920 --> 01:29:11,680 THEY WERE ROUND UP. 1855 01:29:11,680 --> 01:29:15,920 THOSE WHO GET 200 POINTS, ONE OF 1856 01:29:15,920 --> 01:29:17,480 THE BIGGEST PROSECUTORS IN THE 1857 01:29:17,480 --> 01:29:22,960 PAST IS THEY WERE ONLY EXPOSED 1858 01:29:22,960 --> 01:29:24,600 TO LOCAL OR REGIONAL ORGANS. 1859 01:29:24,600 --> 01:29:27,480 THE LIKELIHOOD OF FIND MATCH IF 1860 01:29:27,480 --> 01:29:29,200 YOU'RE HIGHLY SENSE TYPE OFFED 1861 01:29:29,200 --> 01:29:30,240 IS MUCH GREATER IF YOU CAN SEE 1862 01:29:30,240 --> 01:29:31,720 EVERY ORGAN THAT COMES OUT IN 1863 01:29:31,720 --> 01:29:36,720 THE COUNTRY. 1864 01:29:36,720 --> 01:29:42,240 THAT'S WHAT THE 200 POINTS DID. 1865 01:29:42,240 --> 01:29:43,360 YOU CAN SEE IN THE PAPER THERE'S 1866 01:29:43,360 --> 01:29:45,160 AN INFLEXION POINT IF YOU TAKE 1867 01:29:45,160 --> 01:29:49,920 THE CPRA OUT TO FOUR DIGITS AND 1868 01:29:49,920 --> 01:29:53,320 AT ABOUT 99.7 THE LIKELIHOOD OF 1869 01:29:53,320 --> 01:29:57,600 A MATCH STARTS TO DROP OFF. 1870 01:29:57,600 --> 01:29:59,920 AT 99.9 YOU'RE REALLY NOT 1871 01:29:59,920 --> 01:30:01,400 IMPROVING THE LIKELIHOOD OF THEM 1872 01:30:01,400 --> 01:30:07,240 FINDING A NACH. 1873 01:30:07,240 --> 01:30:10,080 -- MATCH, NOW, THE DATA ON THE 1874 01:30:10,080 --> 01:30:12,320 NEXT SLIDE I'LL SHOW AFTER THE 1875 01:30:12,320 --> 01:30:14,240 BOLUS PERIOD DURING THE 1876 01:30:14,240 --> 01:30:16,440 STABILITY PERIOD THIS IS WHAT 1877 01:30:16,440 --> 01:30:20,320 THE FATE OF HIGHLY SENSITIZED 1878 01:30:20,320 --> 01:30:24,760 PATIENTS ARE NOW IN THE 1879 01:30:24,760 --> 01:30:27,000 POST/PAST ERA. 1880 01:30:27,000 --> 01:30:30,120 STARTING ON THE LEFT SIDE, THE 1881 01:30:30,120 --> 01:30:35,240 FIRST TWO BARS THE TRANSPLANT 1882 01:30:35,240 --> 01:30:39,960 RATE IS GOOD BUT AS YOU MOVE OUT 1883 01:30:39,960 --> 01:30:42,080 MORE SENSITIZATION NOW AT 99.9 1884 01:30:42,080 --> 01:30:47,120 THAT PATIENT IS MORE LIKELY TO 1885 01:30:47,120 --> 01:30:50,960 DIE GET D LISTED THAN TO GET 1886 01:30:50,960 --> 01:30:52,600 TRANSPLANTED AND ON AVERAGE 1887 01:30:52,600 --> 01:30:54,840 THEY'LL RECEIVE .1 OFFERS A 1888 01:30:54,840 --> 01:30:55,280 YEAR. 1889 01:30:55,280 --> 01:30:56,800 IT WILL TAKE THEM 10 YEARS TO 1890 01:30:56,800 --> 01:31:01,400 GET AN OFFER. 1891 01:31:01,400 --> 01:31:04,720 NOW, IT'S NOT JUST THAT GROUP 1892 01:31:04,720 --> 01:31:04,960 THOUGH. 1893 01:31:04,960 --> 01:31:06,960 SOME INTERESTING THINGS FELL OUT 1894 01:31:06,960 --> 01:31:07,760 AS WELL. 1895 01:31:07,760 --> 01:31:10,960 FIRST, WE USED TO BE ABLE TO 1896 01:31:10,960 --> 01:31:12,560 WITH DESENSITIZATION TRANSPLANT 1897 01:31:12,560 --> 01:31:14,320 A LOT OF PATIENTS WITH A LIVING 1898 01:31:14,320 --> 01:31:16,040 DONOR. 1899 01:31:16,040 --> 01:31:17,200 LIVING DONORS ON AVERAGE LAST 1900 01:31:17,200 --> 01:31:24,880 TWICE AS LONG AS DECEASED OWNER 1901 01:31:24,880 --> 01:31:25,360 KIDNEYS. 1902 01:31:25,360 --> 01:31:29,600 NOW 1.1 PAIR WOULD GET A LIVING 1903 01:31:29,600 --> 01:31:31,400 DONNER BECAUSE ALL THE GROUPS 1904 01:31:31,400 --> 01:31:33,520 DECIDED WE'LL PUT THESE PATIENTS 1905 01:31:33,520 --> 01:31:35,480 ON OUR LIST. 1906 01:31:35,480 --> 01:31:36,760 THEY'VE GOT THIS ADVANTAGE, 1907 01:31:36,760 --> 01:31:38,440 THEY'LL GET TRANSPLANTED. 1908 01:31:38,440 --> 01:31:40,720 THAT'S NOT EXACTLY WHAT 1909 01:31:40,720 --> 01:31:43,480 HAPPENED. 1910 01:31:43,480 --> 01:31:46,320 NOW, 50% OF THE PATIENTS IN THE 1911 01:31:46,320 --> 01:31:47,160 GROUP HAVE GREATER THAN FIVE 1912 01:31:47,160 --> 01:31:50,200 YEARS OF WAITING TIME AND THE 1913 01:31:50,200 --> 01:31:51,640 MORTALITY RATE FOR A PATIENT ON 1914 01:31:51,640 --> 01:31:57,560 THE LIST FOR FIVE YEARS IS 50%. 1915 01:31:57,560 --> 01:32:03,800 ANYONE WITH A CPA OF 98% WE SAW 1916 01:32:03,800 --> 01:32:05,120 NO IMPROVEMENT IN THE WAIT LIST 1917 01:32:05,120 --> 01:32:08,680 MORTALITY AND THE 99.9% WHICH IS 1918 01:32:08,680 --> 01:32:13,440 THE NEW BENCHMARK OF THE 1919 01:32:13,440 --> 01:32:15,880 APPROPRIATE PATIENT TO HAVE IN 1920 01:32:15,880 --> 01:32:19,080 STUDIES THAT LOOK AT 1921 01:32:19,080 --> 01:32:19,720 DESENSITIZATION IT'S ALMOST 1922 01:32:19,720 --> 01:32:28,680 3,000 PATIENTS. 1923 01:32:28,680 --> 01:32:31,360 UNFORTUNATELY THE FDA HAS USED 1924 01:32:31,360 --> 01:32:36,400 THAT AS THEIR LIT MUSS TEST FOR 1925 01:32:36,400 --> 01:32:38,240 THE PATIENT'S THEY'LL CONSIDER 1926 01:32:38,240 --> 01:32:48,800 WHEN ISSUING AN IND BUT THERE'S 1927 01:32:49,480 --> 01:32:54,520 A LOT OF OTHER S THAT ARE 1928 01:32:54,520 --> 01:32:54,960 DISADVANTAGED. 1929 01:32:54,960 --> 01:32:56,520 THIS IS THE STATE OF LAY. 1930 01:32:56,520 --> 01:32:59,680 IF YOU'RE LUCKY ENOUGH TO HAVE A 1931 01:32:59,680 --> 01:33:05,120 LIVING DONOR YOU CAN GO WITH 1932 01:33:05,120 --> 01:33:09,200 LOW-DOSE IVIG OR DONATION SCHEME 1933 01:33:09,200 --> 01:33:11,880 AND GET TRANSPLANTED THAT WAY 1934 01:33:11,880 --> 01:33:14,640 BUT NOT EVERYBODY IN THE PAIR 1935 01:33:14,640 --> 01:33:18,240 DONATION GETS TRANSPLANTED IF 1936 01:33:18,240 --> 01:33:22,480 YOU HAVE A HIGH CPRA YOU'RE IN A 1937 01:33:22,480 --> 01:33:23,640 LARGER POOL. 1938 01:33:23,640 --> 01:33:29,120 IF YOU DON'T HAVE A LIVE DONOR, 1939 01:33:29,120 --> 01:33:34,840 THAN YOU CAN GET IT UP OR WAIT 1940 01:33:34,840 --> 01:33:36,760 ON THE LIST WITH THE ALLOCATION 1941 01:33:36,760 --> 01:33:39,800 PRIORITY. 1942 01:33:39,800 --> 01:33:42,800 BECAUSE MORE PATIENTS HIGHLY 1943 01:33:42,800 --> 01:33:44,760 SENSITIZED WERE GETTING 1944 01:33:44,760 --> 01:33:48,440 TRANSPLANTED THE FIELD BECAME 1945 01:33:48,440 --> 01:33:53,400 COMPLACENT ABOUT DESENSITIZED. 1946 01:33:53,400 --> 01:33:59,080 IT WAS A YOU'LL SEE IN THE 1947 01:33:59,080 --> 01:34:05,720 STUDIES I SHOW YOU THIS HAPPENED 1948 01:34:05,720 --> 01:34:09,760 THEY'VE BEEN CONCEIVED IN THE 1949 01:34:09,760 --> 01:34:17,240 PRE/PAST ERA AND SUDDENLY 1950 01:34:17,240 --> 01:34:20,600 DESENSITIZATION WAS A HUGE 1951 01:34:20,600 --> 01:34:21,080 PROBLEM. 1952 01:34:21,080 --> 01:34:26,040 THIS IS A GROUP OF AGENTS. 1953 01:34:26,040 --> 01:34:30,400 WHEN DESENSITIZATION WAS LESS 1954 01:34:30,400 --> 01:34:32,040 POPULAR AND EQUIPOISE WAS HARDER 1955 01:34:32,040 --> 01:34:33,320 TO DEMONSTRATE WITH THE NEW 1956 01:34:33,320 --> 01:34:35,920 ALLOCATION SYSTEM WE STARTED TO 1957 01:34:35,920 --> 01:34:38,800 LOOK FOR OTHER ALTERNATIVES FOR 1958 01:34:38,800 --> 01:34:43,360 AGENTS THAT WOULD BE MORE POTENT 1959 01:34:43,360 --> 01:34:47,800 AND RELIABLE AND REDUCE THE 1960 01:34:47,800 --> 01:34:50,440 INCIDENTS OF AMR. 1961 01:34:50,440 --> 01:34:51,760 AMR IN THE STRATEGIES THAT HAVE 1962 01:34:51,760 --> 01:34:55,040 SHOWN YOU WAS AS HIGH AS 40% 1963 01:34:55,040 --> 01:35:04,960 AFTER DESENSITIZATION. 1964 01:35:04,960 --> 01:35:05,880 THERE BECAME A LOT OF INTEREST 1965 01:35:05,880 --> 01:35:08,080 IN TRYING TO REDUCE AMR. 1966 01:35:08,080 --> 01:35:12,080 I'LL TELL YOU ABOUT A COUPLE. 1967 01:35:12,080 --> 01:35:15,840 WE MENTIONED THE PROTEOSOMAL 1968 01:35:15,840 --> 01:35:25,720 INHIBITORS THAT TARGET PLASMA 1969 01:35:25,720 --> 01:35:32,640 SELLS AND RITUXIMAB IS AN IL6 1970 01:35:32,640 --> 01:35:36,720 AGENT AND ANTI-CD38 WAS 1971 01:35:36,720 --> 01:35:37,120 MENTIONED. 1972 01:35:37,120 --> 01:35:42,880 A DRUG WHICH IS A VERY 1973 01:35:42,880 --> 01:35:44,560 INTERESTING DRUG WITH 1974 01:35:44,560 --> 01:35:45,080 STIMULATION BLOCKING WE 1975 01:35:45,080 --> 01:35:55,400 MENTIONED AND BLISS. 1976 01:36:00,800 --> 01:36:02,440 NOW, WE HAD COMPLEMENT 1977 01:36:02,440 --> 01:36:06,120 INHIBITORS AND TOLD YOU ABOUT 1978 01:36:06,120 --> 01:36:09,280 THE CDC CROSS MATCH IS HOW YOU 1979 01:36:09,280 --> 01:36:11,640 KILL THE CELLS SO COMPLEMENT IS 1980 01:36:11,640 --> 01:36:12,720 IMPORTANT. 1981 01:36:12,720 --> 01:36:13,400 THERE'S TONS OF COMPLEMENT 1982 01:36:13,400 --> 01:36:19,360 INHIBITORS IN THE PIPELINE FOR 1983 01:36:19,360 --> 01:36:25,200 OTHER DISEASES MOST LY NONE HAV 1984 01:36:25,200 --> 01:36:26,280 BEEN APPROVED FOR 1985 01:36:26,280 --> 01:36:28,760 TRANSPLANTATION SO THEY'VE BEEN 1986 01:36:28,760 --> 01:36:37,360 USED OFF LABEL. 