IT'S MY PLEASURE TO WELCOME YOU TO THIS AFTERNOON'S SUBCOMMITTEE SESSION. WE HAVE THREE SCIENTIFIC TALKS FROM AD HOC COUNCIL MEMBERS AND A VISITING SPEAKER AND WOLFGANG LEITNER WILL INTRODUCE EACH OF THOSE SPEAKERS AFTER A BRIEF OVERVIEW OF OUR STRATEGIC PLAN AND BRIEF OVERVIEW OF WHAT'S IN THE PLANS. FIRST I WANTED TO GIVE YOU GUIDANCE ON THE REST OF THE DAY. FIRST OF ALL WE HAVE AN UNUSUAL NUMBER OF RESEARCH CONCEPT CLEARANCES. I THINK THERE'S SEVEN PACKED INTO RELATIVELY SHORT TIME. OFTEN IN THE PAST WE'VE GONE OVERTIME BUT I'M A LITTLE CONCERNED ABOUT TIME BECAUSE OF THE TRAVEL ISSUES FOR PEOPLE FLYING TO THE MIDWEST OR ACROSS THE COUNTRY TODAY WITH VERY UNUSUAL WEATHER. SO WE WILL TRY TO FINISH ON TIME. THAT MEANS OUR STAFF NEED TO COVER EACH OF THESE STAFF NEED TO FINISH IN ABOUT TWO MINUTES AND LEAVE SHORT TIME FOR DISCUSSION AND QUESTIONS FROM COUNCIL. TO FACILITATE DOING THAT EXPEDITIOUSLY WE'RE GOING TO ASK YOU FOR A RECOMMENDATION TO GO AHEAD WITH THESE CONCEPT CLEARANCES OR IF THERE ARE OR IF ANY REQUIRE MORE DISCUSSION WE CAN DEFER THOSE TO ANOTHER SESSION OR HAVE DIALOGUE OVER E-MAIL WITH COUNCIL MEMBERS BUT THE HOPED FOR OUTCOME IS WE HAVE CONCEPT APPROVAL AND WE'RE ABLE TO GO AHEAD AND NEIL, I'LL DO THAT THROUGH YOUR ELECTRONIC COUNCIL BOOKS AND ASK FOR THE ON BLOCK RECOMMENDATION. I WANT TO CALL YOUR ATTENTION TO SEVERAL SMALL BUSINESS CONTRACT PROPOSALS. THREE COVER ADJUVANT ACTIVITIES AND ONE IS FOR ANIMAL MODELS THOSE ARE IN THE ELECTRONIC COUNCIL BOOK AND WE NEED YOUR APPROVAL TO GO AHEAD WITH THOSE AND YOU CAN DO THOSE ELECTRONICALLY, OF COURSE. WITH THAT BACKGROUND, WOLFGANG, I'LL TURN IT OVER TO YOU AND HOPE FOR A BRIEF PRESENTATION AND THEN INTRODUCTION OF EACH OF THE GUEST SPEAKERS. >> YES, I'M GOING TRY TO KEEP THIS REALLY SHORT. WE NAME IS WOLFGANG LEITNER FROM THE BASIC IMMUNOLOGY GRANT AND OVERSEE THE ADJUVANT PROGRAM. I'M GOING TO PROVIDE A VERY BRIEF OVERVIEW OF THE RENEWAL OF OUR STRATEGIC PLAN FOR VACCINE ADJUVANT RESEARCH AND IT WILL PROVIDE THE BACKDROP FOR THE PRESENTATIONS FROM THE THREE COUNCIL SPEAKERS. WE HAVE A COMPREHENSIVE VACCINE ADJUVANT PROGRAM. THE GOAL OF THE PROGRAM IS TO EVENTUALLY BUILD A TOOLBOX OF ADJUVANTS THAT WILL EVENTUALLY BE COMBINED WITH VACCINES IN A RATIONAL MANNER TO OBTAIN MAXIMUM EFFICACY OF THE VACCINES. WE'RE DOING BIS THE ESTABLISH PIPELINE OF ADJUVANT PRODUCTS AND WE'RE STRONGLY FOCUSSED ON THE MECHANISM OF ACTION STUDIES. MECHANISM OF ACTION NOT JUST OF NOVEL ADJUVANTS COMING FROM THE PROGRAM BUT OF WELL ESTABLISH AND EVEN LICENSED ADJUVANTS. THE PROGRAM ALSO SUPPORTS THE EARLY STAGE DEVELOPMENT OF VACCINES THAT ARE FORMULATED WITH NOVEL ADJUVANTS. OUR GOAL IS TO BRING TOGETHER THE VACCINE RESEARCH COMMUNITY AND THE ADJUVANT RESEARCH COMMUNITY IN ORDER TO COME UP WITH BETTER VACCINES. THE STRATEGIC PLAN FOR ADJUVANT RESEARCH WAS FIRST RELEASED IN 2011. LAST APRIL WE CONVENED A PANEL OF SUBJECT MATTER EXPERTSES TO REVISE THE NEW STRATEGIC PLAN AND IT WILL BE RELEASED IN THE FIRST QUARTER OF THIS YEAR. THE AREAS ARE IMMUNOLOGY AND DEVELOPMENT AND EVALUATION OF VACCINES FORMULATED WITH THE ADJUVANTED IN PRE-CLINICAL STUDIES AND THE CLINICAL VACCINES FORMULATED WITH NOVEL ADJUVANTS. IN REGARDS TO THESE DIFFERENT RESEARCH AREAS, I'M JUST GOING TO HIGHLIGHT THE MAIN ASPECTS IN THE STRATEGIC PLAN. IN REGARDS TO FUNDAMENTAL IMMUNOLOGY. THE STRATEGIC PLAN DESCRIBES NIAID'S COMMITMENT TO STRENGTHENING BASIC IMMUNOLOGY RESEARCH WHICH WILL LEAD TO BEATER UNDERSTANDING OF ADAPTIVE IMMUNISMS AND THEY'LL DIRECTLY SUPPORT ADJUVANT RESEARCH. THEREFORE FUEL OUR VACCINE ADJUVANT PIPELINE. THE STRATEGIC PLAN PARTICULARLY EMPHASIZES THE NEEDS TO IDENTIFIED BETTER CORRELATES OF ADJUVANTICITY WHICH ARE LACKING NOW AND THOSE INSIGHTS WILL ACCELERATE THE DISCOVERY OF NOVEL ADJUVANT. IN REGARDS TO ADJUVANT DISCOVERY, ONE ASPECT THE STRATEGIC PLAN PARTICULARLY EMPHASIZES IS SUPPORT FOR NOVEL TECHNOLOGIES TO ACCELERATE ADJUVANT DISCOVERY. ONE IS THE PRESCREENING OF COMPOUNDS WHICH WILL THEN FACILITATE, ACCELERATE THE SUBSEQUENT IN VITRO ADJUVANTS AND WE NEED BETTER SCREEN TO PREDICT ADJUVANTICITY AND WHAT ARE THE CORRELATES THAT WILL RESULT IN THE ADJUVANTICITY IN VIVO. IN TERMS OF PRECLINICAL EVALUATION WE'RE DEDICATED EXPANDING THE ABILITY OF NOVEL ADJUVANTS FOR PRECLINICAL VACCINE EVALUATION. WE BELIEVE THAT THE ITERATIVE TESTING OF NOVEL ADJUVANT A BROAD PANEL WILL PROVIDE BETTER INSIGHTS INTO THE CHARACTERISTICS OF ADJUVANTS AN THEREORE PROMOTE THE USE OF MORE TYPES OF VACCINES. WE'RE PLANNING TO CREATE A PUBLIC DATABASE THAT LISTS AND DESCRIBES THE COMPOUNDS AND FORMULATIONS THAT HAVE COME FROM OUR ADJUVANT PROGRAMS. THE STRATEGIC PLAN ALSO STRONGLY ENCOURAGES THE ROUTINE USE OF LICENSED ADJUVANTS AS A BENCHMARK TO ALLOW BETTER COMPARISONS BETWEEN STUDIES AND TO GET A BETTER SENSE OF THE CHARACTERISTICS AND USEFULNESS OF NOVEL COMPOUNDS. WE RECOGNIZE ONE AREA OFTEN OVERLOOKED OR NOT ENOUGH EMPHASIS ON THE FORMULATION. FORMULATION HAS A HUGE IMPACT ON THE EFFICACY OF NOVEL ADJUVANTS AND ALSO THE ADVERSE EVENTS VACCINES MIGHT INDUCE AND WE ALSO RECOGNIZE ONE OF THE BOTTLENECKS FOR ACADEMIC LABS AND SMALL BUSINESS THE COST ASSOCIATE WITH THE PRODUCTION OF NOVEL ADJUVANTS. SO PEER PROPOSING TO ASSIST WITH THAT PROCESS TO GET MORE NOVEL ADJUVANTS INTO THE PIPELINE. AND FINALLY IN REGARDS TO THE CLINICAL EVALUATION OF NOVEL ADJUVANTS WE'RE PROPOSE TO SUPPORT MORE PHASE 1 AND PHASE 2 CLINICAL TRIALS IN ORDER TO COMPARE AND DOWN SELECT NOVEL ADJUVANTS. THIS WILL INCREASE THE AVAILABILITY OF NOVEL COMPOUNDS THAT HAVE ALREADY BEEN TESTED AND IN CLINICAL TRIALS. SINCE THEY REPRESENT A SIGNIFICANT INVESTMENT AND WE WANT TO ANALYZE THE PROFILES FROM THE STUDY OF VACCINES WITH NOVEL ADJUVANTS TO SUPPORT THEIR EXPANDED USE IN CLINICAL TRIAL. . WE ALSO PLAN TO EXPAND THE BIOINFORMATICS RESOURCES AN COMPUTATIONAL MODELS TO HELP RECONCILE THE SOMETIMES INCOMPATIBLE RESULTS FROM CLINICAL STUDIES AND RECOGNIZE THE USEFULNESS OF THE HUMAN MODEL FOR THE EVALUATION OF NOVEL VACCINES. AND BY GAINING NOVEL INSIGHTS INTO THE MECHANISM OF ACTION OF THESE NOVEL ADJUVANTS. 