1987 01:36:37,360 --> 01:36:44,000 SO ECULIZUMAB MADE IT THROUGH 1988 01:36:44,000 --> 01:36:48,680 AND IT WAS BASED ON DATA FROM 1989 01:36:48,680 --> 01:36:50,560 THE MAYO CLINIC SHOWING THE RATE 1990 01:36:50,560 --> 01:36:55,560 OF ANTIBODY REJECTION AFTER 1991 01:36:55,560 --> 01:36:59,360 DESENSITIZATION WITH LOW DOSE 1992 01:36:59,360 --> 01:37:01,400 IVIG IF YOU GAVE THIS DRUG FROM 1993 01:37:01,400 --> 01:37:05,440 THE TIME OF THE TRANSPLANT 1994 01:37:05,440 --> 01:37:10,040 WITHOUT MORE PLASMAPHERESIS AND 1995 01:37:10,040 --> 01:37:12,720 IT WILL REMOVE THE DRUG AND IT'S 1996 01:37:12,720 --> 01:37:19,600 THE MOST EXPENSIVE DRUG IN THE 1997 01:37:19,600 --> 01:37:23,720 WORLD AND THEY WERE RANDOMIZED 1998 01:37:23,720 --> 01:37:34,200 TO GOING ON RITUXIMAB AND THE 1999 01:37:38,600 --> 01:37:45,640 PRIMARY END POINT WAS AMR OR 2000 01:37:45,640 --> 01:37:46,680 LOSS OF THE PATIENT IN THE STUDY 2001 01:37:46,680 --> 01:37:49,360 AND YOU CAN SEE THE P VALUE. 2002 01:37:49,360 --> 01:37:54,040 BUT THIS STUDY WAS FLAWED. 2003 01:37:54,040 --> 01:37:58,720 THE FIRST FLAW AND IT COMES TO 2004 01:37:58,720 --> 01:38:04,640 THE ISSUE OF HOW THESE STUDIES 2005 01:38:04,640 --> 01:38:07,400 ARE DESIGN BY PHARMAIN 2006 01:38:07,400 --> 01:38:09,000 COLLABORATION WITH EXPERTS BUT 2007 01:38:09,000 --> 01:38:12,720 THEY DIDN'T -- FIRST, WE DON'T 2008 01:38:12,720 --> 01:38:16,160 EVEN THINK OF AMR OF HAVING 2009 01:38:16,160 --> 01:38:16,720 GREAT. 2010 01:38:16,720 --> 01:38:18,640 IT'S PATHOLOGIST DEFINITION. 2011 01:38:18,640 --> 01:38:21,000 WE THINK OF AMR AS BINARY. 2012 01:38:21,000 --> 01:38:25,080 EITHER YOU HAVE IT OR DON'T. 2013 01:38:25,080 --> 01:38:30,800 THEY DIDN'T INCLUDE GRADE 1 AF 2014 01:38:30,800 --> 01:38:32,920 MR AND THE CENTRAL PATHOLOGISTS 2015 01:38:32,920 --> 01:38:36,520 DIDN'T HAVE CRITICAL DATA. MR 2016 01:38:36,520 --> 01:38:37,120 AND THE CENTRAL PATHOLOGISTS 2017 01:38:37,120 --> 01:38:37,720 DIDN'T HAVE CRITICAL DATA.MR 2018 01:38:37,720 --> 01:38:38,320 AND THE CENTRAL PATHOLOGISTS 2019 01:38:38,320 --> 01:38:39,360 DIDN'T HAVE CRITICAL DATA. 2020 01:38:39,360 --> 01:38:46,440 WHEN WE WENT BACK AND RELO LOLO 2021 01:38:46,440 --> 01:38:48,840 AT THE DATA AND WE SAW THIS WAS 2022 01:38:48,840 --> 01:38:49,760 A NEGATIVE TRIAL. 2023 01:38:49,760 --> 01:38:51,400 SO IT'S OVER. 2024 01:38:51,400 --> 01:38:52,640 ALL THE WORK EVERYBODY HAD DONE 2025 01:38:52,640 --> 01:38:57,840 WAS A NEGATIVE TRIAL. 2026 01:38:57,840 --> 01:39:02,920 SO IF YOU JUST PUT BACK THE 2027 01:39:02,920 --> 01:39:06,760 DEFINITION YOU HAVE A POSITIVE 2028 01:39:06,760 --> 01:39:10,440 TRIAL AND IF YOU GAVE THE 2029 01:39:10,440 --> 01:39:12,040 CENTRAL PATHOLOGIST THE CLINICAL 2030 01:39:12,040 --> 01:39:13,080 DATA IT EVEN BECAME MORE 2031 01:39:13,080 --> 01:39:19,520 POSITIVE WITH THE P VALUE. 2032 01:39:19,520 --> 01:39:23,840 UNFORTUNATELY IN THE MEANTIME, 2033 01:39:23,840 --> 01:39:24,760 THE MAYO GROUP DEMONSTRATED 2034 01:39:24,760 --> 01:39:30,840 WHILE IT WAS GOOD AT REDUCING 2035 01:39:30,840 --> 01:39:36,520 AMR FROM 43% TO 7% WHEN THEY 2036 01:39:36,520 --> 01:39:39,520 FOLLOWED THE PHASE 2 PATIENTS 2037 01:39:39,520 --> 01:39:43,560 OUT FURTHER THERE WAS NO 2038 01:39:43,560 --> 01:39:46,840 DIFFERENCE IN THE CHRONIC 2039 01:39:46,840 --> 01:39:47,080 LESION. 2040 01:39:47,080 --> 01:39:48,760 THE DRUG BASICALLY IS STILL 2041 01:39:48,760 --> 01:39:51,600 BEING USED OFF LABEL BUT IT WAS 2042 01:39:51,600 --> 01:39:53,080 A NEGATIVE TRIAL IN EVERYONE'S 2043 01:39:53,080 --> 01:40:01,720 MIND. 2044 01:40:01,720 --> 01:40:08,720 NOW, IMLIFIDASE WAS A MOLECULE 2045 01:40:08,720 --> 01:40:16,760 ISOLATED AND IT'S AN EFFECTIVE 2046 01:40:16,760 --> 01:40:26,000 BACTERIA IT CLEAVES HUMAN IGG AT 2047 01:40:26,000 --> 01:40:28,720 THE CONSENSUS. 2048 01:40:28,720 --> 01:40:31,120 THE SINGLE CLEAVE IS NO LONGER 2049 01:40:31,120 --> 01:40:31,400 EFFECTIVE. 2050 01:40:31,400 --> 01:40:36,240 IT BASICALLY INHIBITS FC 2051 01:40:36,240 --> 01:40:46,400 MEDIATED ACTIVITY AND ADCC 2052 01:40:46,400 --> 01:40:47,720 PHAGOCYTOSIS AND IT CLEAVES ALL 2053 01:40:47,720 --> 01:40:56,680 FORMS OF IGG BOUND B CELL 2054 01:40:56,680 --> 01:41:01,480 RECEPTORS AND IT'S DISTRIBUTED 2055 01:41:01,480 --> 01:41:04,880 WITHIN ALL THE COMPARTMENTS AND 2056 01:41:04,880 --> 01:41:05,520 BODIES WITHIN HOURS. 2057 01:41:05,520 --> 01:41:08,160 YOU NO LONGER HAVE THE PROBLEM 2058 01:41:08,160 --> 01:41:10,080 OF ACCESS TO THE VASCULAR SPACE. 2059 01:41:10,080 --> 01:41:16,520 YOU CAN GET RID OF ALL THE IGG 2060 01:41:16,520 --> 01:41:21,560 IN THE BODY SO YOU CAN HAVE A 2061 01:41:21,560 --> 01:41:26,080 KIDNEY COME IN WITH A POSITIVE 2062 01:41:26,080 --> 01:41:30,520 CROSS MATCH HOURS LATER HIM TO 2063 01:41:30,520 --> 01:41:32,360 THE TRANSPLANT ROOM. 2064 01:41:32,360 --> 01:41:33,800 IT DOESN'T DO ANYTHING TO THE 2065 01:41:33,800 --> 01:41:35,480 PLASMA CELLS SO WHEN THE DRUG 2066 01:41:35,480 --> 01:41:37,240 WEARS OFF THE ANTIBODIES START 2067 01:41:37,240 --> 01:41:39,280 TO COME BACK IN SOME CASES NOT 2068 01:41:39,280 --> 01:41:39,480 ALL. 2069 01:41:39,480 --> 01:41:44,720 THE SECOND THING IS HUMANS ARE 2070 01:41:44,720 --> 01:41:48,680 RESPONDED TO THESE NASTY LITTLE 2071 01:41:48,680 --> 01:41:51,160 BACTERIA BY HAVING A PRIMED 2072 01:41:51,160 --> 01:41:51,720 IMMUNE SYSTEM. 2073 01:41:51,720 --> 01:41:53,920 IT'S VERY IMMUNOGENIC. 2074 01:41:53,920 --> 01:41:57,320 YOU CAN ONLY GIVE THE ENZYME TWO 2075 01:41:57,320 --> 01:42:00,760 TIMES AND EVERYBODY HAS 2076 01:42:00,760 --> 01:42:06,600 NEUTRALIZING ANTIBODIES. 2077 01:42:06,600 --> 01:42:12,720 WE DID THIS WITH AN NATIONAL 2078 01:42:12,720 --> 01:42:16,680 GROUP WE TOOK LIVE DONORS AND 2079 01:42:16,680 --> 01:42:21,280 THE CROSS MATCH TURNED NEGATIVE 2080 01:42:21,280 --> 01:42:22,520 IN NEARLY EVERY INCIDENCE. 2081 01:42:22,520 --> 01:42:28,760 AND IT CLEAVES HUMAN AND RABBIT 2082 01:42:28,760 --> 01:42:30,800 ANTIBODY AND MOST THE 2083 01:42:30,800 --> 01:42:38,360 THERAPEUTIC ANTIBODIES DEPLETE T 2084 01:42:38,360 --> 01:42:40,200 CELLS YOU HAVE TO GET ATGAM FROM 2085 01:42:40,200 --> 01:42:43,040 AN HOURS OR WAIT SEVERAL DAYS 2086 01:42:43,040 --> 01:42:45,320 UNTIL THE DRUG DISAPPEARS AND 2087 01:42:45,320 --> 01:42:51,200 YOU GET RITUXIMAB AND WITH THIS 2088 01:42:51,200 --> 01:42:53,000 PROTOCOL WE FOUND ALMOST ANYBODY 2089 01:42:53,000 --> 01:42:54,720 COULD BE DESENSITIZED BUT THE 2090 01:42:54,720 --> 01:42:57,760 RATE OF AMR WAS NO DIFFERENT 2091 01:42:57,760 --> 01:43:01,960 THAN IT WAS WITH PLASMAPHERESIS 2092 01:43:01,960 --> 01:43:04,760 AS YOU WOULD EXPECT BECAUSE MOST 2093 01:43:04,760 --> 01:43:15,120 PATIENTS WILL REBOUND. 2094 01:43:16,680 --> 01:43:18,280 YOU TAKE PATIENTS ON THE 2095 01:43:18,280 --> 01:43:24,680 DECEASED OWNER LIST WHO ARE 2096 01:43:24,680 --> 01:43:30,720 99.9% DESENSITIZED AND GET THEIR 2097 01:43:30,720 --> 01:43:33,360 ANTIBODIES DOWN TO AS CLOSE AT 2098 01:43:33,360 --> 01:43:36,640 99.5% AS THEY CAN TO START TO 2099 01:43:36,640 --> 01:43:38,160 GET OFFERS AND THEN YOU GET AN 2100 01:43:38,160 --> 01:43:40,480 OFFER FROM FOR THE PATIENT AND 2101 01:43:40,480 --> 01:43:43,280 BRING THEM IN AND GO OFF THEIR 2102 01:43:43,280 --> 01:43:45,640 VIRTUAL CROSS MATCH, IF IT'S 2103 01:43:45,640 --> 01:43:48,800 POSITIVE THEY GET RANDOMIZED TO 2104 01:43:48,800 --> 01:43:52,080 EITHER STANDARD OF CARE, WHICH 2105 01:43:52,080 --> 01:44:01,240 IS EITHER PLASMAPHERESIS OR IGIG 2106 01:44:01,240 --> 01:44:02,920 AND THE CLOCK IS TICKING. 2107 01:44:02,920 --> 01:44:05,920 MOST THE PATIENTS WITH A 2108 01:44:05,920 --> 01:44:08,560 POSITIVE CROSS-MATCH WON'T GET A 2109 01:44:08,560 --> 01:44:13,600 TRANSPLANT IN THE STANDARD OF 2110 01:44:13,600 --> 01:44:15,280 CARE ON. 2111 01:44:15,280 --> 01:44:19,560 THIS IS ACCRUING PRETTY WELL AND 2112 01:44:19,560 --> 01:44:20,920 THE END POINT IS AT THE END OF 2113 01:44:20,920 --> 01:44:27,160 ONE YEAR. 2114 01:44:27,160 --> 01:44:29,000 NOW, BASED WORK ANNETTE ALREADY 2115 01:44:29,000 --> 01:44:31,320 TOLD YOU WE NOW HAVE ANOTHER 2116 01:44:31,320 --> 01:44:36,520 TRIAL CALLED THE REBOUND TRIAL 2117 01:44:36,520 --> 01:44:47,080 OF PHASE 2 TRIAL BASED ON IF YOU 2118 01:44:47,320 --> 01:44:52,720 GIVE A PROTEOSOMAL INHIBITER YOU 2119 01:44:52,720 --> 01:44:58,040 WILL KILL CANCER CELLS BUT DON'T 2120 01:44:58,040 --> 01:45:00,360 LOWER THE ANTIBODY BUT THERE ARE 2121 01:45:00,360 --> 01:45:04,280 NOW PLASMA BLASTS REFILLING THE 2122 01:45:04,280 --> 01:45:06,480 NICHES AS YOU KILL THE PLASMA 2123 01:45:06,480 --> 01:45:09,120 CELLS THROUGH THE PERIPHERAL 2124 01:45:09,120 --> 01:45:12,400 LYMPHOID TISSUE AND SIGH THE 2125 01:45:12,400 --> 01:45:14,240 WHOLE THING HAPPENING BEFORE 2126 01:45:14,240 --> 01:45:15,000 YOUR EYES. 2127 01:45:15,000 --> 01:45:25,560 IF YOU GIVE THE INHIBITOR THEN 2128 01:45:30,240 --> 01:45:32,440 YOU DEPLETE AT BOTH ENDS. 2129 01:45:32,440 --> 01:45:34,680 WE PUT TWO PATIENTS THROUGH THIS 2130 01:45:34,680 --> 01:45:36,720 AND NEITHER HAD A SIGNIFICANT 2131 01:45:36,720 --> 01:45:44,120 REBOUND. 2132 01:45:44,120 --> 01:45:46,600 WE DID BONE MARROW BIOPSIES AND 2133 01:45:46,600 --> 01:45:48,760 DEMONSTRATE THE MECHANISM IS 2134 01:45:48,760 --> 01:45:51,560 WHAT WE THOUGHT IT WAS. 2135 01:45:51,560 --> 01:45:52,400 UNFORTUNATELY THIS IS THE THING 2136 01:45:52,400 --> 01:45:54,960 ABOUT PHARMA. 2137 01:45:54,960 --> 01:46:00,440 THE COMPANY DOING THE PHASE 3 2138 01:46:00,440 --> 01:46:03,040 TRIAL AT THE SAME TIME IT'S A 2139 01:46:03,040 --> 01:46:09,720 TERRIBLE TIME FOR INVESTMENT IN 2140 01:46:09,720 --> 01:46:11,960 PHARMA AND THEY HAVE TO TURN IT 2141 01:46:11,960 --> 01:46:13,880 INTO AN INVESTIGATOR-INITIATED 2142 01:46:13,880 --> 01:46:14,080 TRIAL. 2143 01:46:14,080 --> 01:46:24,560 WE BELIEVE IN THIS SO I THINK 2144 01:46:27,880 --> 01:46:29,120 THAT'S THE FUTURE AND IT'S THE 2145 01:46:29,120 --> 01:46:31,400 SAME PEOPLE WHEN WE START THE 2146 01:46:31,400 --> 01:46:36,760 STUDY AT THE END AND THE COMPANY 2147 01:46:36,760 --> 01:46:40,160 HAS CHANGED THREE TIMES AND 2148 01:46:40,160 --> 01:46:41,480 DIFFERENT OWNERSHIP SO THIS 2149 01:46:41,480 --> 01:46:45,320 INVOLVES THE UBER WAY TO GO 2150 01:46:45,320 --> 01:46:47,880 ABOUT THIS USING CAR T CELLS AND 2151 01:46:47,880 --> 01:46:53,280 LEVERAGES THE SAME DATA YOU HAVE 2152 01:46:53,280 --> 01:46:59,360 TO BLOCK THE SUPPLY OF NEW 2153 01:46:59,360 --> 01:47:03,680 PLASMA CELLS BY USING CART 19 2154 01:47:03,680 --> 01:47:06,920 AND THE PLASMA CELLS WITH A CART 2155 01:47:06,920 --> 01:47:17,160 AGAINST BCMA. 2156 01:47:22,080 --> 01:47:28,160 THERE'S A DOSE FINDING PHASE AND 2157 01:47:28,160 --> 01:47:38,480 WE'RE USING THIS 2158 01:47:54,840 --> 01:47:58,160 CYCLOPHOSPHAMIDE SO IT'S A 3X3 2159 01:47:58,160 --> 01:48:00,760 CANCER METHODOLOGY AND WE'LL 2160 01:48:00,760 --> 01:48:03,600 DOSE ESCALATE, IF YOU WILL. 2161 01:48:03,600 --> 01:48:11,440 THIS IS A PHASE 1 TRIAL BUT THE 2162 01:48:11,440 --> 01:48:14,240 SECOND END POINT IS A DROP OF 3% 2163 01:48:14,240 --> 01:48:16,840 IF YOU REMEMBER THE GRAPH WILL 2164 01:48:16,840 --> 01:48:27,120 GET YOU MORE. 2165 01:48:35,160 --> 01:48:38,640 AMR EITHER FROM PRE FORMED 2166 01:48:38,640 --> 01:48:41,320 ANTIBODY INCOMPLETELY REMOVED BY 2167 01:48:41,320 --> 01:48:47,320 DESENSITIZATION OR DE NOVO 2168 01:48:47,320 --> 01:48:53,320 ANTIBODY WHICH AGAIN IS A 2169 01:48:53,320 --> 01:48:54,360 FAILURE IN THE T CELL THERAPY 2170 01:48:54,360 --> 01:49:00,760 AND RESPONSIBLE FOR PROBABLY 50% 2171 01:49:00,760 --> 01:49:03,320 OF GRAFT ASSISTS. 2172 01:49:03,320 --> 01:49:04,760 NOW, THE CURRENT PARADIGM FOR A 2173 01:49:04,760 --> 01:49:08,520 LOT OF TRIALS MENTIONED AND THE 2174 01:49:08,520 --> 01:49:09,960 COUPLE I'M GOING TO MENTION NOW 2175 01:49:09,960 --> 01:49:18,000 FOR AMR IS YOU HAVE A GROUP LIKE 2176 01:49:18,000 --> 01:49:19,440 HOURS INTERESTED IN THE SPACE 2177 01:49:19,440 --> 01:49:24,760 WHO FINDS AN EXISTING DRUG IN 2178 01:49:24,760 --> 01:49:25,440 THE AUTOIMMUNE ORPHAN OR 2179 01:49:25,440 --> 01:49:30,640 ONCOLOGY SPACE OR A NEW COMPOUND 2180 01:49:30,640 --> 01:49:33,400 AND IT LOOKS INTERESTING FROM A 2181 01:49:33,400 --> 01:49:34,280 MECHANISTIC STANDPOINT AND LOOKS 2182 01:49:34,280 --> 01:49:40,240 LIKE IT MAY HELP WITH AMR 2183 01:49:40,240 --> 01:49:42,800 DESENSITIZATION AND DO A PHASE 1 2184 01:49:42,800 --> 01:49:48,200 AND 2 TRIAL AND IT'S POWERED TO 2185 01:49:48,200 --> 01:49:49,440 SHOW EFFICACY AND THEN PHARMA 2186 01:49:49,440 --> 01:49:58,480 COMES IN AND USES A SIMILAR 2187 01:49:58,480 --> 01:50:03,280 METHODOLOGY FOR YOUR PROTOCOL 2188 01:50:03,280 --> 01:50:04,440 AND THREW AN ADVISORY BOARD AND 2189 01:50:04,440 --> 01:50:05,280 LAUNCH THE TRIAL. 2190 01:50:05,280 --> 01:50:11,520 THE FLAWS FROM THAT PILOT TRIAL 2191 01:50:11,520 --> 01:50:15,960 ARE CARRIED FORWARD AND NEW ONES 2192 01:50:15,960 --> 01:50:16,800 ARE INTRODUCED BY A PHARMA 2193 01:50:16,800 --> 01:50:21,480 GROUP. 2194 01:50:21,480 --> 01:50:26,760 WHAT WE KNOW IS IF YOU HAVE AN 2195 01:50:26,760 --> 01:50:28,760 ANTIBODY THAT ACTIVATES 2196 01:50:28,760 --> 01:50:29,720 COMPLEMENT AGAINST HLA YOUR 2197 01:50:29,720 --> 01:50:31,840 OUTCOMES ARE GOING TO BE MUCH 2198 01:50:31,840 --> 01:50:41,920 WORSE. 2199 01:50:44,680 --> 01:50:47,440 THE TREATMENT OF AMR BECAME A 2200 01:50:47,440 --> 01:50:48,040 TOPIC FOR INVESTIGATION. 2201 01:50:48,040 --> 01:50:53,160 WE TOOK PATIENTS AT RISK FOR AMR 2202 01:50:53,160 --> 01:50:55,280 AND HAD PREFORMED ANTIBODY AND 2203 01:50:55,280 --> 01:51:01,920 DEVELOP ACUTE AMR40% AFTER THE 2204 01:51:01,920 --> 01:51:06,080 TRANSPLANT AND WE GAVE THEM 2205 01:51:06,080 --> 01:51:16,160 PLASMAPHERESIS AND AN INHIBITOR. 2206 01:51:16,160 --> 01:51:18,000 IT WAS VERY GOOD AT RESOLVING 2207 01:51:18,000 --> 01:51:22,160 THE AMR AND THIS WAS A PLACEBO 2208 01:51:22,160 --> 01:51:32,160 CONTROLLED TRIAL. 2209 01:51:32,160 --> 01:51:38,040 SO WE MAKE ENDOGENOUS C1 2210 01:51:38,040 --> 01:51:39,840 INHIBITOR IN THE BLOOD. 2211 01:51:39,840 --> 01:51:48,520 SO THE PATIENTS HAD MORE C1 2212 01:51:48,520 --> 01:51:52,760 BECAUSE WE WERE GIVING IT 2213 01:51:52,760 --> 01:51:56,760 EXOGENOUS AND THEY HAD 2214 01:51:56,760 --> 01:52:06,800 TRANSPLANT GLOMERULOPATHY AND WE 2215 01:52:06,800 --> 01:52:07,640 SAID OKAY, THAT WILL BE OUR 2216 01:52:07,640 --> 01:52:12,760 PRIMARY OUTCOME. 2217 01:52:12,760 --> 01:52:14,600 SO THEY WENT TO A PHASE 3 TRIAL 2218 01:52:14,600 --> 01:52:16,760 AND AT THE SAME TIME WE WERE 2219 01:52:16,760 --> 01:52:19,480 DOING THIS THE BOTTOM FELL OUT 2220 01:52:19,480 --> 01:52:27,280 OF DESENSITIZATION. 2221 01:52:27,280 --> 01:52:28,760 THERE WERE A LOT WHO WERE 2222 01:52:28,760 --> 01:52:31,440 GETTING TRANSPLANTED WITH THE 2223 01:52:31,440 --> 01:52:38,720 ANTIBODY. 2224 01:52:38,720 --> 01:52:40,760 THIS WAS THE PHASE 3 TRIAL WHICH 2225 01:52:40,760 --> 01:52:49,080 MIRRORED WHAT WE HAD DONE. 2226 01:52:49,080 --> 01:52:52,760 UNFORTUNATELY IT SUFFERED FROM 2227 01:52:52,760 --> 01:53:03,160 AN ENROLLMENT PROBLEM. 2228 01:53:11,800 --> 01:53:13,440 BASICALLY THIS WAS A STRATEGY -- 2229 01:53:13,440 --> 01:53:20,040 THIS TRIAL, THIS IS THE PHASE 2 2230 01:53:20,040 --> 01:53:23,560 THE END POINT WAS CHANGE IN EFR 2231 01:53:23,560 --> 01:53:25,480 AND THE PHASE 2 TRIAL WAS DONE 2232 01:53:25,480 --> 01:53:30,080 BY THE FRENCH GROUP AND 2233 01:53:30,080 --> 01:53:30,360 CONSORTIUM. 2234 01:53:30,360 --> 01:53:32,240 THIS WAS FOR CHRONIC 2235 01:53:32,240 --> 01:53:35,160 UNRESPONSIVE ANTIBODY MEDIATED 2236 01:53:35,160 --> 01:53:41,760 REJECTION USING ANOTHER C1 2237 01:53:41,760 --> 01:53:48,520 INHIBITOR. 2238 01:53:48,520 --> 01:53:53,240 THE PHASE 3 TRIAL MYIRRORED THA 2239 01:53:53,240 --> 01:53:57,480 AND IT'S A LONG PERIOD AND THE 2240 01:53:57,480 --> 01:53:59,280 PATIENTS GET AN INITIAL ATTEMPT 2241 01:53:59,280 --> 01:54:01,480 OF TREATING THE AMR AND IF IT 2242 01:54:01,480 --> 01:54:04,760 PERSISTS THEY GET RANDOMIZED TO 2243 01:54:04,760 --> 01:54:08,760 HIGH DOSE IVIG PLUS C1 PLUS 2244 01:54:08,760 --> 01:54:11,760 PLACEBO OVER A LONG PERIOD OF 2245 01:54:11,760 --> 01:54:13,440 TIME AND FOUR YEARS OF 2246 01:54:13,440 --> 01:54:13,760 FOLLOW-UP. 2247 01:54:13,760 --> 01:54:15,400 WORRIED ABOUT THE TRIAL. 2248 01:54:15,400 --> 01:54:20,840 IT'S ENROLLING REASONABLY WELL 2249 01:54:20,840 --> 01:54:29,360 NOT GREAT. 2250 01:54:29,360 --> 01:54:32,600 THEY'RE HAVING TO BRING THEM IN 2251 01:54:32,600 --> 01:54:36,400 EVERY MONTH. 2252 01:54:36,400 --> 01:54:40,760 SAME STORY WITH THE IL6 AGENTS. 2253 01:54:40,760 --> 01:54:43,480 THIS WAS THE STAN JORDAN PHASE 2254 01:54:43,480 --> 01:54:50,440 1, PHASE 2 TRIAL. 2255 01:54:50,440 --> 01:54:56,040 THIS IS THE PHASE 3 TRIAL WHICH 2256 01:54:56,040 --> 01:54:59,560 THERE'S NO TREATMENT FOR CHRONIC 2257 01:54:59,560 --> 01:55:00,760 ACTIVE AMR. 2258 01:55:00,760 --> 01:55:05,120 ONCE YOU DEVELOP IT YOUR TIME OF 2259 01:55:05,120 --> 01:55:11,120 HAVING THAT TRANSPLANT IS 2260 01:55:11,120 --> 01:55:11,840 GREATLY CURTAILED. 