9/11 -- NOVEL ADJUVANTS AND WE'RE NOW SUPPORTING THE SEARCH OF MODULE PRODUCTS AND COMPOUNDS TO REVERSE 2H2 RESPONSES INDUCED BY ALLERGENS AND WE SUPPORT THE SEARCH AND EVALUATION OF REVERSE ADJUVANTS. THESE ARE COMPOUNDS THAT INDUCE REGULATORY T CELLS THAT REDUCE DENDRITIC CELLS. I WANT TO INTRODUCE OUR COUNCIL SPEAKERS. THEY'LL GIVE PRESENTATIONS THAT ADDRESS SOME ASPECTS THAT ARE COVERED IN OUR STRATEGIC PLAN AND OUR FIRST SPEAKER IS DR. JACQUES BANCHERREAU HIS LAB LOOKS AT IMMUNE RESPONSES IN HEALTH AND DISEASE AND THAT INCLUDES FOR EXAMPLE THE CHANGES IN THE IMMUNE SYSTEM AS IT DETERIORATES DURING AGING OR THE CHANGES DURING PREGNANCY. ONE OF HIS APPROACHES IS THE USE OF HUMANIZED MICE TO DEVELOP NOVEL THERAPEUTICS INCLUDING NOVEL ADJUVANTS. >> THANK YOU VERY MUCH. I DO APPRECIATE THE INVITATION TO THIS DISTINGUISHED AUDIENCE. I WANTED YOU TO THINK ABOUT ADJUVANTS. I'M BASICALLY THE HAPPY RECIPIENT OF A U1 FROM MMCA AND I'D LIKE TO THANK THE HEAD BUT THE STORIES I'M GOING TO TALK TO YOU ABOUT COME FROM MANY YEARS OF WORK WITH THE WORK WITH THE NIH AND PARTICULARLY NIAID WITH CCHI IN MY DAYS IN TEXAS TWICE AND THEN I MOVED. ALL THAT HAS BEEN VERY GOOD SUPPORT BUT TODAY I I HAVE A COMBINATION IN CONSIDERATION THAT I'M BIASSED BY SAYING DENDRITIC CELLS BY NATURAL ADJUVANT PUT TOGETHER A PROJECT COMBINATION AND WE WERE SUCCESSFUL WHICH WAS GOOD NEWS. AND THE PROJECT WITH THREE GOALS, ONE IS TO SELECTED A COMBINATION THAT WOULD INDUCE MAXIMUM IMMUNOLOGY IN VITRO AND WE WANTED TO USE THE PC AND WE WENT TO IPS BECAUSE WE HAD TROUBLE WITH THE P34 AND THEN EVENTUALLY WE WOULD DO A FEW EXPERIMENTS WITH MICE. I'M GOING TO TELL YOU STORIES THAT ALL RELATE TO THE TOPIC. I'LL TELL YOU SOMETHING THAT CAME FROM NOW FINDING OF OURS AND OTHERS THAT FOUND IT IN THE BLOOD OF HUMANS. WE RECEIVED A VACCINE IN ABOUT 36 HOURS. I'LL TELL YOU SOMETHING THAT CAME IN THE NATURE OF MEDICINE ISSUE I RESOURCED -- I RECEIVED THIS WEEK ON TH10 AND THE DAY WE LOOKED AT THE DC AND I'LL SPEND TIME ABOUT THIS AND THE STORY IS VERY SIMPLE. WE LOOKED AT 17 VACCINES FOR THE EFFECT ON HUMAN DENDRITIC CELLS. AND WE OBSERVED ONE THING, THE FLU ZONE AND THEY WERE ACTIVATING DENDRITIC CELLS OR MONOCYTES OR DC2 IN A DIFFERENT FASHION. AND THEY ACTIVATE DIFFERENTLY AND WE SPENT TIME ON THE FLUZONE WHERE WE HAD SOME DREN -- DENDRITIC CELLS BEING ACTIVATED AND WE SHOWED THE FLUZONE 910 WAS ACTIVATING THE CDCs IN A WAY WE HAD INFORMATION ON AND THE ONE VACCINE FROM 2010 WAS BARELY DOING THAT. AND SOME WERE NOT PRODUCING THE IP10 BY COMPARISON TO FLUZONE AND SOME WERE PRODUCING THAT. WE COULDN'T FIGURE OUT WHAT IN THE FLUZONE WAS MAKING THIS AND STILL DON'T KNOW. WE HAVE MORE SOPHISTICATED TOOLS WHICH I THINK WOULD BE USEFUL FOR THE FUTURE ADJUVANT AND WE EXPOSED PDMC TO FLUZONE AND HAVE DONE SINGLE CELL AND IN GREEN ARE THOSE WITH THE CONTROL, NOTHING, MEDIUM AND IN PINK ARE THE PBMC THAT HAVE SEEN THE FLU VACCINE. SO THERE'S A DRASTIC EFFORT AND INTERESTINGLY THIS PINK HERE IS THIS ONE WHERE THE CD8 CELLS ARE FULL. THIS IS THIS BUN HERE THE CD40 CELLS AND HERE WE HAVE MONOCYTES WHERE WE HAVE THIS SIGNATURE. SO WE THINK ONCE WE REDUCE THEIR COST WILL BE INCREDIBLY USEFUL TO DID THAT. I DON'T BELIEVE EVERYTHING COMES FROM HERE. I THINK THERE'S SOMETHING ELSE WHICH DOES ACTIVATE WHICH WE WANT TO TRY TO UNDERSTAND. THE SECOND STORY LOOK AT THE IMMUNE TI AND WE'RE MOSTLY INTERESTED IN NEGATIVITIES THOUGH WE LIKE TO LOOK AT THAT. AND WE JUST CLOSED THE 27 YEAR REQUEST. WE DEMONSTRATED IN 1992 AFTER THE CLONING THAT I THINK WAS VERY POWERFUL FACTOR FOR HUMANS. ABSOLUTELY NOT IN THE MOUSE. BIG BIG DIFFERENCE. THE SWITCH FACTOR TO IGG1 AND IGG3. IT'S THE SWITCH FACTOR FOR IGA2. AND NO MOUSE MODEL CAN TELL US ABOUT IT BECAUSE THEY DON'T RESPOND AND CLOSE IN THE MOUSE. WE HAD A STORY WITH THE DIFFERENT SETS. AND THEN WE FOUND THAT THE SUBSET WERE ACTIVATING T CELLS AND C CELLS AND THEY WERE DIFFERENT. AND THEY INTERFIDE IN THE BLOOD OF THE HUMAN BEING TFX AND IDENTIFIED THREE SUBSETS AND WITH VIRGINIA WE FOUND THAT PDC THAT ARE ACTIVATE OXIDIZED MONONU MONONU MONONUKE WITH THE CELLS AND WE SEPARATED THEM AND WE SUPPLIED THEM FROM HUMAN SKINS AND WE HAVE TO DOWNLOAD THE CCD14 AND CC1A AND THIS IS MORE COMPLEX BUT WE CULTURED THE CELLS WITH CD4 CELLS AND SAW THE ACTIVITY OF THE T CELLS AND PUT THEM WITH B CELLS AND THEN WE SEE ONLY THE CELLS EXPOSED TO THOSE IN RED AND IT WAS POWERFUL AND THE T CELLS ARE NOT ABLE TO DO THAT. NOW, WHAT WE FIND IN THIS CONDITION IS THOSE T CELLS HERE THE CFC18 AND 21 IS A CHARACTERISTIC OF TFHH. AND THIS TFH IN THE BLOOD REPRESENTS A PERCENTAGE IN THE BLOOD AND THEY'RE BEAUTIFULLY SEPARATED ACCORDING TO CXCL13 AND WHEN WE SEE IS THE TFH1 CELL WHICH MAKES A DIFFERENT GAMMA WHILE THE TFH2 CELL AS YOU EXPECT WITH IGG AND IGE AND THE TFH17 MAKES ESSENTIALLY IGA WHEN WE HAVE THE NIGG WHEN IT'S CONSISTENT. SO WHEN WE STUDIED THE LUPUS AND FUND THEY WERE USING THE PRODUCTS OXIDIZED WHEN ACTIVATING PDC WERE MAKING A T CELL THAT WAS SLIGHTLY DIFFERENT FROM THE T CELL THAT WAS MADE WITH PDC ACTIVATED WITH CPGA. JUST NOTE CPGA DOES NOT EXIST. IT'S AN ARTIFICIAL PRODUCT. IT COMES FROM THE MITOCHONDRIA AND IN THIS CONDITION HERE THE T CELLS THAT ARE MADE THAT ARE REGULAR T CELLS DO NOT PROLIFERATE MUCH. THESE WERE MAKING A DIFFERENT GAMMA AND R3 AND THEY WERE ALSO HELPING THE CELLS IN A FABULOUS FASHION AND THEY HAVE HIGHLY PROLIFERATED COMPLETELY DIFFERENT FROM THE TR1. IT TOOK A LONG TIME TO FIGURE OUT. SO THOSE B CELLS AND I'LL SHOW YOU MORE OF THAT AND THEY'RE NOT TFH THEY'RE PD1 POSITIVE. WHEN YOU COMPARE THEM WITH TFH YOU SEE 1200 TRANSCRIPT DIFFERENCES BETWEEN THE T CELL TYPE. THIS IS HERE A DEMONSTRATION YOU HAVE A LOT OF CHEMO KINES ASSOCIATED TO TOXICITY. I DON'T KNOW WHAT IT MEANS IN TERMS OF HELPING THE B CELLS. . AND YES, THERE ARE B CELL HELPER. AND IF WE COULD CULTURE THE CELLS WITH NEGATIVE B CELLS WE SEE THEY MAKE AS MANY PLASMA BLASTS AS THE TFH WOULD DO BOTH ISOLATED FROM TO THE BLOOD OF HUMAN INDIVIDUALS AND WHAT WE SEE IS IN THE T PATIENTS THOSE CELLS ARE AMPLIFIED. FINALLY, WHAT WE HAVE DEMONSTRATED IS THAT THOSE T CELLS ARE ACTIVATED BY 01 BUT NOT BLOCKED BY I21 RECEPTOR BY THE POSITION TO TFH. TFH AND YOU SEE TFH ARE PARTLY BLOCKED. THERE ARE TWO POSSIBILITIES. THE TFH AND THE B CELLS AND WE HAVEN'T EVER PUBLISHED THAT AND IT'S AN IMPORTANT QUESTION WE NEED TO ADDRESS. NOW, THE SURPRISING FINDING IS THAT WE FOUND THAT I0 WAS DOING PART OF THE JOB -- L10. BUT NOT ALL THE JOB. BUT TO THE WHOLE STORY WE ALLOW ALLOWED FOR THE B CELLS. SOMETHING ELSE WAS PRODUCED BY THE CELLS. WE FOUND THEY HAD RECEPTORS. NOW, WE HAD A VIEW INDIVIDUAL WERE VACCINED WITH FLU. -- VACCINATED WITH FLU AND WE DIDN'T KNOW WHETHER THEY RESPONDED OR NOT. WE HAD TWO GUYS THAT ON DAY ONE SHOWED AN INCREASED PRESENCE MUCH THE CH10 I CALL THEM LIKE BECAUSE IT'S NOT PROVEN THEY WERE HELPER. EAST JUST SHOWN THE PHENOTYPE. AND THOSE GUYS KEEP ON GOING. THIS ONE DO NOT MAKE THE TH10 CELLS. THERE ARE TWO POSSIBLES. POSSIBILITIES EITHER THAI DON'T MAKE A VACCINE TO THE FLU OR DON'T INCREASE ANTIBODIES. THIS VACCINE DOESN'T DO ANYTHING. SO WHAT WE THINK IS HAPPENING HERE IS WE HAVE HAD THE DICHOTOMY BETWEEN THE REACTION DISPLAYED AND IN THE EARLY '90s AND THE TFH ARE PLAYING HERE WHERE WE THINK THE TH10 ARE PLAYING IN THE NON-GERMINAL CENTER ALL DUE TO THE RECEPTOR THE GENES EXPRESS. STORY NUMBER TWO. LET'S SPEND A LITTLE TIME ON STORY THREE. STORY THREE IS BASICALLY THE RA AND WE ARE STUDYING ONLY HUMAN AND GETTING DENDRITIC CELLS AND STARTED MAKING THEM FROM MONOCYTES AND THEN ISOLATED THEM AND ACTIVATE AND LOOKED AT TRANSCRIPTION AND LOOKED AT WHAT THE T CELLS DO AND WHERE WEATHER THEY'RE HELPING. WE WANT A COMBINATION OF ADJUVANT THAT MAKES A LOT OF TH1 EVENTUALLY. WE SAID TFH1 AND 10 BUT WE WANT TO LOOK AT AND WE DON'T WANT TO INDUCE AN ALLERGIC