2261 01:55:11,840 --> 01:55:16,760 THERE'S NO FOR IT. 2262 01:55:16,760 --> 01:55:19,240 WE WERE FORTUNATE TO HAVE THAT 2263 01:55:19,240 --> 01:55:23,880 WITH THE PLACEBO VERSUS THE IL6 2264 01:55:23,880 --> 01:55:24,320 BLOCKING AGENT. 2265 01:55:24,320 --> 01:55:30,800 THIS IS STILL ENROLLING 2266 01:55:30,800 --> 01:55:32,160 OBVIOUSLY COVID HAD A BIG IMPACT 2267 01:55:32,160 --> 01:55:35,240 ONLY BOTH TRIALS. 2268 01:55:35,240 --> 01:55:37,480 ANYWAY, THAT'S AN ATTEMPT TO 2269 01:55:37,480 --> 01:55:42,600 SUMMARIZE 30 YEARS OF MOSTLY 2270 01:55:42,600 --> 01:55:43,480 MESSY CLINICAL TRIALS IN THE 2271 01:55:43,480 --> 01:55:51,800 SPACE. 2272 01:55:51,800 --> 01:55:53,120 I THINK THERE'S INTERESTING 2273 01:55:53,120 --> 01:55:56,360 POSSIBILITIES AHEAD OF US BUT I 2274 01:55:56,360 --> 01:55:57,560 SAID THAT 20 YEARS AGO. 2275 01:55:57,560 --> 01:55:59,000 THESE ARE REALLY DIFFICULT 2276 01:55:59,000 --> 01:56:00,600 TRIALS TO DO THESE THINGS. 2277 01:56:00,600 --> 01:56:06,240 SORRY, WE RAN A LITTLE BIT OVER. 2278 01:56:06,240 --> 01:56:08,760 I DON'T KNOW IF WE HAVE TIME FOR 2279 01:56:08,760 --> 01:56:19,280 QUESTIONS BUT I'LL BE AROUND. 2280 01:56:30,600 --> 01:56:36,560 >> 2281 01:56:36,560 --> 01:56:38,720 >>'M WONDERING IF THERE'S BEEN 2282 01:56:38,720 --> 01:56:44,760 ENOUGH UPTAKE THERE TO GET A 2283 01:56:44,760 --> 01:56:48,760 LITTLE BIT MORE AND IF YOU 2284 01:56:48,760 --> 01:56:52,760 WANTED TO SPECULATE DIFFERENCE 2285 01:56:52,760 --> 01:56:58,080 IN ALLOCATION AND TAKES CARE OF 2286 01:56:58,080 --> 01:57:00,160 THE PROBLEM WITH THE DIFFERENT 2287 01:57:00,160 --> 01:57:00,880 ALLOCATION SYSTEM IN EUROPE. 2288 01:57:00,880 --> 01:57:04,480 DIFFERENT ENVIRONMENT. 2289 01:57:04,480 --> 01:57:07,000 >> THEIRS IS CALLED THE 2290 01:57:07,000 --> 01:57:09,640 ACCEPTABLE MISMATCH ALLOCATION 2291 01:57:09,640 --> 01:57:10,360 SYSTEM. 2292 01:57:10,360 --> 01:57:13,560 IT BASICALLY DOES WHAT WE DO 2293 01:57:13,560 --> 01:57:15,800 WITH TAS GETTING TO THE SAME END 2294 01:57:15,800 --> 01:57:16,240 POINT. 2295 01:57:16,240 --> 01:57:22,200 I THINK THEY'RE STRUGGLING QUITE 2296 01:57:22,200 --> 01:57:24,040 A BIT. 2297 01:57:24,040 --> 01:57:28,040 IN THE PHASE 2 TRIAL THE FDA 2298 01:57:28,040 --> 01:57:28,800 INSISTED ON PLACEBO CONTROLLED 2299 01:57:28,800 --> 01:57:37,040 PHASE 3 TRIAL. 2300 01:57:37,040 --> 01:57:39,400 I WOULD SAY THE UPTAKE HASN'T 2301 01:57:39,400 --> 01:57:40,560 BEEN GREAT. 2302 01:57:40,560 --> 01:57:43,160 THERE'S A HANDFUL OF CENTERS 2303 01:57:43,160 --> 01:57:46,440 WITH A HISTORY LIKE THE PARIS 2304 01:57:46,440 --> 01:57:48,400 CONSORTIUM OF DOING 2305 01:57:48,400 --> 01:57:49,880 DESENSITIZATION AND IT'S EASIER 2306 01:57:49,880 --> 01:57:51,160 FOR THEM TO UNDERSTAND WHICH 2307 01:57:51,160 --> 01:57:54,680 PATIENTS ARE GOOD HAND DATES FOR 2308 01:57:54,680 --> 01:57:58,760 THE DRUG. 2309 01:57:58,760 --> 01:58:03,840 -- GOOD CANDIDATES AND IT'S SO 2310 01:58:03,840 --> 01:58:06,320 POTENT YOU CAN GET IN TROUBLE. 2311 01:58:06,320 --> 01:58:11,920 IF YOU TAKE SOMEBODY IN WITH 2312 01:58:11,920 --> 01:58:15,360 HIGH LEVELS OR AGAINST THEIR 2313 01:58:15,360 --> 01:58:20,280 DONOR, WHEN THE REBOUND OCCURS 2314 01:58:20,280 --> 01:58:26,240 IT'S GOING TO BE ONE OR TWO OF 2315 01:58:26,240 --> 01:58:30,600 THOSE AND THE RUMORS AND 2316 01:58:30,600 --> 01:58:31,440 ENTHROUGHSIASM. 2317 01:58:31,440 --> 01:58:36,760 YOU HAVE TO UNDERSTAND IT TO 2318 01:58:36,760 --> 01:58:40,560 AVOID THIS SITUATION. 2319 01:58:40,560 --> 01:58:42,400 >> A QUICK QUESTION AND FEEL 2320 01:58:42,400 --> 01:58:48,080 FREE NOT TO ANSWER IF YOU DON'T 2321 01:58:48,080 --> 01:58:54,560 WANT BUT WHAT DO YOU THINK WE AT 2322 01:58:54,560 --> 01:58:58,840 THE NIH COULD DO TO ALLEVIATE 2323 01:58:58,840 --> 01:59:00,760 WHAT YOU BROUGHT UP WITH THE 2324 01:59:00,760 --> 01:59:01,280 MESSY CLINICAL TRIALS? 2325 01:59:01,280 --> 01:59:11,760 >>T'S A GREAT QUESTION. 2326 01:59:11,760 --> 01:59:12,960 QUIN OF THE PROBLEMS WITH THE 2327 01:59:12,960 --> 01:59:20,000 FDA I SEE MAYBE CHANGING IS THAT 2328 01:59:20,000 --> 01:59:22,840 WE NOW HAVE A BUNCH OF DRUGS AND 2329 01:59:22,840 --> 01:59:24,760 INTERVENTIONS EACH BY THEMSELVES 2330 01:59:24,760 --> 01:59:34,520 DOESN'T DO THE WHOLE JOB. 2331 01:59:34,520 --> 01:59:36,760 BUT I'M CERTAIN IN COMBINATION 2332 01:59:36,760 --> 01:59:38,920 WITH EACH OTHER IT WOULD BE A 2333 01:59:38,920 --> 01:59:39,920 DIFFERENT PICTURE. 2334 01:59:39,920 --> 01:59:43,400 THAT'S SOMETHING UP UNTIL 2335 01:59:43,400 --> 01:59:47,360 RECENTLY THE FDA HAS NOT BEEN 2336 01:59:47,360 --> 01:59:48,800 COMFORTABLE WITH COMBINING TWO 2337 01:59:48,800 --> 01:59:49,600 EXPERIMENTAL OR THREE 2338 01:59:49,600 --> 01:59:50,760 EXPERIMENTAL DRUG TOGETHER. 2339 01:59:50,760 --> 01:59:55,720 AGAIN, WE DON'T HAVE A LABEL FOR 2340 01:59:55,720 --> 02:00:02,480 ANYTHING.NOT EVEN, PLASMA FOR 2341 02:00:02,480 --> 02:00:03,680 PHERESIS HAS BEEN RECOGNIZED BUT 2342 02:00:03,680 --> 02:00:06,280 IT'S NOT LABELLED SO. 2343 02:00:06,280 --> 02:00:08,760 SO I THINK THAT ONE THING THAT 2344 02:00:08,760 --> 02:00:18,840 COULD REALLY HELP IS TO ALLOW US 2345 02:00:18,840 --> 02:00:23,600 THAT FREEDOM TO COMBINE ONCE THE 2346 02:00:23,600 --> 02:00:26,520 SAFETY OF EACH DRUG HAS BEEN 2347 02:00:26,520 --> 02:00:27,200 PRETTY CLEARLY SHOWN TO COMBINE 2348 02:00:27,200 --> 02:00:37,560 THE MODALITIES TODAY. 2349 02:00:56,000 --> 02:00:58,000 [OFF-MIC] 2350 02:00:58,000 --> 02:01:00,800 >>T IS BUT IT'S NEVER BEEN 2351 02:01:00,800 --> 02:01:11,120 THOUGHT OF THAT WAY. 2352 02:01:31,320 --> 02:01:31,800 [OFF-MIC] 2353 02:01:31,800 --> 02:01:35,640 TO THE OTHER PROBLEM IS YOU 2354 02:01:35,640 --> 02:01:37,440 DON'T HAVE THE CONSTITUENCY AS 2355 02:01:37,440 --> 02:01:39,240 IN CANCER OR AIDS. 2356 02:01:39,240 --> 02:01:40,760 WE DON'T HAVE A BUNCH OF PISSED 2357 02:01:40,760 --> 02:01:42,040 OFF PEOPLE. 2358 02:01:42,040 --> 02:01:45,840 WE HAVE A FEW PEOPLE WHO GOT A 2359 02:01:45,840 --> 02:01:47,960 TRANSPLANT AND FEEL SUPER LUCKY. 2360 02:01:47,960 --> 02:01:50,360 THEY FEEL THEY CAN'T SAY 2361 02:01:50,360 --> 02:01:52,000 ANYTHING BECAUSE SOMEBODY ELSE 2362 02:01:52,000 --> 02:01:54,760 HAD TO DIE IN ORDER FOR THAT TO 2363 02:01:54,760 --> 02:01:55,720 HAPPEN. 2364 02:01:55,720 --> 02:02:00,760 WE DON'T HAVE A GOOD PATIENT 2365 02:02:00,760 --> 02:02:03,600 ADVOCACY SO IT'S EASIER TO 2366 02:02:03,600 --> 02:02:04,320 IGNORE IT AND IT'S COMMISSION 2367 02:02:04,320 --> 02:02:14,600 VERSUS OMISSION. 2368 02:02:27,320 --> 02:02:32,400 >> THERE'S INDUSTRY PARTNERSHIP 2369 02:02:32,400 --> 02:02:36,200 AND THE CLINICAL IS WAY MORE 2370 02:02:36,200 --> 02:02:36,560 INTERESTING. 2371 02:02:36,560 --> 02:02:42,600 >> WE'RE SUPER EXCITED ABOUT 2372 02:02:42,600 --> 02:02:42,800 CTOC. 2373 02:02:42,800 --> 02:02:44,760 THAT IS GOING TO BE DRAMATIC ONE 2374 02:02:44,760 --> 02:02:55,080 WAY OR THE OTHER. 2375 02:02:59,880 --> 02:03:00,760 WE ARE A LITTLE BIT BEHIND TIME 2376 02:03:00,760 --> 02:03:03,320 BUT WELL WORTH SPENDING TIME ON 2377 02:03:03,320 --> 02:03:07,920 THESE TERRIFIC TALKS. 2378 02:03:07,920 --> 02:03:12,760 YOU'LL START OFF WITH THE 2379 02:03:12,760 --> 02:03:14,400 CONCEPT CLEARANCE. 2380 02:03:14,400 --> 02:03:16,160 I'LL ASK TO YOU INTRODUCE 2381 02:03:16,160 --> 02:03:16,760 YOURSELF AND SAME FOR YOUR 2382 02:03:16,760 --> 02:03:17,040 COLLEAGUES. 2383 02:03:17,040 --> 02:03:20,560 >> OKAY. 2384 02:03:20,560 --> 02:03:24,720 >>'M A PROGRAM OFFICER IN THE 2385 02:03:24,720 --> 02:03:28,760 BASIC IMMUNOLOGY BRANCH, KENTNER 2386 02:03:28,760 --> 02:03:32,360 SINGLETON AND YOU'LL GET A TWO 2387 02:03:32,360 --> 02:03:33,000 FOR HERE. 2388 02:03:33,000 --> 02:03:35,880 I'LL BE PRESENTING TWO FY25 2389 02:03:35,880 --> 02:03:37,240 INITIATIVE CONCEPTS WHERE THE 2390 02:03:37,240 --> 02:03:40,480 GOAL IS TO SUPPORT RESEARCH TO 2391 02:03:40,480 --> 02:03:41,120 ADVANCE OUR UNDERSTANDING OF THE 2392 02:03:41,120 --> 02:03:47,120 SYSTEM. 