RESPONSE. IN THE HUMAN WE HAVE TWO MAJOR ONES CD C CALLED DC2 AND CD141 CALLED DC1. THEN THIS DISPLAYS A UNIQUE PATTERN OF RECEPTOR WHICH IS VERY DIFFERENT THAN THAT OF THE MOUSE. FOR INSTANCE, WE DON'T HAVE THOSE ON THE HUMAN DENDRITIC CELLS IN POSITION TO THE MOUSE. SO WE JUST DID A COMBINATION TOGETHER AND WE GOT TOOLS TO ACTIVATE AND WE USED THE AMP AND WE USED THE CLASSIC JOLE. WE DO FIND THIS COULD BE EASILY ACTIVATED. AND THE REASON IS BECAUSE THEIR BASAL LINE EXPRESSION ARE LOW. WE FIND THE LABELS ARE HIGHER BUT THE COMBINATION WE FIND THE MOST EFFICIENT IS THE COMBINATION OF THE MORE EFFICIENT. WE FIND BY FLOW THAT THE COMBINATION OF ADJUVANTS IS OFTEN THE BEST TO INDUCE TFH LIKE CELLS AND AS WELL AS TO INDUCE TH10 COMPARED TO OTHER SINGLE CELLS BUT R84 IS NOT BAD AT ALL AND WONDERING HOW MUCH WE'RE DOING CYCLING THE MP AND WE ARE MANUFACTURING THE CELLS AND THIS WAS A SURPRISE TO ME AFTER ALL WE HAVE DONE, WE FOUND SIGNIFICANT DIFFERENCE BETWEEN THESE. NOW, I HAVE ANOTHER PROJECT ON MEN AND WOMEN. AND I'M WONDERING WHETHER THERE IS SOMETHING IMPORTANT WITH RESPECT TO ADJUVANTS. THAT I DON'T KNOW. WE CERTAINLY KNOW WHEN CELLS ARE ACTIVATED THE MP YOU SEE THE DIFFERENCE. THE MP DOES SOMETHING. THERE'S ALWAYS AN EFFECT. I DON'T THINK A DRAMATIC EFFECT AND THEN IN THIS COLOR HERE THAT ACTIVATED AND THE COMBINATION FOR IT WHICH IS SLIGHTLY DIFFERENT. SO THIS IS BEING PURSUED AND TRYING TO UNDERSTAND WHETHER THIS IS GOING TO GIVE US WHAT WE'RE LOOKING BUT WHERE DO WE THINK ADJUVANTS ARE GOING TO GO? HOW WILL WE STUDY HUMAN ADJUVANTS? THERE'S A DIFFERENCE BETWEEN MOUSE ADJUVANTS AN HUMAN ADJUVANTS. AND WE THINK THE ONLY WAY IS TO GO THROUGH THE HUMAN IPS. BECAUSE I'VE LOOKED AT THIS FOR 15 YEARS AND THEY CAN DO KNOCKOUT AND CAN HAVE GENETIC RESPONSES WHICH WE BASICALLY CANNOT DO. SO HOW COULD WE DO THAT? WELL, WE THINK THAT THE ONLY WAY TO REALLY ADDRESS ADJUVANTS AND UNDERSTAND COMPLEX ADJUVANTS IS TO HAVE A SET OF HUMAN DENDRITIC CELLS THAT WOULD BE KNOCK OUT A OR B OR A AND B AND SEE HOW EACH IS GOING TO RESPOND TO THE COMBINATION ADJUVANT OR TO YOUR COMPLEX ADJUVANT LIKE FLUZONE. THE FIRST DAY SINCE WE DISCOVERED HOW TO MAKE DENDRITIC CELLS FROM C34 WE SPENT TWO YEARS A TON OF MONEY AND COULD NOT -- AND FOR SOME OTHER PEOPLE BUT WE HAVE NOT BEEN SUCCESSFUL AND WE'VE HAD MANY IDEAS. AND WE TOOK AN IPS AND WE WERE ABLE TO GENERATE CONDITIONS CONNECTING THE DENDRITIC CELLS OUT OF THE IPS. WE COULD GET A FAIR AMOUNT OF DENDRITIC CELLS. IN ADDITION THIS IS THE CLINICAL CONDITION. REMEMBER, AND WE LOOKED AT CANCER OR HIV VACCINE. THE DENDRITIC CELLS WE GENERATE HAVE PROPERTIES AND SOME EXPRESSED CD1C. AND ACCORDING TO A SLIGHT MODIFICATION IN THE CONDITION WE REACHED CD41 WHICH IS A DENDRITIC CELL GOOD FOR CROSS PRESENTATION AND IT GIVES YOU MORE CD8 THAN THE CD1C IS THE OTHER DENDRITIC CELLS. SO THESE CELLS CAN BE ACTIVATE AND CAN GIVE YOU A REACTION YOU SEE HERE AND THE CD1C BEING BETTER THAN THE CD141. AND WE'RE AT THE END OF THE STORY. MY FRIEND WAS THERE AND SAID JACQUES, DENDRITIC CELLS, YOU NEED FIVE OF THEM TO HAVE GAY REACTION. WE DON'T -- TO HAVE A GOOD REACTION. WE DON'T HAVE FIVE YET BUT THIS IS WHAT WE'RE DOING. AND THE CELLS WE HAVE GENERATED IN VITRO ARE THE RIGHT PHENOTYPE AND THIS ONE EXPRESSED CD1C BUT NOT CD141. SO WE COMPARED THEM AND WE LOOKED AT THE EXPRESSED GENE BETWEEN THE DENDRITIC CELLS AND SEE THE CD1C CREATED IN VITRO IS ISOLATED AND VICE VERSA FOR CD4141. SO WHERE ARE WE? WE HAVE NOW STUDIED LOOKING AT THE GENES. WE HAVE A FEW. THIS IS FOR INSTANCE A CLONE THAT IS REGI NEGATIVE AND BOTH ALLELES AND USING A CELL LINE MY COLLEAGUE HAS GENERATED WHICH LOOKS AT THE DELETION. WE HAVE ALL THESE MOLECULES THE SCREENING IS UNDERGOING. CLONE EXPANSION IS MADE FOR NONE OF THEM AND WE HAVE AN EDITION IN PROGRESS. WE'RE ALSO DOING THE WORK OF THE IPS. WE'RE DOING THAT WITH THE BLOOD. IT'S CD82 POSITIVE AND THE FIRST DAY SURPRISED US A LITTLE BIT. THIS IS REGI NEGATIVE DC AND WE SEE WE HAVE THE NUMBERS WERE STILL LOW. WE HAVE ACTIVATED THE DCs BY REGI AND SEE THE REGIVE NEGATIVE ARE LESS ACT VATD. WE NEED MORE STUDIES AND THIS IS ONGOING AND WHERE WE'LL BE KEEPING ON DOING AND TESTING AND WHAT WE DID TO THOSE TO THE DIFFERENT ONES THAT KNOCKED OUT DC AND WE THINK THERE'S CLINICAL APPLICATION. WE THINK THAT FOR CANCER AND MAYBE SOME OTHER CONDITION WE'LL HAVE SUPER DCs WHERE IT WILL ELIMINATE MOLECULES THAT ARE THE RECEPTOR FOR THE CHECK POINTS. ON THE OTHER SIDE, WE'LL ELIMINATE THE NUMBER OF MOLECULE ACTIVATING DCs. AND WE HAVE ALREADY DONE CD 40 AND WE'LL SEE WHAT WILL HAPPEN WITH THAT. AND WE THINK WE HAVE COMBINATION OF ADJUVANT THAT PERMIT TO ACTIVATE TFH1 AND TH17 AND NOC CELLS. WE HAVE A FAIRLY GOOD EVIDENCE THAT WE CAN MAKE HUMAN SUBSET FROM HUMAN IPS AND THAT WE CAN GENERATE ENGINEERED AND THIS COULD BE CREATED FOR COMPLEX ADJUVANTS. AND IDENTIFY THE MECHANISM OF ACTION AND UNDERSTAND HOW THIS WORKS. AND FINALLY, I WANT TO THANK THE NIAID LEADER FOR THEIR HIGHLY VALUABLE SUPPORT AND ADVICE. THANK YOU VERY MUCH. MARK. >> SO A LOT OF THE REACTIONS YOU'RE TALKING ABOUT ARE HAPPENING IN THE SECONDARY LYMPHOID TISSUE AND THERE'S GROUPS NOW FINDING FINE NEEDLE AS PAR ASPIRATES TO TRAIN THE LYMPH NODE. >> IT'S NOT ALWAYS EASY. I HAVE GOOD QUOTES SAYING YOU SHOULD TAKE IT BUT WE WERE TALKING ABOUT TALKING ABOTALKING ABOUT NEONATES. I WISH I COULD TAKE THE LYMPH NODE AND HAVE THE STRUCTURE. THAT'S WHAT I WISH WE COULD DO. LYMPH NODE S AND WITH BABIES, FORGET ABOUT IT AND FD38 IS OKAY. IT'S FUNDAMENTAL. >> QUICK QUESTION FOR JACQUES AND A COMMENT. SO WE'RE SEEING IGAG4 IN THE ROLE OF SURVIVORS. IT'S A LITTLE BIT OF A SURPRISE IN THE COMMUNITY BECAUSE IT'S A HALLMARK OF THE LONG-TERM ANTIGENS AND ALLERGEN IMMUNOTHERAPY AND I WONDER IF YOU BELIEVE THE 10 IS THE PRIMARY SWITCH. >> NO, IT STEMS BACK FROM MY OLD LIFE. THE ONE WE NEVER FOUND AND NOBODY HAS IT IS THE IGG2 SWITCH FACTOR. I LOOKED FOR THAT BECAUSE THIS WAS IN THE DATA AND I THINK THE OTHERS ARE BASICALLY MORE OR LESS KNOWN. NOW, YOU COULD HAVE A SWITCH WITH IG AND IGG4 AND AFTERWARDS HAVE YOU THE AMPLIFICATION OF A TH10 CELL THAT WON'T BE FUNDAMENTAL FOR THE SWITCH BECAUSE YOU WON'T BE IN THE SWITCHING POSITION. I HAVE HEARD OF AN IMMUNE DISEASE IN THE IGG4 SO IT WAS NEGLECTED AND COMING BACK AND LIKE TO SEE THE EXPRESSION FINALLY MAKE SENSE. >> GOING BACK TO MARK'S POINT ABOUT THE AS PAPIRATES THIS IS BECOMING MORE WIDELY USED THAN YEARS AGO. AND IT'S COMING UP IN SEVERAL GRANT APPLICATIONS AND IN OUR NETWORKS WHERE WE'RE THINKING OF CONVENING SOME KIND OF A SMALL WORKING GROUP TO EXPLORE HOW THE TECHNOLOGY'S DEVELOPING AND WHAT THE SUCCESS RATE IS IN TERMS OF ADEQUATE SIZE AND HOW MANY ASPIRATES YOU CAN DO AND SOME OTHER GROUPS ARE CONSIDERING OR ALREADY DOING BIOPSIES LARGER THAN A FINE NEEDLE ASPIRATES AND THERE'S NOT INFORMATION OUT THERE YET ABOUT THE SAFETY AND WHAT KIND OF ARCHITECTURAL CHANGES YOU MIGHT INDUCE WITH THESE AND IT REALLY SEEMS LIKE A TOPIC THAT'S REALLY