2393 02:03:47,120 --> 02:03:49,960 AND THE W.H.O. ESTIMATED 75% OF 2394 02:03:49,960 --> 02:03:51,720 EMERGING DISEASES COME FROM 2395 02:03:51,720 --> 02:03:53,920 ZOONOTIC PATHOGENS BUT THE 2396 02:03:53,920 --> 02:03:54,800 MAJORITY ARE COMING FROM BATS 2397 02:03:54,800 --> 02:03:56,760 AND MICE. 2398 02:03:56,760 --> 02:03:59,160 WHAT WE KNOW ARE THAT BATS CAN 2399 02:03:59,160 --> 02:04:02,040 SERVE AS RESERVOIR HOSTS FOR A 2400 02:04:02,040 --> 02:04:06,920 NUMBER OF HUMAN PATHOGENS 2401 02:04:06,920 --> 02:04:08,760 INCLUDING CORONAVIRUS AND RABIES 2402 02:04:08,760 --> 02:04:13,000 AND FOR MANY VIRUSES THEY CAN 2403 02:04:13,000 --> 02:04:17,040 ELICIT IN HUMANS A STORM OF 2404 02:04:17,040 --> 02:04:18,920 CYTOKINES THAT RESULTS IN 2405 02:04:18,920 --> 02:04:20,720 INFORMATION AND TISSUE DAMAGE 2406 02:04:20,720 --> 02:04:22,000 AND ULTIMATELY PATHOLOGY AND 2407 02:04:22,000 --> 02:04:27,040 POTENTIALLY DEATH IN HUMANS. 2408 02:04:27,040 --> 02:04:30,000 HOWEVER, BATS APPEAR TO BE WELL 2409 02:04:30,000 --> 02:04:31,720 ADAPTED TO THE RESULTING 2410 02:04:31,720 --> 02:04:38,920 INFORMATION. 2411 02:04:38,920 --> 02:04:40,520 THESE APPEAR TO BE WELL ADAPTED 2412 02:04:40,520 --> 02:04:42,640 AT PREVENTING OR RESOLVING THE 2413 02:04:42,640 --> 02:04:46,840 INFORMATION WHILE STILL 2414 02:04:46,840 --> 02:04:55,240 CONTROLLING THE PATHOGEN. 2415 02:04:55,240 --> 02:04:57,760 SO WE KNOW INFORMATION ABOUT THE 2416 02:04:57,760 --> 02:04:59,640 SYSTEM AND THEY SHARE COMPONENT 2417 02:04:59,640 --> 02:05:01,040 WITH HUMANS. 2418 02:05:01,040 --> 02:05:04,280 THEY HAVE T CELL RECEPTORS AND 2419 02:05:04,280 --> 02:05:07,280 MCH CLASS 1 AND 2 AND HAVE 2420 02:05:07,280 --> 02:05:12,760 ANTIBODIES AND THEY HAVE BEEN 2421 02:05:12,760 --> 02:05:15,560 FORMALIZED AND THEY CAN 2422 02:05:15,560 --> 02:05:17,040 RECOGNIZE AND BIND TO PATHOGENS. 2423 02:05:17,040 --> 02:05:23,400 THEY ALSO HAVE THE SAME FAMILY 2424 02:05:23,400 --> 02:05:24,000 OF CYTOKINES. 2425 02:05:24,000 --> 02:05:31,040 THERE ARE SOME DIFFERENCES BATS 2426 02:05:31,040 --> 02:05:36,040 HAVE SO BATS CAN CLEAR VIRAL 2427 02:05:36,040 --> 02:05:37,320 INFECTIONS HOWEVER, DIFFERENT 2428 02:05:37,320 --> 02:05:39,800 BAT SPECIES CAN TAKE DIFFERENT 2429 02:05:39,800 --> 02:05:42,880 APPROACH IN CONTROLLING AND 2430 02:05:42,880 --> 02:05:46,040 CLEARING THE INFECTIONS. 2431 02:05:46,040 --> 02:05:50,240 SOME BATS HAVE ALPHA GENES BUT 2432 02:05:50,240 --> 02:06:00,200 CAN EXPRESS THEIR mRNA THING 2433 02:06:00,200 --> 02:06:03,200 CAN UPREGULATE THE IMMUNE 2434 02:06:03,200 --> 02:06:08,720 RESPONSE AND DOWNREGULATE BACK 2435 02:06:08,720 --> 02:06:08,920 DOWN. 2436 02:06:08,920 --> 02:06:15,720 OTHER BATS DON'T EXPRESS mRNA 2437 02:06:15,720 --> 02:06:20,600 BUT HAVE EXPANDED INTERFERON 2438 02:06:20,600 --> 02:06:20,800 OMEGA. 2439 02:06:20,800 --> 02:06:24,760 THAT HAS 22 INTERFERON OMEGAS IN 2440 02:06:24,760 --> 02:06:27,760 CONTRAST TO HUMANS WITH MICE AND 2441 02:06:27,760 --> 02:06:29,880 ONE COMMON THING THAT'S COME UP 2442 02:06:29,880 --> 02:06:34,200 OVER AND OVER AGAIN THE LIMITED 2443 02:06:34,200 --> 02:06:35,760 BAT RESEARCH THAT'S OCCURRED IS 2444 02:06:35,760 --> 02:06:43,480 BATS HAVE EVOLVES TO AVOID 2445 02:06:43,480 --> 02:06:47,200 INFLAMMATION. 2446 02:06:47,200 --> 02:06:48,320 NOM KNOWLEDGE GAPS AROUND 2447 02:06:48,320 --> 02:06:49,960 RESEARCH AND THERE'S LITTLE 2448 02:06:49,960 --> 02:06:52,120 KNOWN ABOUT THE IMMUNE RESPONSE 2449 02:06:52,120 --> 02:06:55,480 TO THE PATHOGENS AND WHY THEY'RE 2450 02:06:55,480 --> 02:07:03,120 NOT PRESENTING WITH DISEASE. 2451 02:07:03,120 --> 02:07:04,560 WRL OF ONE ISSUE IS THEY'RE 2452 02:07:04,560 --> 02:07:06,480 LIMITING AND IF YOU CAN'T DO THE 2453 02:07:06,480 --> 02:07:11,960 PHENOTYPING IT CAN LIMIT YOUR 2454 02:07:11,960 --> 02:07:12,720 STUDIES SIMILARLY IF YOU DON'T 2455 02:07:12,720 --> 02:07:16,080 HAVE THE CYTOKINES IT CAN LIMIT 2456 02:07:16,080 --> 02:07:18,320 THE STUDIES YOU CAN END UP WITH 2457 02:07:18,320 --> 02:07:23,920 AND ONE OF THE OPPORTUNITIES 2458 02:07:23,920 --> 02:07:26,320 FROM HERE IS UNDERSTANDING THE 2459 02:07:26,320 --> 02:07:27,600 MAJOR S BUT IT'S TWEAKED AND 2460 02:07:27,600 --> 02:07:30,560 THEY HAVE DIFFERENCES IN THE 2461 02:07:30,560 --> 02:07:35,240 REGULATORY CIRCUITS TO PROVIDE 2462 02:07:35,240 --> 02:07:37,000 INSIGHTS ON THERAPEUTIC 2463 02:07:37,000 --> 02:07:39,920 APPROACHES WE CAN TAKE FOR 2464 02:07:39,920 --> 02:07:43,480 TREATING PEOPLE THAT HAVE BEEN 2465 02:07:43,480 --> 02:07:49,280 AFFECTED WITH THE PATHOGENS. 2466 02:07:49,280 --> 02:07:51,040 THESE ARE THE PROPOSED 2467 02:07:51,040 --> 02:07:51,320 INITIATIVES. 2468 02:07:51,320 --> 02:07:56,000 THE FIRST IS THE RESEARCH 2469 02:07:56,000 --> 02:07:56,280 COMPONENT. 2470 02:07:56,280 --> 02:07:59,560 THE RESEARCH COMPONENT MAY BE ON 2471 02:07:59,560 --> 02:08:04,520 THE MECHANISM AND UNDERSTAND THE 2472 02:08:04,520 --> 02:08:07,240 PROTECTIVE IMMUNE MECHANISM FOR 2473 02:08:07,240 --> 02:08:09,640 THE POTENTIAL OF HARBORING 2474 02:08:09,640 --> 02:08:11,360 ZOONOTIC PATHOGENS AND PROPOSE 2475 02:08:11,360 --> 02:08:16,840 AN RO1 STYLE MECHANISM AND THE 2476 02:08:16,840 --> 02:08:20,360 PROJECT FOR FIVE YEARS. 2477 02:08:20,360 --> 02:08:23,440 IN PARALLEL WE PROPOSE TO 2478 02:08:23,440 --> 02:08:24,680 ANOTHER INITIATIVE TO SUPPORT 2479 02:08:24,680 --> 02:08:26,320 REAGENT DEVELOPMENT. 2480 02:08:26,320 --> 02:08:28,280 THIS IS TO SUPPORT THE 2481 02:08:28,280 --> 02:08:31,520 DEVELOPMENT OF ANTIBODIES, 2482 02:08:31,520 --> 02:08:33,720 CYTOKINES TO SUPPORT THE 2483 02:08:33,720 --> 02:08:36,760 IMMUNOLOGICAL STUDIES CONDUCTED 2484 02:08:36,760 --> 02:08:40,120 NOT ONLY BY THE R01 GRANTS AND 2485 02:08:40,120 --> 02:08:41,320 COMMUNITY AS A WHOLE. 2486 02:08:41,320 --> 02:08:43,320 THE CRITICAL COMPONENT IS THE 2487 02:08:43,320 --> 02:08:45,600 VALIDATION OF REAGENTS ACROSS 2488 02:08:45,600 --> 02:08:46,920 BAT SPECIES AND THEY'LL DO THAT 2489 02:08:46,920 --> 02:08:51,760 ON THEIR OWN AND IN PARTNERSHIP 2490 02:08:51,760 --> 02:08:55,680 WITH THE RO1 USING THE U24 2491 02:08:55,680 --> 02:08:56,400 MECHANISM. 2492 02:08:56,400 --> 02:08:58,640 IT'S A COOPERATIVE AGREEMENT AND 2493 02:08:58,640 --> 02:08:59,160 SUBSTANTIAL PROGRAMMATIC 2494 02:08:59,160 --> 02:09:01,400 INVOLVEMENT WITH THE GRANTEE FOR 2495 02:09:01,400 --> 02:09:04,760 DEVELOPMENT OF THE AGENTS AND TO 2496 02:09:04,760 --> 02:09:10,320 WORK WITH THEM ALONG WITH THE 2497 02:09:10,320 --> 02:09:12,080 BAT COMMUNITY TO DIRECT THEM ON 2498 02:09:12,080 --> 02:09:13,480 WHAT ARE NEEDED TO MOVE THE 2499 02:09:13,480 --> 02:09:15,320 RESEARCH FORWARD. 2500 02:09:15,320 --> 02:09:18,000 WITH THE RO1s WE EXPECT IT'D BE 2501 02:09:18,000 --> 02:09:21,560 A FIVE-YEAR GRANT AWARD. 2502 02:09:21,560 --> 02:09:23,360 WE SEE THESE TWO MECHANISMS 2503 02:09:23,360 --> 02:09:24,120 WORKING TOGETHER. 2504 02:09:24,120 --> 02:09:26,080 WE'D HAVE AN ANNUAL MEETING TO 2505 02:09:26,080 --> 02:09:27,800 BRING EVERYONE TOGETHER TO 2506 02:09:27,800 --> 02:09:28,960 DISCUSS IN PERSON. 2507 02:09:28,960 --> 02:09:32,800 THIS IS SOMETHING THAT'S WORKED 2508 02:09:32,800 --> 02:09:34,480 WELL FOR US IN OTHER INITIATIVES 2509 02:09:34,480 --> 02:09:37,520 AND LAY A FOUNDATION FOR THE 2510 02:09:37,520 --> 02:09:39,320 FIELD FROM WHICH IT CAN GROW 2511 02:09:39,320 --> 02:09:41,760 AFTER THE INITIATIVES ARE 2512 02:09:41,760 --> 02:09:43,480 COMPLETE. 2513 02:09:43,480 --> 02:09:44,520 WITH THAT I'M HAPPY TO ANSWER 2514 02:09:44,520 --> 02:09:54,760 ANY QUESTIONS. 2515 02:10:13,120 --> 02:10:13,760 >> GOOD AFTERNOON. 2516 02:10:13,760 --> 02:10:21,160 I'M MARILYN AND I'M A PROGRAM 2517 02:10:21,160 --> 02:10:27,000 OFFICER. 2518 02:10:27,000 --> 02:10:32,160 IT WAS ESTABLISHED IN 2004 AND 2519 02:10:32,160 --> 02:10:40,920 WE TAKE OUR RESEARCH AND MY 2520 02:10:40,920 --> 02:10:44,200 FOCUS FOR THIS INITIATIVE IS 2521 02:10:44,200 --> 02:10:47,880 GOING TO BE ON THE MISSION 2522 02:10:47,880 --> 02:10:48,080 SPACE. 2523 02:10:48,080 --> 02:10:54,760 WE HAVE THREE SPECIFIC ENTRIES. 2524 02:10:54,760 --> 02:10:59,680 ONE IS TRIAGE AND DISASTER AND 2525 02:10:59,680 --> 02:11:02,640 FOR THOSE CONCERNED THAT MAY BE 2526 02:11:02,640 --> 02:11:07,480 EXPOSED TO RADIATION AND THOSE 2527 02:11:07,480 --> 02:11:12,760 ACTUALLY EXPOSED AND FIRST 2528 02:11:12,760 --> 02:11:18,920 RESPONDERS ARE TRIAGED AND THIS 2529 02:11:18,920 --> 02:11:20,640 WILL HELP THE MEDICAL COMMUNITY 2530 02:11:20,640 --> 02:11:22,920 TO COME UP WITH STRATEGIES TO 2531 02:11:22,920 --> 02:11:24,760 TREAT THEM AND ADVISE THEM HOW 2532 02:11:24,760 --> 02:11:26,760 TO COME UP WITH THE FOLLOW-UP 2533 02:11:26,760 --> 02:11:30,440 STRATEGY. 