RIPE FOR IT AND WE'D BE HAPPY TO HAVE PEOPLE NOT DOING THESE BUT DOING SOME OF THE IMMUNOLOGICAL ASSAYS WITH THESE. >> OUR NEXT SPEAKER IS DR. FRANCISCO QUINTANA FROM NEUROLOGY AT BRIGHAM AND WOMEN'S HOSPITAL. HIS FOCUS IS ON THE MECHANISMS THAT CONTROL IMMUNE RESPONSES AN HIS ULTIMATE GOAL IS TO IDENTIFIED NOVEL THERAPEUTIC PRODUCTS AN BIOMARKERS FOR IMMUNE DISORDERS. HE'LL FOCUS ON NANO PARTICLES WITH ANTIGEN-SPECIFIC IMMUNE MODULATIONS. >> GOOD. THANKS FOR THE INVITATION. I'LL SHOW YOU ACTUALLY FROM MY POINT OF VIEW TO TELL YOU HOW YOU HAVE SHEPHERDED ME THROUGH ANY SPECIFIC CAREER IN SUPPORTING MY TRANSITION TO AN INDEPENDENT GROUP LEADER AND EVENTUALLY ESTABLISHING MYSELF AS A GROUP AT MY HOME INSTITUTION. SO WHAT I'M GOING TO BE DOING TODAY IS TALKING ABOUT NANO PARTICLES FOR THE INDUCTION OF AN TI-GEN RISK TOLERANCE AND IN A SPECIFIC PATHWAY. I HAVE SOME FINANCIAL DISCLOSURE TO MAKE. AND THE PROBLEM I DON'T HAVE TO DESCRIBE HOW MANY ATTEMPTS AND INTERESTING IS THE FEE TO INDUCE TOLERANCE. AND WITH THE AUTOIMMUNE DISEASES WE CAN TALK ABOUT THE EFFECTER CELLS WHICH ARE THE CELLS WE WANT TO INDUCE AND INDUCE THE CELLS SUCH AS TR1 CELLS OR SIMILAR AND THEY'RE INTEGRAL TO THOSE OLDER AND LESS CHARACTERIZED POPULATIONS. THE PROPERTIES WE CAN AGREE FOR IMMUNE MEDIATED RESPONSES AND OUR GOAL IS TO SWITCH BACK THE BALANCE TOWARDS INCREASED REGULATION USING ANTIGEN SPECIFIC MANNERS AND THAT'S THE CHALLENGE. THIS IS A CHALLENGE THAT'S BEEN FOLLOWED UP MANY YEARS. THERE'S STUDIES AND IN MY Ph.D. STUDIES IN WORKING WITH DNA VACCINES AND THEY CAN SUPPLEMENT AND ADMINISTER IN A WAY TO CAUSE A RESPONSE. I THINK THE LEADER IN THE U.S. WAS ABLE TO COMPLETE SUCCESS NHL FULL STUDIES OF THE PHASE 2 STUDIES IN THE CONTEXT OF DIABETES AND MULTIPLE SCLEROSIS ANOTHER APPROACH IS PEPTIDE THERAPIES USED AND WITHIN THOSE I'M INCLUDING SUB CUTANEOUS ADMINISTRATION AND NOT LONG AGO A SUCCESSFUL TRIAL WHERE THEY WERE ADMINISTERING PEPTIDES WITH RED BLOOD CELLS AND IT'S AN OLD CONCEPT INITIALLY DEVELOPED BY STEVE MILLER DURING HIS Ph.D. STUDIES IN THE '70s. AND BASED ON THOSE FINDINGS, STEVE MILLER HIMSELF DEVELOPED WHAT WOULD BE THE NEXT GENERATION WHICH IS INSTEAD OF USING RED BLOOD CELLS AS AN ADJUVANT TO INDUCE RESPONSES, HE G GENERATE WHAT'D YOU COULD CONSIDER ARTIFICIAL RED CELLS AND CREATED NANO PARTICLES BECAUSE OF THEIR SIZE AND THAT'S AN IMPORTANT POINT WE CALL THEM NANOPARTICLES BECAUSE THEY'RE 50 NANO METERS AND TARGETING SPECIFIC CELL TYPES INSIDE THE MACRO RECEPTOR AND CREATES ANTIGEN SPECIFIC REGULATION. AND FINALLY A THIRD APPROACH IS A NEWER APPROACH THAT WAS ACTUALLY BEING SPEARHEADED IN CANADA AND THE IDEA IS TO GENERATE METALLIC NANOPARTICLES WHICH ARE LOADED WITH THE PEPTIDES AND THEN THE IDEA IS THE NANOPARTICLES WOULD INTERACT WITH THE EFFECTER CELLS IN ADDITION THEY'RE GOING TO EXHAUST HEM OR TURN THEM INTO -- THEM OR TURN THEM INTO TR1 CELLS TO INDUCE TOLERANCE. THAT'S ONE OF THE CHALLENGES WE'RE GOING FACE WITH ALL THESE APPROACHES. THE IDEA IS TO COME UP WITH APPROACHES TO A CERTAIN EXTENT AND FORCE DOMINANT TOLERANCE. SO WITH THE LIMITATIONS MUCH THE SYSTEMS WHICH THERE ARE OTHERS BUT MANY HAVE BEEN THERE FOR A WHILE, THE DNA, PEPTIDE AND NANOPARTICLE VACCINES ARE BASED ON THE PRESENTATION OF YOUR ANTIGENAL FEATURES THROUGH SOME KIND OF TOLLEROGENIC MECHANISM. THERE'S NO ACTIVE ENFORCEMENT. YOU'RE NOT CO-ACTIVATING. YOU'RE HOPING PRESENTATION OF THESE ANTIGEN VIA THE MACROPOSITIVE CELLS WILL INDUCE TOLERANCE AND THOSE MECHANISMS MAY NOT BE ENOUGH IN ORDER TO SUPPRESS ONGOING IN FLAMATION AND THE MECHANISMS ARE DYSFUNCTIONAL IN THE IMMUNE DISORDERS. AND WITHIN THE LIMITATION OF THE PEPTIDE NANOPARTICLES GENERATE THE SANTA MARIA GROUP SEEM TO BE VERY SPECIFIC AND EFFICIENT. pBUT IF YOU THINK IN THE CLINICAL TRANSLATION, YOU NEED TO GENERATE PEPTIDE COMPLEXES AND THAT IN TERMS OF THE CLINICAL AND IN THE CONTEXT OF ANTIGENS MAY BE CHALLENGING. THIS IS THE BACKGROUND OF WHAT YOU WOULD TRY TO DO AND WHEN I STARTED MY LAB A FEW YEARS BACK I TRIED TO IDENTIFY NEW PATHWAYS IN CONTROLLING THE BALANCE BETWEEN EFFECTER AND REGULATORY CELLS. AND WHAT WE DECIDED TO DO WAS TAKE AN APPROACH THAT AT THE MOMENT WASN'T THAT ORTHODOX WAS TO IDENTIFY REGULATORS OF ADAPTI ADAPTIVE IMMUNITY IN ZEBRA FISH AND THEY DO NOT HAVE AN ADAPTIVE IMMUNE RESPONSE. THAT WAS ACTUALLY PRETTY MUCH ESTABLISHED IN THE CONTEXT OF ZEBRA FITCH AND -- FISH AND YOU CAN IDENTIFY T CELLS AND MANY OF THE ELEMENTS THE MODELS THAT ARE IMPORTANT NOR CONTROL OF T CELL RESPONSES IN MAMMALS ARE REPRESENTED THERE. YOU CAN PUT THOSE TOGETHER AND THOSE ADVANTAGES WITH OUR INTEREST TRYING TO IDENTIFY MECHANISMS THAT CONTROL THE EFFECTER BETWEEN REGULATORY CELLS AND IDENTIFIED MULTIPLE PATHWAYS WE THOUGHT WOULD BE RELEVANT. AND ONE WE IDENTIFIED IS THIS PATHWAY HERE THE RECEPTOR. AND TO CUT IT SHORT YOU CAN THINK OF IT AS A RECEPTOR. WHEN ENACTIVITY WHEN INACTIVITY SITS IN THE CYTOPLASM AND IT MOVES IN THE NUCLEUS AND WILL CONTROL THE ACTIVITY AT THE EXPRESSION OF TARGET GENES AND IT'S GOING TO DO IT BY INTERACTING WITH TRANSCRIPTION FACTORS AND WE'VE TRIED TO IDENTIFY THE DIFFERENT MECHANISMS AND MOLECULAR MECHANISMS BY WHICH IT CAN CONTROL THE ACTIVITY OF REGULATORY CELLS AND ALSO OF ANTIGEN PRESENTING CELLS IN PARTICULAR DENDRITIC CELLS. AND WE THOUGHT THROUGH THE STUDIES WE COULD TRY TO DEVELOP TECHNIQUES IN ORDER TO INDUCE ANTIGEN SPECIFIC TOLERANCE. THE REASON IS THE FOLLOWING. FOR OUR STUDIES WE IDENTIFIED THE SIGNALLING WITHIN THE DENDRITIC CELLS CAN EFFECT THE ABILITY OF THOSE DENDRITIC CELLS TO LOOK AT THE EFFECTIVE REGULATORY CELLS. THERE'S AN LIGAND TRANSCRPTION FACTOR MEANING WE CAN ALWAYS GENERATOR IDENTIFY, ISOLATE SMALL MOLECULES THAT WILL ACTIVATE OR INHIBIT THE ACTIVITY. WITH THAT IN MIND, WE THOUGHT OF TRYING TO DEVELOP TECHNIQUES IN ORDER TO MODULATE THE SIGNALLING WITHIN DENDRITIC CELLS IN ORDER TO CONTROL THE EXPANSION OF FUNCTION IN REGULATORY CELLS. ONE OF THE FIRST THINGS WE HAD TO FACE WAS IT HAD A BAD NAME. IF YOU THINK ABOUT IT, AHI WAS IDENTIFIED AS A RECEPTOR AND AS WE HEARD BEFORE ABOUT THE COMMENTS IN TERMS OF GRANTS IS ONE OF THE FINEST COMMENTS I GOT IN TERMS OF MY GRANTS AND INITIAL PAPER WHERE YOU'RE FOCUSSING TO STUDY THE RECEPTOR AND IT EVOLVED IN NATURE MANY YEARS SO IT HAS TO BE A PHYSIOLOGICAL WORD FOR IT AND WE AND OTHERS HAVE IDENTIFIED MULTIPLE SOURCES OF WHAT WE CALL PHYSIOLOGICAL LIGANDS FOR HR. SOME COMING FROM THE GUT FLORA. SOME PROVIDED BY METABOLISM. SOME PROVIDED BY THE DIET. SO DOING OUR BASIC STUDIES WHAT WE HAVE TRIED TO DO OVER THE YEARS IS USE THIS PATHWAY AS A PATHWAY TO IDENTIFY HOW IS IT THE ENVIRONMENT CAN HAVE SPECIFIC MECHANISMS AND IF WE ZOOM OUT ONE OF THE MOST IMPORTANT DRIVERS OF INFLAMMATORY CELLS NOT ONLY GENOMIC DRIVERS BUT FACTORS WHICH IS WHY WE'RE FOCUSSED ON THAT. NOW GOING BACK TO WHAT WE'RE TRYING TO DO TODAY WHICH IS DISCUSS THE EXPLOITATION OF THE ANTIGEN SPECIFIC THERAPY WE THOUGHT WE CAN DEVISE A WAY OF ACTIVATING THE PATHWAYS IN THE DENDRITIC CELLS AS A WAY TO BOOST THE GENERATION OF WHAT WE CALL DEN DRITSIC CELLS KNOWING IT'S A LOOSE TERM AND MOSTLY A FUNCTIONAL DEFINITION. TO APPROACH THAT, A FEW YEARS BACK AROUND 2008 AND 2009 WE STARTED TO WORK WITH THE PARTICLES AND STUDIED NANOPARTICLES BECAUSE THEY WERE THE EASE YEFTS F-- USIEST FOR US TO WORK IN THE -- THE EASIEST FOR TO US USE IN THE LABS AND WE SENT TWO SIGNALS TO DENDRITIC CELLS. THE FIRST SIGNAL WAS GOING AND WE IDENTIFIED EFFECTS IN THE DENDRITIC CELLS MEANING IF YOU ACTIVATE AHR IN THE DENDRITIC CELLS YOU CAN INDUCE DIFFERENTIATION SO WE DECIDED IF WE CAN ACTUALLY DELIVER AN AGONIST AND ACTIVATORS TO DENDRITIC CELLS WE CAN ESSENTIALLY BOOST THE ABILITY TO EXPAND T CELL AND CONTROL AUTOIMMUNITY. WE DECIDED TO GO BACK TO NATURE AND FOCUS ON THE MULL PAL -- PUT PAL LIGANDS AND -- MULTIPLE LIGANDS AN SHOW ACTIVATORS OF THE PATHWAY. WE FOCUSSED ON THIS LIGAND HERE WHICH IN SHORT IS CALLED I.T. THE REASON IS BECAUSE IT'S BEEN ISOLATED IN THE GUT AND OTHER MUCOSAL TISSUES AND SHOWN BY MULTIPLE GROUPS INCLUDING US TO INDUCE DIFFERENTIATION OF DENDRITIC CELLS OR THE ACQUISITION OF FUNCTION BY DENDRITIC CELLS AND WE HAVE SHOWN IT HAS NO TOXICITY AND FOR MULTIPLE PERIODS OF TIME WE COULD SEE NO TOXICITY AND SAW IT DEGRADED FAST AND THERE'S SPECIFIC SETS THAT ARE REGULATING THE LEVELS OF THIS AND OTHER CIRCULATION AND THE IDEA SIT PROVIDES A SYSTEM WELL DEFINED IN TERMS OF WHERE IT'S ACTIVATED. WITH THIS IN MIND THE FIRST SET OF STUDIES WERE TRYING TO IDENTIFY IF THIS ACTUALLY COULD BE A STRONG THEROGENIC MODELS AND WE HAD MICE WHERE WE WERE ABLE TO INDUCE INFLAMMATORY BOWEL DISEASE. WE WERE ABLE TO SHOW IF WE TREAT THESE MICE WITH I.T. THE HR AGONIST WE CAN EXPAND GUT REGULATORY CELLS AND CAN HAVE EXPRESSION IN VIVO OF THE INFLAMMATION. SO WE HAVE AN ACTIVE COMPONENT TO INDUCE THIS IN THE CELLS AND WE WANTED THEM TO BE ANTIGEN SPECIFIC AND WE DECIDED OUR NAN NANOPARTICLES SHOULD CARRY TWO MESSAGES. ON THE OTHER HAND WE WANTED THEM TO DELIVER AN ANTIGEN RELATED TO THE DISEASE AND THEIR INVESTIGATION. FOR SOME THIS COULD BE PANCREATIC ANTIGENS AND SOMETIMES WE HAVE USED ANTIGENS TO HELP FOR DISEASES SUCH AS IBD WHERE NO SINGLE ANTIGEN HAS BEEN IDENTIFIED BUT SOME STILL HELP ANCHOR THE ANTI-INFLAMMATORY RESPONSE WITHIN THE GUT. SO OVER THE YEARS WE ACTUALLY CHANGED THE MATERIALS WITH WHICH WE BUILT THEM AND NOW WE'RE USING THE CELLS. THERE'S TWO IMPORTANT REASONS. FIRST, THE CELLS ALLOW US TO HAVE MORE CONTROL IN TERMS OF WHAT IS RELEASED AND GIVES MORE CONTROL IN TERMS OF HOW TO SCALE UP THE PRODUCTION OF THESE PARTICLES AND MAKE THEM COMPATIBLE AND THERE'S MULTIPLE EXAMPLES OF THOSE IN THE CLINIC AND THERE'S LIMITED EXAMPLES AND SUGGESTED WE CAN HAVE SOMETHING TO GIVE TO PEOPLE THIS WOULD ABE SHORTER ROUTE TO IT. SO THIS GIVES YOU AN IDEA WHERE OUR DIFFERENT COMPONENTS ARE DISTRIBUTED IN THE LIPO PHILLIC LAYER WHERE THE AGONIST IS SITTING AND I'LL SHOW YOU AT THE END OF THE DAY WE CAN GO INTO SITUATIONS WHERE WE WANT TO BOOST IMMUNE RESPONSES INSTEAD OF SUPPRESSING THEM AND HERE THE CAVITY HERE WE HAVE THE ANTIGENS AND THEY COULD BE PEPTIDED WITH A COMBINATION AND IT'S VERY HARD FOR YOU TO QUANTIFY HOW MUCH OF EACH ONE OF THE PEPTIDES HAVE YOU LOADED AND DON'T THINK FROM THE TRANSLATION POINT OF VIEW IT'S RELEVANT. WE HAVE USED THE EXTRA CELLULAR DOMAIN WHEN WE ARE TRYING TO COME UP WITH APPROACHES. AND ADDITIONAL DATA THE NANOPARTICLES HAVE A NEGATIVE CHARGE AND WHAT IS INTERESTING THEY'RE ACTUALLY VERY STABLE. THEY CAN BE STABLE IN TERMS OF SIZE, CHARGE, CONTENT, LOAD FOR UP TO SIX MONTHS WHICH IS IMPORTANT BECAUSE IT HAS TO DO WITH HOW WE'LL ACTUALLY PASS THAT TO PEOPLE. THE INTERESTING THING ABOUT IT IF WE THINK ABOUT IT IS IT'S A PRETTY MODULAR SYSTEM. YOU HAVE THE THEROGEN IT COMPONENT AND YOU CAN CHANGE THE ANTIGEN YOU'RE LOADING AND LOOK AT THE RESPONSE OF EVERY PATIENT AND IF YOU HAD A WAY TO LOOK AT THE IMMUNITY. THE FIRST WE LOOKED AT THE MODEL AND HAD TOOLS IN THE BACKGROUND IN ORDER TO STUDY THIS MODEL. AND WE HAD NANOPARTICLES LOADED WITH ANTIGEN AND STARTED WITH A COMBINATION OF BOTH. YOU CAN SEE THERE WAS A SIGNIFICA SIGNIFICA SIGNIFICANT SUPPRESSION AND WE ADMINISTERED THE NANOPARTICLES, THERE WAS AN ANTI-INFLAMMATORY COMPONENT AND WE KNOW THEY WORK SUBCUTANEOUSLY WHICH IS IMPORTANT FOR TRANSLATION BUT WE KNOW WE NEED THE ANTI-INFLAMMATORY AGONIST AND ANTIGEN TO BE IN THE SAME NANOPARTICLE. WE CANNOT HAVE SEPARATE ENTITIES WE BASED ON THE MIXED IMMUNE RESPONSE FOR EVERY PERSON AND IS A CHALLENGE WE SEE FOR THE FUTURE. LOOKING AT MORE THERAPEUTIC APPROACHES, WE USED THE SIMILAR MODEL INDUCED BY THE DIFFERENT BACKGROUND AND WHAT YOU CAN SEE IS USUALLY AFTER ONE OR TWO INCIDENT WE SEND THE SECOND PROGRESSIVE AND THIS IS PROBLEMLY ONE -- PROBABLY ONE OF THE MOST UNMET CLINICAL NEEDS FOR TREATING THOSE IN THE FIRST PHASE OF THE DISEASE WHICH ARE USUALLY WELL CONTROLLED BUT BEING TO CONTROL THE PATIENT WHERE'S INFLAMMATION STARTS TO SIT AND ALMOST LOCALIZED. WE WAITED ABOUT A MONTH AFTER THE INDUCTION AND ONCE THEY HAVE THE PHASE WE CALL PROGRESSIVE EIE, WE STARTED TO TREAT THEM AND YOU SEE A SIGNIFICANT AMELIORATION AND BASICALLY THIS IS MEDIATE TI1 CELLS THAT ARE ABLE TO DEACTIVATE. IT TOUCHES UPON THE PRODUCING CELLS AND IDENTIFIED THOSE WITH POSITIVE CELLS AND WE LOOK AT INFLAMMATION. GETTING MORE TO THE MECHANISMS, WE DO DETECT REGULATORY T CELLS. IF WE TRANSFER THEM WE CAN TRANSFER PROTECTION IN THE ACUTE MODEL. AND IF WE START TO FOCUS ON THE SPECIFICITY OF THE T CELLS REMEMBER BY USING TETROMERES AND THOSE BETWEEN THE CELLS WE CAN DETECT IN THE PERIPHERY AND WITHIN THE CNS A SIGNIFICANT CHUNK THAT ARE POSITIVE. I'M SORRY THEY HAVE AN AN IMMUNO DOMINANT MODEL. WE WANTED TO ADDRESS THE MECHANISM MEDIATING THE EFFECTS. WE WANTED TO VIEW THE LIBRARY OF CONDITIONAL KNOCKOUTS FOR IT AND THE DENDRITIC CELLS AND TRYING TO IDENTIFY WHICH ONE OF THEM WE NEEDED TO ACTUALLY ACTIVATE THE HHR SIGNALLING. AND THE DATA STRONGLY SUGGESTS THE ACTIVATION OF HHR HAS TO OCCUR IN THE DENDRITIC CELLS BECAUSE IF WE KNOCK THE HR FROM THE DENDRITIC CELLS WE INCREASE THE EFFECT OF THE NANOPARTICLES. IN STUDIES WE WERE ABLE TO TARGET THE POPULATIONS INVOLVED AND WE BELIEVE THIS IS TRYING TO CONTROL THE SPECIFIC DENDRITIC CELL POPULATIONS. WHAT WE HAVE STUDIED AND LEARN OVERRULED THE YEARS IN TERMS OF HOW THE SIGNALLING PATHWAYS OPERATE WITHIN THE DENDRITIC CELLS. WE KNOW ONE THING AHR DOES IS S THE IN THE -- INTERACTION AND THERE'S NOT ONE MECHANISM IN WHICH IT SEEMS TO CONTROL THE DENDRITIC FUNCTION BUT CONTROLS THE EXPRESSION WHICH RESULTS IN ANTI-INFLAMMATORY CELLS AND NOW IT SEEMS TO BE OPERATING ON DENDRITIC CELLS AS WELL AND SEEMS TO HAVE AN IMPORTANT ROLE IN CONTROLLING THE METABOLISM OF THOSE CELLS AND CONTROLLING THE D DENDRITIC CELLS TO PROMOTE ANTI-INFLAMMATORY RESPONSES. THE NANOPARTICLES CAN EXPAND AND SEEM TO SUPPRESS ONGOING INFLAMMATION AND IN ORDER TO ADDRESS THAT WE LOOKED AT THE DIABETES MODEL. THE