2534 02:11:30,440 --> 02:11:32,360 ANOTHER ASPECT TO OUR PORTFOLIO 2535 02:11:32,360 --> 02:11:40,760 IS THE PREDICTIVE ASPECT AND TO 2536 02:11:40,760 --> 02:11:44,760 SAY WHAT IS THE OUTCOME OF THE 2537 02:11:44,760 --> 02:11:51,040 EXPOSURE TAKING INTO ACCOUNT THE 2538 02:11:51,040 --> 02:11:58,160 SENSITIVITY AND THE AIM AND 2539 02:11:58,160 --> 02:12:00,120 PERHAPS DIETARY STATUS AND ALL 2540 02:12:00,120 --> 02:12:05,600 FACTOR INTO THE OUTCOME 2541 02:12:05,600 --> 02:12:06,080 EXPOSURE. 2542 02:12:06,080 --> 02:12:16,840 AND WE USE A PLETHORA OF GRANT 2543 02:12:16,840 --> 02:12:18,680 MECHANISMS. 2544 02:12:18,680 --> 02:12:27,320 OUR RESEARCH SUPPORT WE HAVE A 2545 02:12:27,320 --> 02:12:31,080 HUGE FOCUS AND WE REGISTER WITH 2546 02:12:31,080 --> 02:12:33,640 THE AGENCY BECAUSE WE NEED THIS 2547 02:12:33,640 --> 02:12:34,960 COLLABORATION TO ADVANCE OUR 2548 02:12:34,960 --> 02:12:37,200 DEVICES AND IN ADDITION TO THAT 2549 02:12:37,200 --> 02:12:39,920 WE HAVE DEEP CONNECTIONS WITH 2550 02:12:39,920 --> 02:12:40,760 SISTER AGENCIES AS WELL AS 2551 02:12:40,760 --> 02:12:43,480 COMPANIES AND ACADEMIA THAT 2552 02:12:43,480 --> 02:12:47,400 ACTUALLY DO THE RESEARCH. 2553 02:12:47,400 --> 02:12:49,600 I CAN'T EMPHASIZE ENOUGH WHY THE 2554 02:12:49,600 --> 02:12:50,840 INTERACTIONS ARE IMPORTANT 2555 02:12:50,840 --> 02:12:54,360 BECAUSE TO DATE WE DON'T HAVE A 2556 02:12:54,360 --> 02:12:55,480 SINGLE DEVICE THAT'S BEEN FDA 2557 02:12:55,480 --> 02:12:59,080 CLEARED FOR USE FOR HUMANS WITH 2558 02:12:59,080 --> 02:13:02,440 CLEAR INCIDENT. 2559 02:13:02,440 --> 02:13:12,760 THIS PARTICULAR U01 WE 2560 02:13:12,760 --> 02:13:17,200 ANTICIPATE IF PEOPLE COME TO US 2561 02:13:17,200 --> 02:13:22,280 IF THEY COME TO US WITH WE WON'T 2562 02:13:22,280 --> 02:13:24,800 SEE IT BECOME READY TO GET A 2563 02:13:24,800 --> 02:13:25,640 CONTRACTOR A MORE ADVANCED 2564 02:13:25,640 --> 02:13:31,640 FUNDING MECHANISM. 2565 02:13:31,640 --> 02:13:34,840 THIS IS A QUICK SNAPSHOT OF THE 2566 02:13:34,840 --> 02:13:36,000 PORTFOLIO. 2567 02:13:36,000 --> 02:13:39,200 WE'VE HAD SEVERAL VERY EARLY 2568 02:13:39,200 --> 02:13:41,280 SUPPORT FOR OUR RESEARCHERS AND 2569 02:13:41,280 --> 02:13:42,600 CONTRACTS AND FINAL GOAL OF 2570 02:13:42,600 --> 02:13:44,160 COURSE IS FDA APPROVAL WITHIN 2571 02:13:44,160 --> 02:13:46,600 THE LIFE OF THESE CONTRACTS AND 2572 02:13:46,600 --> 02:13:49,280 GRANTS WE DO ASK OUR P.I.s TO 2573 02:13:49,280 --> 02:13:51,200 HAVE A CONVERSATION WITH THE FDA 2574 02:13:51,200 --> 02:13:55,080 BECAUSE THEY CAN GIVE REALLY 2575 02:13:55,080 --> 02:13:56,360 GOOD FEEDBACK ON WHAT THE 2576 02:13:56,360 --> 02:13:57,200 DEVELOPMENT LOOKS LIKE AND HOW 2577 02:13:57,200 --> 02:13:58,120 TO MAKE IT HAPPEN. 2578 02:13:58,120 --> 02:14:00,680 IN ADDITION TO THAT WE ARE 2579 02:14:00,680 --> 02:14:02,840 REALLY HAPPY TO SAY WE'VE HAD 2580 02:14:02,840 --> 02:14:04,760 SEVEN PROJECTS THAT THE 2581 02:14:04,760 --> 02:14:06,560 TRANSITION FROM OUR EARLY 2582 02:14:06,560 --> 02:14:08,360 RESEARCH PORTFOLIO TO BARTER 2583 02:14:08,360 --> 02:14:09,720 CONTRACTS FOR DEVELOPMENT. 2584 02:14:09,720 --> 02:14:12,760 AS I SAID, WE STILL HAVE NOT HAD 2585 02:14:12,760 --> 02:14:15,160 SUCCESS. 2586 02:14:15,160 --> 02:14:17,960 IN ADDITION TO PROVIDING FUNDING 2587 02:14:17,960 --> 02:14:20,000 TO THE AGENCY AS WELL AS BORDER 2588 02:14:20,000 --> 02:14:24,000 WE ALSO PROVIDE RESOURCES TO OUR 2589 02:14:24,000 --> 02:14:25,440 GRANTEES BECAUSE THEY START WITH 2590 02:14:25,440 --> 02:14:27,800 IN VITRO ASSAYS AND STARTED WITH 2591 02:14:27,800 --> 02:14:31,480 STUDIES IN MICE BUT THE 2592 02:14:31,480 --> 02:14:36,760 TRANSLATION ASPECT GIVEN THE 2593 02:14:36,760 --> 02:14:40,880 GLOBAL THAT'S BEEN A HUGE DEAL 2594 02:14:40,880 --> 02:14:42,960 AND THEY'VE NOT HAD ACCESS TO 2595 02:14:42,960 --> 02:14:43,520 THE PRIMATES. 2596 02:14:43,520 --> 02:14:46,760 SO WE CONDUCT STUDIES IN 2597 02:14:46,760 --> 02:14:50,880 PRIMATES AND MAKE THE BIO 2598 02:14:50,880 --> 02:14:52,000 SAMPLES AVAILABLE TO THE 2599 02:14:52,000 --> 02:14:54,200 COMMUNITY AND WE WERE ABLE TO 2600 02:14:54,200 --> 02:14:57,520 CONDUCT STUDIES WITH 10 PRIMATE 2601 02:14:57,520 --> 02:14:59,040 AND PROVIDE THEM TO 12 MONKEYS 2602 02:14:59,040 --> 02:15:06,720 WHICH I THINK WAS A BIG DEAL. 2603 02:15:06,720 --> 02:15:10,040 CURRENTLY THE UL 1 CORBS SHUM WE 2604 02:15:10,040 --> 02:15:12,440 AWARDED SEVEN AWARDS IN TOTAL 2605 02:15:12,440 --> 02:15:16,760 AND YOU CAN SEE THERE ARE 2606 02:15:16,760 --> 02:15:17,880 MULTIPLE APPROACH TO ADDRESSING 2607 02:15:17,880 --> 02:15:25,840 THE DIFFERENT ASPECTS OF THE 2608 02:15:25,840 --> 02:15:27,240 MULTI-OMICS. 2609 02:15:27,240 --> 02:15:31,080 AND METABOLOMICS TO PREDICT IF 2610 02:15:31,080 --> 02:15:32,240 YOU'LL HAVE LATE EFFECTS TWO 2611 02:15:32,240 --> 02:15:33,440 MONTHS OR TWO YEARS DOWN THE 2612 02:15:33,440 --> 02:15:36,320 LINE OR 20 YEARS DOWN THE LINE. 2613 02:15:36,320 --> 02:15:40,480 PROTEOMICS OR A QUICK YES OR NO 2614 02:15:40,480 --> 02:15:43,120 ANSWER AT ONSET AND 2615 02:15:43,120 --> 02:15:44,400 TRANSCRIPTOMICS MORE FOCUSSED ON 2616 02:15:44,400 --> 02:15:46,920 IMMUNE CHANGES BECAUSE WE KNOW 2617 02:15:46,920 --> 02:15:48,760 RADIATION CAUSES ALL SORTS OF 2618 02:15:48,760 --> 02:15:54,360 DYSFUNCTION. 2619 02:15:54,360 --> 02:15:55,560 AND YOU CAN DO A QUICK 2620 02:15:55,560 --> 02:15:59,440 PAPER-BASED ASSAY. 2621 02:15:59,440 --> 02:16:05,640 THAT BRINGS US TO WHAT THE UO1 2622 02:16:05,640 --> 02:16:08,240 CONSORTIUM AND THE GOAL REMAINS 2623 02:16:08,240 --> 02:16:14,480 THE SAME A RAPID DIAGNOSTIC KIT 2624 02:16:14,480 --> 02:16:17,840 AND DOSE ASSAYS AND IT'S A TRUE 2625 02:16:17,840 --> 02:16:18,720 PARTNERSHIP WITH P.I.s. 2626 02:16:18,720 --> 02:16:20,760 THE DURATION WILL BE FOUR OR 2627 02:16:20,760 --> 02:16:24,640 FIVE YEARS. 2628 02:16:24,640 --> 02:16:29,720 WE ANTICIPATE BEING ABLE TO WARD 2629 02:16:29,720 --> 02:16:32,600 SIX TO EIGHT AWARDS. 2630 02:16:32,600 --> 02:16:36,440 WITH THAT I'LL BE HAPPY TO 2631 02:16:36,440 --> 02:16:37,320 ADDRESS YOUR QUESTIONS.WARD SIX. 2632 02:16:37,320 --> 02:16:37,880 WITH THAT I'LL BE HAPPY TO 2633 02:16:37,880 --> 02:16:48,280 ADDRESS YOUR QUESTIONS. 2634 02:17:18,440 --> 02:17:25,560 >>'M THE WITH IN THE ALLERGIC 2635 02:17:25,560 --> 02:17:26,120 MECHANISMS SECTION IN THE 2636 02:17:26,120 --> 02:17:30,200 BIOLOGY BRANCH. 2637 02:17:30,200 --> 02:17:34,560 AND I'M GOING TO DISCUSS AN 2638 02:17:34,560 --> 02:17:35,440 INITIATIVE ON DRUG ALLERGY. 2639 02:17:35,440 --> 02:17:37,560 I WANT TO SAY FROM THE START 2640 02:17:37,560 --> 02:17:38,920 THAT WHEN I'M TALKING DRUG 2641 02:17:38,920 --> 02:17:43,040 ALLERGY IN THIS SENSE I'M 2642 02:17:43,040 --> 02:17:45,440 TALKING ABOUT IMMUNE DRIVEN 2643 02:17:45,440 --> 02:17:48,240 IDIOSYNCRATIC FORMS OF DRUG 2644 02:17:48,240 --> 02:17:48,520 REACTION. 2645 02:17:48,520 --> 02:17:51,480 SO NOT JUST MEDIATED BUT 2646 02:17:51,480 --> 02:17:54,800 DEFINITELY NOT TOXIC REACTIONS. 2647 02:17:54,800 --> 02:17:57,200 SO ALLERGY IS A COMMON 2648 02:17:57,200 --> 02:17:59,160 DIAGNOSIS. 2649 02:17:59,160 --> 02:18:03,160 IT'S A BIG CAUSE OF VISITS TO 2650 02:18:03,160 --> 02:18:05,760 THE E.R. IF YOU'RE IN THE 2651 02:18:05,760 --> 02:18:07,920 HOSPITAL AND HAVE AN ALLERGY 2652 02:18:07,920 --> 02:18:10,560 DIAGNOSIS YOU'LL BE OFTEN GIVEN 2653 02:18:10,560 --> 02:18:11,840 LESS THAN TOP LINE DRUG OR 2654 02:18:11,840 --> 02:18:15,520 INDICATED DRUGS AND HAVE A 2655 02:18:15,520 --> 02:18:19,720 PROBLEM WITH CDIF AND INCREASES 2656 02:18:19,720 --> 02:18:25,960 THE CHANCE OF VRE AND SM8 AND 2657 02:18:25,960 --> 02:18:26,280 INFECTIONS. 2658 02:18:26,280 --> 02:18:28,120 OUR PROBLEM IS THAT WE DON'T 2659 02:18:28,120 --> 02:18:32,280 FUND MANY GRANTS IN THE AREA AT 2660 02:18:32,280 --> 02:18:32,480 ALL. 2661 02:18:32,480 --> 02:18:35,560 IN THE PAST 14 YEARS I THINK 2662 02:18:35,560 --> 02:18:36,400 WE'VE HAD 10. 2663 02:18:36,400 --> 02:18:39,840 THREE WERE K AS AND Fs SO EARLY 2664 02:18:39,840 --> 02:18:40,160 STAGE. 2665 02:18:40,160 --> 02:18:42,600 AND THERE'S BEEN ABOUT THAT MANY 2666 02:18:42,600 --> 02:18:45,520 ACROSS THE NIH IN THAT PERIOD. 2667 02:18:45,520 --> 02:18:47,800 MOST COMES HERE BUT IT'S NOT 2668 02:18:47,800 --> 02:18:48,320 VERY MUCH PERIOD. 