REASON IS THAT'S A MODEL FOR THE SIGNIFICANT SPREADING AND CONTROL THAT SPREADING AND THERE'S A VERY IMPORTANT COMPONENT OF CD8 IMMUNE T CELLS SOMETHING IN MOST MODDOL -- MODELS YOU DON'T HAVE AND WE LOADED THEM WITH AN INSULIN. WE HAVE A SIGNIFICANT EXPRESSION OF TYPE 1 DIABETES. THIS IS A SPONTANEOUS MODEL AND IN THIS CASE WE TREATED OUR MICE STARTING AT THE AGE OF 10 WEEKS. BY THAT AGE THE MICE ALREADY HAVE SIGNIFICANT ONGOING INFLAMMATION AND IN THE MICE IN THE FACILITY. WE CAN LOOK AT THE EFFECTS FOR THE PEPTIDES FOR INSULIN AND THAT'S IMPORTANT BECAUSE FROM THE PRACTICAL POINT OF VIEW IT'S MUCH EASIER AND CHEAPER AND MUCH MORE CONTROLLED TO GENERATE A NANO PARTICLE LOADED WITH ONE PEPTIDE OPPOSED TO A NANO PARTICLE LOADED WITH A PROTEIN. AND WITH HUMAN CELLS, THERE WAS A NICE COLLECTION OF T CELLS DERIVED FROM THE PATIENTS. ACTUALLY, WE USED THE CELLS WITH THE ANTIGEN AND WE GENERATED NANO PARTICLES AS A WAY LOOK AT THE EFFECTS IN THE MODEL AND GOT SIGNIFICANT EXPRESSION OF THE ACTIVATION OF THE C CELLS IN VITRO. WE CAN ALSO EXPRESS T1D RESPONSES. AND THERE'S A LOCALIZED FACTOR 8 AND WE CAN USE THE APPROACH IN THIS CASE NANO PARTICLES LOADED WITH FACTOR 8 BY DIMINISHING THE INDUCTION OF FACTOR 8 ANTIBODIES. THIS IS TO SUM ADVISE -- SUMMARIZE TO THE STUDIES AND WE USED NANOPARTICLES AND WE TRIED THE IDEA OF BEING ABLE TO ADMINISTER UNDER CERTAIN CONDITIONS THE NANO PARTICLES. AND OBVIOUSLY THERE'S MULTIPLE LIMITATIONS AND MANY ANTIGEN SPECIFIC APPROACHES. FIRST IS ANTIGEN SELECTION IS NOT TRIVIAL TO IDENTIFY WHAT ANTIGENS WE'LL BE USING TO TREAT HUMAN DISEASES AND FOR MANY OF THE DRUGS WE USED FOR M.S. HAVE BEEN VALIDATED OR COMING FROM STUDIES IN THE I.E. AND FOR WE CAN LOOK AT THE MOST REPRESENTATIVE MODELS TO TASTE THESE AND OTHER APPROACHES AND THERE'S IMPORTANT MANUFACTURING AND REGULATORY ISSUES BECAUSE IT'S NOT JUST A RECUMBENT PROTEIN BUT A COMBINATION OF THINGS AND THAT IMPOSE OR PRESENTS US WITH MULTIPLE CHALLENGES. FINALLY, WHERE ARE WE GOING WITH THESE? FIRST WE MAY NOT NEED NANOPARTICLES AND WE HAVE GENERAT GENERATED PROBIOTICS AND WE HAVE GENERATED PROBIOTICS BY SYNTHETIC BIOLOGY TO AGONISTS AND IN SOME PRELIMINARY STUDY WE IDENTIFIED SOME STRAINS ALLOWING US TO SUPPRESS INFLAMMATION IN THE MODEL AND WITH THERAPY AND I START SAYING THIS PATHWAY WAS NOT ACTUALLY INVENTED OR CREATED FOR US TO REACT TO DIOXIN. THIS IS PART OF BIOLOGY. AND THIS HAS EXPLODED IN SOME PATH OWE LOGIC CONDITION. BRAIN TUMORS ARE A RICH SOURCE OF ONE OF THE MOST POTENT ENDOGENOUS ACTIVATORS AND ONE CORE COMPONENT IS IT SEEMS TO BE A MECHANISM WHERE THE CELLS SEEM TO BE DRIVING T CELL EXHAUSTION. WHAT WE HAVE DEVELOPED IS THE NANOPARTICLES AND INSTEAD OF DELIVERING AN AGONIST TO ACTIVATE THE PATHWAY THEY DELIVER AN ANTAGONIST. IT'S BEING INVESTIGATED AS A WAY TO INTERFERE WITH THE CYTOGENIC SIDESQU SIDESQUES -- SIDE EFFECTS AND WE HAVE COLLABORATED WITH GROUPS IN BRAZIL AND ARGENTINA AND WE WERE ABLE TO IDENTIFIED VIRUSES CAN REGULATE THE REGULATE THE CELLS AND WE HAVE GENERATED THIS INHIBITORY NANOPARTICLES AND SHOWED WE HAVE A WAY TO USE THEM IN IN VITRO AND IN VIVO IN ZIKA INFECTION. AND WE WERE ABLE TO GET SIGNIFICANT EXPRESSION IN VIVO AND WE WERE ABLE TO INTERFERE WITH THE FETAL FORMATIONS ASSOCIATED WITH THE DEE -- ZIKA CONGENITAL MODELS. WITH THAT I'LL FINISH AND WITH THIS INVESTIGATIONS WERE FUNDED SINCE I GOT MY FIRST K99 GRAVENTS -- GRANTS SO THANK YOU FOR THAT AND I'LL BE HAPPY TO TAKE ANY QUESTIONS YOU MAY HAVE. >> TAKING THE NANOPARTICLE WITHOUT THE ANTIGEN AND IT WAS pDO YOU HAVE ANY CONCERNS ABOUT NON-SPECIFICITY IN PARTICLE ESPECIALLY IF GIVEN SYSTEMICALLY. >> GREAT QUESTIONS. WE DO SEE THE NANO PARTICLES GOING TO MACROPHAGES AND THIS IS WHY WE HAVE THE LIBRARY OF CONDITIONAL KNOCKOUTS THOUGH THEY'RE TAKEN BY THEM THEY DON'T SEEM TO BE NECESSARY FOR THE PROTECTIVE EFFECTS OF THE NANO PARTICLES. THE WAY WE TEASE IT OUT IS BY THE CONDITIONS IN THE KNOCKOUT. BASED ON THE STRUCTURES WE HAVE AND WE HAVE DENDRITIC CELL ANTIBODIES BUT WE DECIDED TO STEP BACK AND NOT USE THEM AFTER THE RESULTS BECAUSE THE SIMPLER THEY ARE THE MORE LIKELY THEY ARE TO HAVE TRANSLATIONAL VALUE. THE SECOND QUESTION WAS REGARDING THE I.T. EFFECTS IN THE ABSENCE OF ANTIGEN. THAT'S A REAL FINDING. WE DO SEE IT IN SOME DISEASES AND IN THE T1 MODEL WE SEE IT. WE DO NOT SEE IT IN THE RHEUMATOID ARTHRITIS MODEL AND IF WE GO TO MORE CHALLENGING SITUATIONS, FOR EXAMPLE, TREATING EIE MICE ONES ALREADY SICK OR COMING LATER, WE DO NOT SEE THOSE EFFECT. SO WE DO BELIEVE THERE'S NON-SPECIFIC SUPPRESSION BUT THAT DOESN'T SEEM TO BE ENOUGH TO HAVE SIGNIFICANT EFFECTS. AND BY THE WAY, WE LOOK AT THE RESPONSES BY THE ANTIGEN IN THOSE MICE AND WE DID NOT SEE A SIGNIFICANT CHANGE. >> IN TERMS OF THE DELIVERY OF THE NANOPARTICLES IS IT EFFECTED BY -- DO YOU HAVE EVIDENCE OR THINK IT WOULD BE EFFECTED BY EXPOSURES I'M THINKING ABOUT DIFFERENT LIGANDS BUT I JUST WONDER IN CASES WHERE THERE IS A SIGNIFICANT AMOUNT OF EXPOSURE THAT'S ALSO FEEDING INTO THE SAME PATHWAY, HOW'S THAT GOING TO EFFECT THE DELIVERY OF THESE NANOPARTICLES? >> THAT'S A GREAT QUESTION. SO ONE OF OUR MAIN CONCERNS WAS INITIALLY THE ACTIVATION BY THE PARTICLES AND WE DO NOT SEEM TO SEE AN EFFECT THERE. IN TERMS OF THE EXPOSURES, WHAT WE NOTICE IS THOUGH IT WAS PUBLISHED THAT THERE WAS A MAIN METABOLISM OF THE LIGANDS THAT DOESN'T TO BE THE SAME IN THE MULTIPLE GROUPS. C1A1 IS MOST RESPONSIVE AND EXPOSED TO DIOXINS AND THERE ARE THREE THINGS OR THREE ADVANTAGES BY WHICH WE USE THE NANOPARTICLES. FIRST HAS TO DO WITH THE CELLS AND SECOND HAS TO DO WITH THE ANTIGEN OF CHOICE AND THE THIRD IS THE LIGANDS ARE RELATIVELY PROTECTED AND DELIVERED WITHIN THE DENDRITIC CELLS OR THE CELLS UPDATED. >> THE RECEPTOR ALSO DRIVES DIFFERENTIATION 1. WHY DO YOU THINK THAT DOESN'T HAPPEN HERE? >> THAT'S INTERESTING. IN THE THERE A PUBLICATION AND WE SHOWED IT WAS IMPORTANT FOR BOTH TH17 AND TRX AND WE HAVE SHOWN IT IS IMPORTANT FOR TH17 CELLS BUT TO INDUCE NON-PATHOGEN IT T17 CELLS AND POTENTIALLY YOU CAN EVEN INDUCE THEM INTO A FULL EFFECT OF THEROGENIC CELLS AND THERE'S A STUDY WHERE THEY SHOWED THE SIGNALLING TURNS THEM INTO TR1 CELLS. I THINK INITIALLY THEY WORE CONFUSING BECAUSE WE WERE ALL IMMUNIZING WITH A TON OF CFA AND THEN THAT TRANSITION HAPPENS VERY FAST. IF YOU DO IT IN VITRO AND USE THE RIGHT TOOL YOU CAN SEE THE NON-PATHOGENIC TH17 CELLS AND POTENTIALLY FOR THE CONVERSION TO TH1 CELLS. >> THE THIRD SPEAKER IS ANGUS THOMPSON FROM THE UNIVERSITY OF PITTSBURGH. HIS NIH SPONSORED PROGRAM FOCUSES ON THE INTERACTION BETWEEN INHIBITORY DENDRITIC CELLS AND T CELLS WITH THE IDEA OF INDUCING TOLERANCE TO TRANSPLANTATION. >> THANK YOU VERY MUCH, DR. LEITNER. I'D ALSO LIKE TO THANK YOU FOR THE PRIVILEGE OF BEING ABLE TO TALK WITH YOU THIS AFTERNOON. SO MANY PEOPLE WOULD AGREE THE CURRENT PROBLEM IN CLINICAL ORGAN TRANSPLANTATION IS THE IMMUNOLOGICAL I'D EFFECTS AND THE LIFE SPAN FROM A DONOR IS 50% AND FROM A LIVING DONOR IT'S SIGNIFICANTLY GREATER THAN THAT BUT WE HAVE A PROBLEM AND THE SIDE EFFECTS WITH IMMUNOSUPPRESSION. THERE'S LIMITATIONS CORE STIMULATION IN THE FORM OF RENAL SPEARING RESULTS IN ACUTE REJECTION AND THE USE OF ANTIBODIES AS INDUCTION OF THE ANTIBODIES AND EFFORTS TO INDUCE TOLERANCE USING THE STEM CELLS WHILE PROMISING FACES MANY HURDLES IN TERMS OF SAFETY AND WIDESPREAD APPLICABILITY. SO ATTENTION HAS TURNED TO POTENTIAL OF USING ENDOGENOUS AND EX-VIVO GENERATOR OR EXPANDED IMMUNE CELLS FOR CELL-BASED THERAPY AND REJECTION. SINCE WE ALL RECOGNIZE REGULATORY DENDRITIC AND T CELLS ARE KNOWN TO MAINTAIN TOLERANCE IN THE HEALTHY STUDY STATE IN RODENTS AND ABSENCE OF EITHER REGULATORY T CELLS OR POSITIVE T CELLS IN MICE OR CONVENTIONAL DENDRITIC CELLS RESULTS IN A PROGRESSIVE LETHAL AUTOIMMUNE DISEASE. WE KNOW A NUMBER OF THERAPIES IN EXPERIMENTAL ANIMALS CAN ENHANCE IMMUNE CELL FUNCTION AND IN VIVO THESE AGENT ALONE OR TOGETHER MAY HAVE THE CAPACITY TO RENDER THESE CELLS MORE ACTIVE THAN IN THE ABSENCE OF THE DRUGS. REGULATORY IMMUNE CELL THERAPY POSES MANY QUESTIONS. THIS LIST IS BY NO MEANS EXCLUSIVE TO CURRENT CHALLENGES REGARDING REGULATORY T CELL THERAPY BUT I CONTEND EXTENDS TO MANY OF THE STRATEGIES CURRENTLY CONSIDERED USING IMMUNE CELLS TO IMPROVE OUTCOMES IN ORGAN TRANSPLANTATION. THERE'S MANUFACTURING ISSUES AND ISSUES CONTAINING DOSAGE. WHAT WOULD THE APPROPRIATE TIMING AND FREQUENCY OF CELL INFUSION BE. THERE'S ISSUES REGARDING SPECIFICITY. DOES ADMINISTERING A LARGE NUMBER OF REGULATORY T CELLS, EXPANDED EX VIVO HAVE TOWARDS NON-SPECIFIC IMMUNE EXPRESSION. WE'RE MOVING NOW TOWARDS THE REGULATORY T CELLS. WE DON'T KNOW A GREAT DEAL ABOUT THE HOMING ABILITY OF DENDRITIC T CELLS IN FUSED IN PATIENTS AND KNOW LITTLE ABOUT THEIR REGENERATIVE CAPACITY AND WHETHER WE NEED AN AGENCY TO HELP EXPAND THEIR SURVIVAL AND FUNCTION. THESE CELLS APPLY TO REGULATORY MYELOID AND REGULATORY T CELLS HAVE BEEN LOOKED AT UNDER INFLAMMATORY CONDITIONS. AND WHAT'S APPROPRIATE IN THE EXPRESSIVE AGENT TO USE IN CONJUNCTION WITH IMMUNE CELL THERAPY AND CAN WE OVERCOME MEMORY IN THESE CELLS USING THESE APPROACHES. SO AS DEPICTED HERE REGULATED DENDRITIC CELLS PLAY A KEY CENTRAL ROLE IN INHIBITING EFFECTER T CELL PROLIFERATION AND DIFFERENTIATION AND THIS HAS EFFECTED A NUMBER OF GENE PRODUCTS AS SHOWN HERE. AND REGULATORY DENDRITIC CELLS CAN INDUCE THE PROLIFERATION OF REGULATORY T CELLS. THAT THEMSELVES WILL INFLUENCE IN THE NEGATIVE FASHION THE STIMULATIVE FUNCTION OF THESE IMPORTANT CELLS. OUR OWN INTEREST IN TARGETING OR USING USING EX VIVO CELLS FOR ORGAN TRANSPLANTATION GOES BACK MANY YEARS. WE HAVE BEEN INTERESTED ESSENTIALLY IN TWO APPROACHES IN TARGETING OF QUISETHETIC CELLS. THERE'S ADDITIONAL APPROACHES THAT HAVE BEEN TESTED INCLUDING THE USE OF DONOR-DERIVED CELLS AND DONOR-DRIVED EXOSOMES BUT USING THE STANDARDIZATION OF THESE PRODUCTS AN ENSURING THAT THESE TYPES OF CELLS OF DONOR ORIGIN CAN BE OB STAINED IN SIGNIFICANT QUANT FOR HUMAN USE IS CHALLENGING. MORE COMMONLY WE HAVE GENERATED REGULATORY DENDRITIC CELLS IN VITRO AND THESE TAKE A VARIETY OF FORMS. REGULATORY DENDRITIC CELLS CAN BE IMMATURE, THEY CAN BE DENDRITIC CELLS THAT HAVE BEEN CONDITIONED, EXPANDED FROM BONE MARROW PRECURSORS OR MONOCYTES USING A VARIETY OF AGENT AND IN PARTICULAR ANTI-INFLAMMATORY CYTOKINES ALONE OR IN COMBINATION AND THEY ALTERNATIVELY ACTIVATE THE DENDRITIC CELL. A DENDRITIC CELLS EXPOSED TO MEDIATORS AND THEN EXPOSED TO AN ACTIVATING AGENT SUCH AS A LIGAND HAS BEEN USED TO GENERATE CLINICAL REGULATORY DENDRITIC CELLS. SO THE APPROACH THAT'S MOST COMMONPLACE IS TO TAKE A DONOR-DERIVED DENDRITIC CELLS TAKE ON THE CHARACTERISTICS OF THE CELL AND LIBERATES THE PRODUCT WILL REGULATE T CELL FUNCTION AND ALSO RETAINS STABILITY SUCH AS THE CELLS RESISTANT TO PRO-INFLAMMATORY MEDIATORS AS WOULD BE ENCOUNTERED IN AN IN VIVO INFLAMMATORY CELL SCENARIO. OUR WORK HAS TAKEN US FROM EARLY CHARACT CHARACTERIZED THROUGH CLINICAL TESTING IN SMALL ANIMAL AND THEN NON-HUMAN PRIMATE MODELS TO OUR CURRENT UNDERTAKING OF PHASE 1 CLINICAL TRIALS OF THE FEASIBILITY AND SAFETY OF REGULATORY DENDRITIC CELLS IN CLINICAL ORGAN TRANSPLANTATION. AND THESE STUDIES HAVE BEEN SUPPORTED BY A NUMBER OF GRANTS FOR THE PRECLINICAL WORK AND CLINICAL STUDIES THAT HAVE BEEN EXTREMELY VALUABLE IN TRANSLATING THE TECHNOLOGY FROM THE INITIAL IN VITRO STUDIES ALL THE WAY THROUGH TO CLINICAL EVALUATION. SO OUR INITIAL INTEREST IN REGULATORY DENDRITIC CELLS WAS IN THE EARLY 1990s IN THE CONTEXT OF THE ROLE OF DONOR-DERIVED DENDRITIC CELLS WITH ORGAN TRANSPLANTATION. CHRIS LARSSON AND OTHERS HAVE PUBLISHED DATA IMPLICATING DONOR-DERIVED DENDRITIC CELLS IN THE CONTEXT OF SKIN AND HEART TRANS PLANTATION. HOWEVER, WE WERE INTRIGUED BY THIS ESPECIALLY IN THE CONTEXT OF THE SPONTANEOUS ACCEPTANCE OF MISMATCHED LIVER ALLO GRAPHS IN MODELS. SPONTANEOUS MODELS OCCURS WITH LARGE PIG ALLOGRAPHS AND OF COURSE IN HUMANS DENDRITIC CELLS HAVE BEEN IMPLICATED IN REGULATION OF AUTOIMMUNITY. WE GENERATED DENDRITIC CELLS FROM NORMAL LIVER. THESE WERE MADE BY DEN -- GENERATING CELLS IN AND CONTROVERSIED THE DONOR-DERIVED REGULATORY DENDRITIC CELLS PROPAGATE FROM THE LIVER WERE ABLE TO MARKEDLY PAROLE THE ALLOGRAPHS IN THE ABSENCE OF IMMU IMMUNOSUPPRESSIVE THERAPY. I WOULD BE FIRST TO CONCEDE THERE'S NO CONSENSUS HOW ONE CAN GENERATE A REGULATORY DENDRITIC CELL IN VITRO. HOWEVER THEY'RE CHARACTERISTIC OF THE CELLS AND HAVE LOW EXPRESSION OF MHC CLASS 2 AND THEY PRODUCE VERY LITTLE BIOACTIVE P12 AND P70. HOWEVER, THEY EXPRESS HIGH LEVEL OF ANTI-INFLAMMATORY BETA AND COMPARATIVELY HIGH LEVELS WITH SIMULATORY MOLECULES SUCH AS PD011 AND MAY EXPRESS COMPARATIVELY HIGH LEVEL OF DEATH-INDUCING MOLE CULES AND SHOULD RETAIN CCR7 AS IMPORTANT HOMEORECEPTORS FOR TISSUE. THE APPROACHES THAT HAVE BEEN USED TO RENDER THESE PROPERTIES IN EX VIVO-GENERATED CELLS INCLUDING ENGINEERING APPROACHES IN THE UPPER LEFT AND MANY PHARMACO LOGIC MEDIATORS HAVE RENDER THE DENDRITIC CELL SHOWING RESISTANT TO MATURATION AND SHOWN TO ADHERE TO TISSUE AND PRETRANSPLANT ADMINISTRATION OF REGULATORY DENDRITIC CELLS PROMOTE GRAPHS OF SURVIVAL. THIS IS TRUE OF VA VASCULARIZED GRAPHS WITH ADDITIONAL ADMINISTRATION OF TREATMENT TO THE GRAPHED RESENT ENTAND ADMINISTRATION OF THESE CELLS CONSISTENTLY IN ALL THE STUDIES LEADS TO INDEFINITE GRAPH SURVIVAL. SO IN RODENTS THE ADOPTIVE TRANSFER OF DENDRITIC CELLS INDUCES ANTIGEN SPECIFIC TOLERANCE AND PROMOTES DEFINITE GRAPH SURVIVAL. INTERESTINGLY AS MY COLLEAGUE HAS SHOWN VERY ELEGANTLY, THE THERAPEUTIC EFFECT DOES NOT DEPEND ON THE IN VIVO PERSISTENCE OF THE POTENTIAL ADVANTAGE OVER OTHER CELL FLAPPY -- THERAPY APPROACHES WHERE ADDITIONAL ADMINISTRATION OF THE IMMUNO CELL POPULATION MAY BE REQUIRED TO ACHIEVE AND SUSTAIN THERAPEUTIC EFFICACY. AND WE KNOW FROM STUDIES THAT A DONOR DRIVE TO REGULATORY DENDRITIC CELL IN THE MOUSE SYSTEM WILL CONVEY ANTIGEN VIA INDIRECT PATHWAY TO T CELLS SUBVERTING THEIR FUNCTION AND IMPAIRING CELL MEDIATED