2669 02:18:48,320 --> 02:18:52,440 SO THE PROPOSAL IS TO ENHANCE 2670 02:18:52,440 --> 02:18:54,160 UNDERSTANDINGS OF THE MECHANISMS 2671 02:18:54,160 --> 02:18:56,480 AND MANAGEMENT OF DRUG ALLERGY 2672 02:18:56,480 --> 02:19:00,040 WITH AN INITIAL FOCUS ON 2673 02:19:00,040 --> 02:19:01,280 ANTIBIOTICS AND VACCINES AND 2674 02:19:01,280 --> 02:19:03,320 WHEN WE SAY ANTIBIOTICS WE 2675 02:19:03,320 --> 02:19:05,680 INCLUDE OTHER ANTIMICROBIALS 2676 02:19:05,680 --> 02:19:09,040 BECAUSE WE'RE TRYING TO JUMP 2677 02:19:09,040 --> 02:19:12,400 START THE FIELD WHERE WE WERE 2678 02:19:12,400 --> 02:19:14,280 WITH FOOD ALLERGY 15 YEARS OR SO 2679 02:19:14,280 --> 02:19:14,720 AGO. 2680 02:19:14,720 --> 02:19:18,080 WE STARTED RIDGE R21s. 2681 02:19:18,080 --> 02:19:20,440 WE HAVE A VERY ROBUST FOOD 2682 02:19:20,440 --> 02:19:21,800 PORTFOLIO NOW AND HOPING TO MOVE 2683 02:19:21,800 --> 02:19:32,320 DRUG ALLERGY IN THAT DIRECTION. 2684 02:19:32,840 --> 02:19:34,840 AND THE ALLERGY IS COMMON IN THE 2685 02:19:34,840 --> 02:19:37,480 HOSPITAL CHART. 2686 02:19:37,480 --> 02:19:47,920 33% OF THE CASE LINKED TO 2687 02:19:49,080 --> 02:19:50,200 SYLPHONOMIDES AND YOU HAVE 2688 02:19:50,200 --> 02:19:51,080 REACTION TO ALL THE OTHERS AS 2689 02:19:51,080 --> 02:19:53,040 WELL PRETTY MUCH ALL OF THEM. 2690 02:19:53,040 --> 02:19:55,040 WE DON'T REALLY UNDERSTAND WHAT 2691 02:19:55,040 --> 02:19:56,680 THE TRUE PREVALENCE IS. 2692 02:19:56,680 --> 02:19:58,840 WE DON'T REALLY UNDERSTAND WHY 2693 02:19:58,840 --> 02:20:02,840 THEY HAPPEN AND WHAT WE TELL 2694 02:20:02,840 --> 02:20:08,520 PEOPLE TO DO IS EXPERT OPINION 2695 02:20:08,520 --> 02:20:10,680 NOT DATA DRIVEN. 2696 02:20:10,680 --> 02:20:14,280 AND WE HAVE INCREASED SIDE 2697 02:20:14,280 --> 02:20:15,520 EFFECTS AND CONTRIBUTE TO 2698 02:20:15,520 --> 02:20:16,760 ANTIBIOTIC RESISTANCE WHICH WE 2699 02:20:16,760 --> 02:20:19,680 KNOW IS A HUGE PROBLEM ALL BY 2700 02:20:19,680 --> 02:20:27,640 ITSELF. 2701 02:20:27,640 --> 02:20:29,400 WE KNOW LESS ABOUT VACCINE 2702 02:20:29,400 --> 02:20:31,120 ALLERGY. 2703 02:20:31,120 --> 02:20:39,840 THE MOST COMMON HYPERSENSITIVITY 2704 02:20:39,840 --> 02:20:43,160 REACTION INCLUDING TOUCH AND HE 2705 02:20:43,160 --> 02:20:45,320 H1N1 AND mRNA VACCINES. 2706 02:20:45,320 --> 02:20:49,960 THERE'S A SMALL PROPORTION DUE 2707 02:20:49,960 --> 02:20:57,520 TO GELATIN AND EGG AND THEY SEEM 2708 02:20:57,520 --> 02:20:59,720 TO BE NON-SPECIFIC BUT THERE'S 2709 02:20:59,720 --> 02:21:00,760 REALLY NOT MUCH KNOWN ABOUT 2710 02:21:00,760 --> 02:21:08,760 THIS. 2711 02:21:08,760 --> 02:21:10,040 THERE'S CONSEQUENCES IF A PERSON 2712 02:21:10,040 --> 02:21:11,120 GETS LABELLED THAT AND MAY GET 2713 02:21:11,120 --> 02:21:15,440 MORE UNNEEDED VACCINES AND MAY 2714 02:21:15,440 --> 02:21:17,400 ACCOUNT FOR VACCINE HESITANCY 2715 02:21:17,400 --> 02:21:19,320 WHEN WORD GETS OUT THIS PERSON 2716 02:21:19,320 --> 02:21:21,200 HAD THIS OR THAT WITHOUT 2717 02:21:21,200 --> 02:21:24,760 BACKGROUND TO SAY HOW COMMON IS 2718 02:21:24,760 --> 02:21:30,800 THIS OR ANYTHING ELSE? 2719 02:21:30,800 --> 02:21:36,440 OR IMPROVE THE UNDERSTANDING OF 2720 02:21:36,440 --> 02:21:38,280 ALLERGY THAT ARE DIAGNOSTICS AND 2721 02:21:38,280 --> 02:21:39,840 INFORMATION OF MECHANISMS. 2722 02:21:39,840 --> 02:21:42,360 WE WANT TO GROW THE RESEARCH IN 2723 02:21:42,360 --> 02:21:48,760 THE FIELD AND RESEARCHERS. 2724 02:21:48,760 --> 02:21:53,320 IDEALLY JUNIOR RESEARCHER AND 2725 02:21:53,320 --> 02:21:54,680 HAVE EXPERIENCE IN THE FIELD 2726 02:21:54,680 --> 02:21:57,200 WE'LL TAKE THEM TOO AND 2727 02:21:57,200 --> 02:22:01,560 PROPOSING THE UG3 AND UH3 AND 2728 02:22:01,560 --> 02:22:03,080 IT'S A COOPERATIVE AGREEMENT AND 2729 02:22:03,080 --> 02:22:04,760 WE'LL HAVE PROJECT SCIENTISTS 2730 02:22:04,760 --> 02:22:08,800 WORK WITH THE INVESTIGATORS. 2731 02:22:08,800 --> 02:22:10,720 WE'RE ALSO PLANNING ON ANNUAL 2732 02:22:10,720 --> 02:22:16,440 MEETINGS TO ENCOURAGE MIXING OF 2733 02:22:16,440 --> 02:22:18,160 IDEAS AND UNDERSTANDING HAVING 2734 02:22:18,160 --> 02:22:19,760 TAKEN FROM ONE DRUG TO ANOTHER 2735 02:22:19,760 --> 02:22:29,960 POTENTIALLY. 2736 02:22:30,560 --> 02:22:33,160 THE FIRST TWO YEARS YOU PROPOSE 2737 02:22:33,160 --> 02:22:35,680 MILESTONES AND IF YOU MEET THE 2738 02:22:35,680 --> 02:22:36,280 MILESTONES YOU CAN MOVE INTO 2739 02:22:36,280 --> 02:22:41,520 ANOTHER THREE YEARS. 2740 02:22:41,520 --> 02:22:43,680 SO WE'RE MOVING FORWARD THE BEST 2741 02:22:43,680 --> 02:22:46,440 OF THE PROPOSALS WE GET NOT 2742 02:22:46,440 --> 02:22:47,280 NECESSARILY ALL OF THEM. 2743 02:22:47,280 --> 02:22:49,000 IF THEY WERE ALL GRET THAT WOULD 2744 02:22:49,000 --> 02:22:51,120 BE GREAT. 2745 02:22:51,120 --> 02:22:52,760 SO WE'RE ANTICIPATING FOUR OR 2746 02:22:52,760 --> 02:22:53,320 FIVE AWARDS. 2747 02:22:53,320 --> 02:22:56,040 AS I SAID IT'S A SMALL FIELD. 2748 02:22:56,040 --> 02:22:59,200 HOPEFULLY WE'LL GET IT MOVING. 2749 02:22:59,200 --> 02:23:06,960 I'D BE HAPPY TO TAKE QUESTIONS. 2750 02:23:06,960 --> 02:23:09,840 >>T'S A GOOD ANALOGY WHEN YOU 2751 02:23:09,840 --> 02:23:16,040 SAID THIS IS HOW YOU GOT THE 2752 02:23:16,040 --> 02:23:18,200 FOOD COVERED IN THE THEME AND AS 2753 02:23:18,200 --> 02:23:21,760 THE RFA GETS WRITTEN IT'S GOOD 2754 02:23:21,760 --> 02:23:24,240 TO ACKNOWLEDGE THAT IN THE RFA 2755 02:23:24,240 --> 02:23:25,840 THERE'S DESCRIPTIVE INFORMATION 2756 02:23:25,840 --> 02:23:26,640 NEEDED AND WHY A LOT OF GRANTS 2757 02:23:26,640 --> 02:23:28,320 HAVEN'T BEEN FUNDED IN THE PAST 2758 02:23:28,320 --> 02:23:31,840 IN THIS AREA BECAUSE THE AREA IS 2759 02:23:31,840 --> 02:23:34,000 BEHIND AND PEOPLE PROPOSE 2760 02:23:34,000 --> 02:23:35,720 DESCRIPTIVE THINGS THAT KIND OF 2761 02:23:35,720 --> 02:23:37,040 GET DOWNGRADED FOR THAT REASON 2762 02:23:37,040 --> 02:23:38,800 BUT THAT'S SORT OF FOUNDATIONAL 2763 02:23:38,800 --> 02:23:40,760 INFORMATION IS REALLY NEEDED. 2764 02:23:40,760 --> 02:23:41,480 >> RIGHT. 2765 02:23:41,480 --> 02:23:44,600 AND WE ARE REQUIRING MECHANISMS 2766 02:23:44,600 --> 02:23:48,880 IN THE UH3 BUT NOT PRELIMINARY 2767 02:23:48,880 --> 02:23:51,120 DATA OR IT BE MECHANISTIC IN THE 2768 02:23:51,120 --> 02:23:52,240 FIRST TWO YEARS. 2769 02:23:52,240 --> 02:23:54,280 IT COULD IN FACT INCLUDE 2770 02:23:54,280 --> 02:23:59,720 GATHERING THIS KIND OF DATA AND 2771 02:23:59,720 --> 02:24:02,160 FINDING THE RIGHT PARTICIPANTS. 2772 02:24:02,160 --> 02:24:03,800 THERE'S NO CLINICAL TRIAL THERE. 2773 02:24:03,800 --> 02:24:12,560 ANY OTHER COMMENTS? 2774 02:24:12,560 --> 02:24:15,160 >> ALLERGIC REACTIONS ARE WELLED 2775 02:24:15,160 --> 02:24:16,000 IN THE MEDICAL RECORDS IS THAT 2776 02:24:16,000 --> 02:24:16,440 NOT TRUE? 2777 02:24:16,440 --> 02:24:20,880 >> THEY'RE DOCUMENTED. 2778 02:24:20,880 --> 02:24:22,760 THE WELL I WOULD DISAGREE WITH. 2779 02:24:22,760 --> 02:24:25,640 >> WAS WONDERING IF YOU COULD 2780 02:24:25,640 --> 02:24:29,040 DO A LOT OF DATA GATHERING. 2781 02:24:29,040 --> 02:24:30,840 >> THINK THERE ARE PEOPLE 2782 02:24:30,840 --> 02:24:35,080 WORKING ON DHR RESEARCH AND 2783 02:24:35,080 --> 02:24:36,520 TRYING TO FIGURE OUT WHAT IS 2784 02:24:36,520 --> 02:24:37,920 DOCUMENTED AND WHAT IT ACTUALLY 2785 02:24:37,920 --> 02:24:40,720 MEANS AND THEN THEY COULD FOR 2786 02:24:40,720 --> 02:24:42,120 INSTANCE TAKE THOSE IN THE 2787 02:24:42,120 --> 02:24:42,560 MECHANISMS. 2788 02:24:42,560 --> 02:24:45,640 THESE PEOPLE ALL SAY THEY HAVE 2789 02:24:45,640 --> 02:24:46,680 HAD STEVEN JOHNSON TO X. 2790 02:24:46,680 --> 02:24:48,760 WHAT CAN WE FIND OUT ABOUT THOSE 2791 02:24:48,760 --> 02:24:52,960 PEOPLE. 2792 02:24:52,960 --> 02:24:57,840 IF YOU'RE GOING TO DO GENOMICS 2793 02:24:57,840 --> 02:24:59,400 HLA IS LINKED TO DRUG 2794 02:24:59,400 --> 02:24:59,680 SENSITIVITY. 2795 02:24:59,680 --> 02:25:10,320 IF YOU'RE DOING GENOMICS -- 2796 02:25:14,720 --> 02:25:17,160 >> THINK IT'S OVER DOCUMENTED. 2797 02:25:17,160 --> 02:25:17,560 >>T IS. 2798 02:25:17,560 --> 02:25:22,240 THIS IS ABSOLUTELY CLEAR IF YOU 2799 02:25:22,240 --> 02:25:25,000 TEST PEOPLE FOR JUST PENICILLIN 2800 02:25:25,000 --> 02:25:28,760 ONLY 10% OF THOSE ACTUALLY ARE 2801 02:25:28,760 --> 02:25:31,600 PENICILLIN ALLERGIC BUT THAT'S 2802 02:25:31,600 --> 02:25:40,760 THE ONLY DRUG WE CAN TEST. 2803 02:25:40,760 --> 02:25:49,000 THANK YOU. 2804 02:25:49,000 --> 02:25:51,360 >> YOU THUD BE ONLINE. 2805 02:25:51,360 --> 02:25:52,840 >>'M HERE. 2806 02:25:52,840 --> 02:25:58,440 >> THANKS. 2807 02:25:58,440 --> 02:26:03,040 >>'M ARI JOFFE AND I'LL BE 2808 02:26:03,040 --> 02:26:04,400 PRESENTING WHAT IS THE FINAL 2809 02:26:04,400 --> 02:26:07,600 INITIATIVE CONCEPT OF THIS 2810 02:26:07,600 --> 02:26:07,840 SESSION. 2811 02:26:07,840 --> 02:26:13,560 THIS IS TITLED UNDERSTANDING 2812 02:26:13,560 --> 02:26:16,760 MECHANISMS OF TRAINED IMMUNITY. 2813 02:26:16,760 --> 02:26:22,560 TO BRIEFLY INTRODUCE THIS THINK 2814 02:26:22,560 --> 02:26:29,880 OF IT AS INNATE IMMUNITY BEING 2815 02:26:29,880 --> 02:26:33,480 EXPOSED TO PATHOGENS AND IT'S 2816 02:26:33,480 --> 02:26:34,800 DIFFERENT FROM TRADITIONAL 2817 02:26:34,800 --> 02:26:35,880 ADAPTIVE COMMUNITY THINKING OF T 2818 02:26:35,880 --> 02:26:36,720 CELLS AND B CELLS. 2819 02:26:36,720 --> 02:26:40,040 ONE WAY IT'S DIFFERENT IS IT'S 2820 02:26:40,040 --> 02:26:43,080 NOT SPECIFIC AND SPECIFIC TO ONE 2821 02:26:43,080 --> 02:26:45,640 ANTIGEN AND IT'S REALLY MORE OF 2822 02:26:45,640 --> 02:26:51,200 A WAY IN WHICH CELLS ARE PRIMED 2823 02:26:51,200 --> 02:26:55,400 AND RESPOND TO SUBSEQUENT 2824 02:26:55,400 --> 02:26:55,720 CHALLENGES. 2825 02:26:55,720 --> 02:26:58,720 THERE'S A LOT MECHANISMS AND 2826 02:26:58,720 --> 02:27:03,240 THERE'S EPIGENETIC ALTERATIONS 2827 02:27:03,240 --> 02:27:04,760 IN THE IMMUNE CELLS AND 2828 02:27:04,760 --> 02:27:10,240 METABOLIC REWIRING AND YOU HAVE 2829 02:27:10,240 --> 02:27:11,800 A MACROPHAGE WHICH UNDER GOES 2830 02:27:11,800 --> 02:27:12,480 STIMULATION AND BECOMES ACTIVATE 2831 02:27:12,480 --> 02:27:15,800 AND WHEN IT GOES BACK TO ITS 2832 02:27:15,800 --> 02:27:16,760 RESTING STATE IT'S DISTINCT FROM 2833 02:27:16,760 --> 02:27:20,760 THE NAIVE STATE AND MAY HAVE A 2834 02:27:20,760 --> 02:27:22,840 DIFFERENT EPIGENETIC LANDSCAPE 2835 02:27:22,840 --> 02:27:25,600 AND WILL RESPOND DIFFERENTLY 2836 02:27:25,600 --> 02:27:36,080 UPON A SUBSEQUENT STIMULATION. 2837 02:27:36,080 --> 02:27:40,600 BACK IN 2021 THERE WAS A 2838 02:27:40,600 --> 02:27:43,440 NON-SPECIFIC EFFECTS OF VACCINES 2839 02:27:43,440 --> 02:27:46,880 AND SOME TAKEAWAYS WERE THAT 2840 02:27:46,880 --> 02:27:48,800 TRAINED IMMUNITY OFFERED A 2841 02:27:48,800 --> 02:27:52,160 LIKELY EXPLANATION OF 2842 02:27:52,160 --> 02:27:53,920 NON-SPECIFIC VACCINE EFFECTS BUT 2843 02:27:53,920 --> 02:27:56,120 ALSO THERE'S A LOT TO BE LEARNED 2844 02:27:56,120 --> 02:27:59,160 HERE SO WE NEED A BASIC 2845 02:27:59,160 --> 02:28:00,000 UNDERSTANDING OF TRAINED 2846 02:28:00,000 --> 02:28:01,360 IMMUNITY BEFORE THE CONCEPT CAN 2847 02:28:01,360 --> 02:28:04,560 BE MORE BROADLY APPLIED AND 2848 02:28:04,560 --> 02:28:06,520 EFFICIENTLY APPLIED TO VACCINES 2849 02:28:06,520 --> 02:28:06,880 AND THERAPIES. 2850 02:28:06,880 --> 02:28:09,880 FURTHER SCIENTIFIC GAPS 2851 02:28:09,880 --> 02:28:11,720 IDENTIFIED ARE WE NEED 2852 02:28:11,720 --> 02:28:13,600 IDENTIFICATION OF BIO MARKERS 2853 02:28:13,600 --> 02:28:14,680 ASSOCIATED WITH THE CELL 2854 02:28:14,680 --> 02:28:16,000 TRAINING AND WE NEED TO KNOW 2855 02:28:16,000 --> 02:28:18,520 MORE ABOUT THE DURATION AND 2856 02:28:18,520 --> 02:28:19,560 PLASTICITY AND FUNCTIONAL 2857 02:28:19,560 --> 02:28:22,360 SIGNIFICANCE OF THE SIGNATURES 2858 02:28:22,360 --> 02:28:24,560 AND FINALLY A LOT MECHANISTIC 2859 02:28:24,560 --> 02:28:26,360 UTILITIES NEED TO BE UNCOVERED 2860 02:28:26,360 --> 02:28:27,320 INCLUDING HOW CELLS ARE TRAINED 2861 02:28:27,320 --> 02:28:30,080 IN THE FIRST PLACE AND ONCE 2862 02:28:30,080 --> 02:28:38,160 THEY'RE TRAINED HOW THE INNATE 2863 02:28:38,160 --> 02:28:40,760 MEMORY FUNCTIONS DURING 2864 02:28:40,760 --> 02:28:45,040 SUBSEQUENT CHALLENGES. 2865 02:28:45,040 --> 02:28:47,800 WITH APPLICATIONS WE HAVE 2866 02:28:47,800 --> 02:28:48,800 RECEIVED IN THE PAST. 2867 02:28:48,800 --> 02:28:51,440 THERE'S INCREASING INTEREST IN 2868 02:28:51,440 --> 02:28:52,640 THIS FIELD WHICH IS RELATIVELY 2869 02:28:52,640 --> 02:28:56,440 NEW. 2870 02:28:56,440 --> 02:28:59,360 YOU CAN SEE IT IN THE RO1 2871 02:28:59,360 --> 02:29:00,000 APPLICATIONS THAT MENTION THE 2872 02:29:00,000 --> 02:29:01,280 TERM TRAINED IMMUNITY. 2873 02:29:01,280 --> 02:29:04,280 YOU CAN SEE THE DEFINITE 2874 02:29:04,280 --> 02:29:06,200 INCREASE IN THESE APPLICATIONS 2875 02:29:06,200 --> 02:29:07,200 THOUGH THEY'RE NOT NECESSARILY 2876 02:29:07,200 --> 02:29:08,200 AN INCREASE IN THE AMOUNT 2877 02:29:08,200 --> 02:29:08,440 FUNDED. 2878 02:29:08,440 --> 02:29:11,000 WHEN YOU DIG INTO THE 2879 02:29:11,000 --> 02:29:13,600 APPLICATION OF THE ACTIVELY 2880 02:29:13,600 --> 02:29:15,560 FUNDED GRANTS THERE'S ONLY FIVE 2881 02:29:15,560 --> 02:29:16,760 EXPLORING FUNDAMENTAL ASPECTS OF 2882 02:29:16,760 --> 02:29:18,800 TRAINED IMMUNITY. 2883 02:29:18,800 --> 02:29:19,600 AND SOME OF THE POTENTIAL 2884 02:29:19,600 --> 02:29:23,320 BARRIERS FOR FUNDING HERE ARE 2885 02:29:23,320 --> 02:29:24,760 THE IDENTIFICATION OF NOVEL 2886 02:29:24,760 --> 02:29:28,000 BIOMARKERS WHICH IS NEEDED HERE 2887 02:29:28,000 --> 02:29:32,680 IS REALLY DESCRIPTIVE IN NATURE 2888 02:29:32,680 --> 02:29:35,920 AND AS DISCUSSED IN THE LAST 2889 02:29:35,920 --> 02:29:40,720 PRESENTATION THE PROJECTS DON'T 2890 02:29:40,720 --> 02:29:42,960 NECESSARILY FARE WELL AND 2891 02:29:42,960 --> 02:29:44,760 THERE'S TRAINED IMMUNITY AND I'D 2892 02:29:44,760 --> 02:29:46,560 ARGUE WE'RE TOO EARLY IN THE 2893 02:29:46,560 --> 02:29:48,840 FIELD TO SAY WHETHER THIS IS 2894 02:29:48,840 --> 02:29:59,080 VALID OR NOT. 2895 02:30:02,800 --> 02:30:06,480 THE PROPOSED INITIATIVE FOR 2896 02:30:06,480 --> 02:30:08,400 FISCAL YEAR 2025 IS 2897 02:30:08,400 --> 02:30:09,480 UNDERSTANDING MECHANISMS AND 2898 02:30:09,480 --> 02:30:12,200 OUTCOMES OF TRAINED IMMUNITY. 2899 02:30:12,200 --> 02:30:14,240 THIS WOULD BE PAR, PROGRAM 2900 02:30:14,240 --> 02:30:15,280 ANNOUNCEMENT WITH SPECIAL REVIEW 2901 02:30:15,280 --> 02:30:16,520 CONSIDERATIONS AND THE OBJECTIVE 2902 02:30:16,520 --> 02:30:21,600 WOULD BE TO SOLICIT PROJECTS 2903 02:30:21,600 --> 02:30:23,840 THAT AIM TO DEFINE BIOMARKERS 2904 02:30:23,840 --> 02:30:28,760 AND TRAINED IMMUNITY PROJECTS 2905 02:30:28,760 --> 02:30:31,640 BEING SUBMITTED TO THIS AND THEN 2906 02:30:31,640 --> 02:30:35,760 WE MAKE AN ALLOWANCE FOR 2907 02:30:35,760 --> 02:30:36,480 DESCRIPTIVE STUDIES. 2908 02:30:36,480 --> 02:30:41,840 THE MECHANISM RO1 AND R21 AND 2909 02:30:41,840 --> 02:30:43,520 FIVE YEARS FOR THE RO1 AND TWO 2910 02:30:43,520 --> 02:30:44,760 YEARS FOR THE R21. 2911 02:30:44,760 --> 02:30:48,760 I'M HAPPY TO TAKE ANY QUESTIONS 2912 02:30:48,760 --> 02:30:55,960 IF THERE ARE ANY. 2913 02:30:55,960 --> 02:30:56,200 ASK 2914 02:30:56,200 --> 02:30:57,480 >>T SEEMS THERE ARE NOT. 2915 02:30:57,480 --> 02:30:57,720 >> OKAY. 2916 02:30:57,720 --> 02:31:04,480 THANK YOU. 2917 02:31:04,480 --> 02:31:08,240 >> ALL RIGHT, BEFORE WE GO AHEAD 2918 02:31:08,240 --> 02:31:09,560 TO THE ON BLOCK RECOMMENDATION I 2919 02:31:09,560 --> 02:31:14,840 NEED TO BRING TO COUNCIL'S 2920 02:31:14,840 --> 02:31:17,000 ATTENTION TWO NOTICES OF SPECIAL 2921 02:31:17,000 --> 02:31:19,600 INTEREST IN THE ELECTRONIC 2922 02:31:19,600 --> 02:31:28,240 COUNCIL BOOK. 2923 02:31:28,240 --> 02:31:31,280 THE SECOND IS RNA DELIVERY 2924 02:31:31,280 --> 02:31:32,760 TECHNOLOGY TO ALLOW SPECIFIC 2925 02:31:32,760 --> 02:31:41,240 TISSUE HONING BECAUSE THESE ARE 2926 02:31:41,240 --> 02:31:47,880 NOTICES OF SPECIAL INTEREST OR 2927 02:31:47,880 --> 02:31:50,400 NOSIS AND WE'LL NOT KEEP YOU 2928 02:31:50,400 --> 02:31:53,440 LONGER FOR DISCUSSION OF THOSE. 2929 02:31:53,440 --> 02:31:58,480 AT THES POINT I'M GOING ASK FOR 2930 02:31:58,480 --> 02:32:00,240 UNBLOCK RECOMMENDATION IN THE 2931 02:32:00,240 --> 02:32:00,920 SECOND FOR THE CONCEPT CLEARANCE 2932 02:32:00,920 --> 02:32:08,760 US YOU HEARD. 2933 02:32:08,760 --> 02:32:10,600 SECOND FROM A COUNCIL MEMBER. 2934 02:32:10,600 --> 02:32:13,600 OKAY, THAT WRAPS US UP FOR 2935 02:32:13,600 --> 02:32:13,800 TODAY. 2936 02:32:13,800 --> 02:32:16,760 THANK YOU TO ALL OF OUR STAFF 2937 02:32:16,760 --> 02:32:17,000 AND SPEAKERS THIS AFTERNOON. 2938 02:32:17,000 --> 02:32:18,480 THIS IS A VERY ENJOYABLE SESSION 2939 02:32:18,480 --> 02:32:30,960 AND LOTS OF GOOD SCIENCE.