AND IMMUNITY. WE ALSO KNOW GENE PRODUCTS CAN BE ACQUIRED VIA CROSS-DRESSING OR EXOSOMES FROM THE DONOR-DERIVED CELLS IN RODENT MODELS HAVE SHOWN NOT TO SURVIVE VERY LONG AND SUSCEPTIBLE TO NK CELL KILLING. WHAT WE ENVISION IS THE GENE PRODUCTS OF THESE CELLS THAT ARE TRANSFERRED TO HOST ANTIGEN PRESENTING CELLS AND AS WE HAVE FOUND IN EXPERIMENTAL MOUSE LIVER TRANSPLANT MODELS, CROSS-DRESSED CELLS HAVE THE ABILITY TO REGULATE THE ANTI-DONOR IMMUNE RESPONSE AND PRODUCE ANTI-DONOR T CELL SENESCENCE AND WE HAVE BEEN ABLE TO TRANSLATE FROM THESE RODENT STUDIES TO CLINICALLY IRRELEVANT NON-PRIMATE MODEL AND THIS SUPPORT HAS BEEN SUPPORTED BY A STUDY GROUP WHICH HAS BEEN A VALUABLE AND COLLEGIAL SETTING IN WHICH TO PRESENT AND EVOLVE THESE STUDIES AND IN THIS PARTICULAR SET OF EXPERIMENTS, WE TESTED THE ABILITY OF DONOR-DERIV DONOR-DERIVED DENDRITIC CELLS FOR A NON-PRIMATE RHESUS MONKEY AND WE INFUSED THE CELLS AS WE HAD IN THE MOUSE MODEL A WEEK BEFORE TRANSPLANT TO DETERMINE FIRST OF ALL THEIR SAFETY AND THEIR EFFICACY. IMPORTANTLY, THE REGIMENT WE USED WAS A MINIMAL EXPRESSIVE REGIMENT OF CO-STIMULATION. AND WE FOUND HERE THAT THE REGULATORY SINGLE DENDRITIC CELL INFUSION ONE WEEK FROM TRANSPLANT SIGNIFICANTLY PROLONG THE SURVIVAL OF THE LIFE-SUSTAINING ALLOGENNATE PRIMATE MODEL.PRECLINICAL SO THESE NON-HUMAN PRIMATE STUDIES PROVED IT WAS SAFE TO INFUSE THESE RY DENDRITIC CELLS AND THE NUMBERS WERE BETWEEN 2.5 AND 10 PER KILOGRAM WEIGHT AND SHOWED SURVIVAL AND IMPORTANTLY WE FOUND NO EVIDENCE DETERMINED BY QUALIFICATION OF ANTI-DONOR ANTIBODY IN THE SYSTEMIC CIRCULATION AND WE NOTED SELECT ATTENUATION OF DONOR REACTIVE MEMORY T CELLS A POTENTIAL BASIS FOR BIOMARKER ANALYSIS FOR MONITORING ANTI-DONOR T CELL RESPONSES. SO WHAT DO WE KNOW ABOUT HUMAN REGULATORY T CELLS? WE KNOW ABOUT STUDIES REPORTED QUITE SOME YEARS AGO THE REGULATORY DENDRITIC CELLS ARE IMMATURE CELLS AND EFFECT THE T CELL FUNCTION. WE KNOW THAT EARLY DATA SUPPORT THE SAFETY OF POST-DENDRITIC CELLS IN THE AUTO-IMMUNE DISEASES LIKE ARTH RIGHTIC AND CROHN'S -- ARTHRITIS AND CROHN'S DISEASE AND IT'S SAFE AND HAS PROVEN TO RESULT IN PATIENTS BEING QUITE STABLE POST YEARS TRANSPLANT IN A SMALL NUMBER OF PATIENTS AT THE UNIVERSITY OF AND DEATH TOGETHER WITH MY COLLEAGUES AND AN IMMUNOLOGIST AND THE CLINICAL DIRECTOR OF OUR ORGAN TRANSPLANT PROGRAM TOGETHER WITH THE MULTIPLE TEAM MEMBERS YOU SEE IN THE SLIDE WE HAVE EMBARKED PON TWO -- UPON TWO STUDIES IN ORGAN DONOR TRANSPLANTATION. THE FIRST SUPPORTED BY OUR INSTITUTION IN LIVING DONOR LIVER TRANSPLANTATION AND THE OTHER SOON TO COMMENCE AND SUPPORTED BY NIAID UO1 STUDY GRANT IN LIVING DONOR RENAL TRANSPLANTATION. SO I WANT TO TALK A LITTLE BIT ABOUT THE TRIAL ALREADY UNDERWAY OF REGULATORY DENDRITIC CELLS OF DONOR ORIGIN IN LIVING DONOR LIVER TRANSPLANTATION. THIS STUDY IS TO HOPEFULLY DEVELOP A NOVEL AND UNIQUE THERAPEUTIC STRATEGY THAT WOULD ALLOW LIVING DONOR, LIVING DONOR TRANSPLANT RECIPIENTS TO DISCONTINUE EXPRESSION EARLY TRANSPLANT AND YET RETAIN EXCELLENT GRAPH FUNCTION. IF SUCCESSFUL, SUCH A STRATEGY WOULD ELIMINATE OR AT LEAST MARKEDLY REDUCE THE WELL-DOCUMENTED RISKS OF LONG-TERM IMMUNOEXPRESSION IN LIVER TRANSPLANT RECIPIENTS. THAT'S NOT NOT UNCOMMON EFFECT OF LIVER FAILURE AND CARDIOVASCULAR DISEASE AND INCREASED RISK OF INFECTION AND CERTAIN TYPES OF MALIGNANCY. IN THESE PATIENTS, THE ABILITY TO WITHDRAW OR REDUCE DEPENDENCY ON ANTI-REJECTION DRUGS EARLY POST-TRANSPLANT WOULD BE TREMENDOUSLY BENEFICIAL. AND THE STRATEGY HERE AS IN THE PRIMATE AND RODENT MODEL IS A ONE-TIME INFUSION OF THE REGULATORY DENDRITIC CELLS ONE WEEK BEFORE TRANSPLANTATION. SO THE OBJECTIVES ARE PRIMARILY IN THE FIRST OF HUMAN STUDY SAFETY EVALUATION FOLLOWED BY INFUSION OF THE CELLS FOLLOWED BY THE WITHDRAWAL OF THE PATIENTS THAT ARE ELIGIBLE FOR ENTERING INTO THE WEANING PROTOCOL ONE YEAR POST-TRANSPLANT. AND WE SEEK TO ENTER THE EFFICACY OF THE QUIN -- INFUSION IN SEEKING THE WITHDRAWAL AND IT CAN BE ACHIEVED IN ONLY ABOUT 10% TO 15% OF ALL PATIENTS IN THE FIRST TWO YEARS POST-TRANSPLANT. INCREASING THE RATE OF DRUG WITHDRAWING TO SIGNIFICANT LIE HIGHER LEVELS OF PATIENT OR GREATER WITH INFUSION WOULD CLEARLY HAVE A SIGNIFICANT IMPACT ON THE FIELD. AND HAVE AN ASSESSMENT OF THE WITHDRAWAL OF THE HOST IMMUNORESPONSE TO DONOR. THIS IS THE CLINICAL PROTOCOL LIVER TRANSPLANTATION IS PERFORMED ON DAY ZERO BETWEEN TWO AND FOUR WEEKS PRIOR TO TRANSPLANT THE LIVING DONOR UNDER GO AS A CONVENTIONAL LEUKO LEUKOFORESIS AND THE MONOCYTES ARE RESUSCITATED AND INFUSED IN DOSES BETWEEN 2.5 AND 10 MILLIGRAMS PER KILO GRAM BODY WAIT IN PROSPECT ONE WEEK BEFORE THE TRANSPLANT. THE PATIENT RECEIVES A DOSE TO MINIMIZE LOW POTENTIAL RISK AND WITH THE EXCEPTION OF THE PATIENT HAVING IF THE PATIENT HAS A PERMISSIVE LIVER BYPASS -- BIOPSY THE PATIENT WILL ENTER INTO THE PROTOCOL I DESCRIBED AND POST-TRANSPLANT THE LIVER BIOPSIES WILL BE REPEATED. SO THIS SAY FIRST IN HUMAN SINGLE-CENTER PROSPECTIVE, OPEN LABEL, NON CONTROLLED, NON RANDOMIZED -- NON-RANDOMIZED TRIAL. BRIEFLY, I WANT TO MENTION SOME UPDATES ON THE FIRST THREE PATIENTS THAT HAVE BEEN ENTERED INTO TRIAL. THE FIRST PATIENT WAS TRANSPLANTED IN SEPTEMBER 2017, AS WITH THE OTHER PATIENTS THERE'S BEEN NO ADVERSE EFFECTS WITH THE CELL INFUSION AND NO CSA DETECTED AT VARIOUS TIME POINTS POST TRANSPLANT. THE MOST RECENT DETERMINATION BEING ONE YEAR. CURRENTLY, PATIENTS LABS WITH LIVER FUNCTION TESTS WERE ALL NORMAL. AND IMMUNOSUPPRESSION HAS NOW BEEN STOPPED AND THE ONE-YEAR GRAPH BIOPSY HAS BEEN EXCELLENT AND THE STEP-DOWN REDUCTION HAS NOW COMMENCED AND IS WELL UNDERWAY. PATIENT NUMBER TWO AGAIN NO ADVERSE EFFECTS WITH VERY WELL INFUSION AND NO SIGNIFICANT ANTIBODIES DETECTED AND THE PATIENT IS DOING WELL AND ON MMF IMMU IMMU IMMU IMMUNOASK SUPPRESSIVE REDUCTION AND THE PATIENT HAS NOW UNDERGONE ADJUVANT CHEMOTHERAPY ANDAL BUE MIN LEVELS ARE TRENDING DOWN AND THE PATIENT IS ON MMF IMMUNOSUPPRESSION. AND THIS REPRESENTS RECRUITMENT OF INFUSION OF THE CELLS. WE'RE NOW ON PATIENT NUMBER EIGHT AND THIS PATIENT UNDERWENT TRANSPLANT LAST THURSDAY. AS YOU CAN SEE THE RECRUITMENT HAS GONE TO ONE PER MONTH HAVING TRANSITIONED THROUGH THE EARLY PHASE IN WHICH WE WERE MANDATED BY THE FDA TO LEAVE A THREE-MONTH PERIOD BETWEEN THE ENROLLMENT OF THE FIRST FOUR PATIENTS NOW ENROLLING UP TO A TOTAL OF 12 PATIENTS IN THE INITIAL STUDY. WE HAVE A NUMBER OF COLLABORATIONS INCLUDING WITH DR. DAVID ROTHSTEIN'S LAB INVESTIGATING REGULATORY B CELLS IN THE PATIENTS. OUR NIAID COLLABORATIVE 1 GRANT IS GOING TO BE CONDUCTING A RELATED STUDY OF DONOR DERIVED CELL THERAPY UNDERGOING RENAL TRANSPLANTATION AND THE CLINICAL DIRECTOR OF THIS STUDY IS DR. HARAHAN. THE STUDY IS ANTICIPATED TO BEG BEGIN AS EARLY AS NEXT MONTH AND WE HAVE FRUSTRAAPPRECIATED THE TEAM INVOLVING THE DETAILS OF THE CLINICAL TRIAL PROTOCOL. SO THERE ARE PROSPECTIVE CLINICAL TRIALS AND OTHER THAN THOSE MENTIONED AT THE UNIVERSITY OF PITTSBURGH. THERE'S INTEREST IN POTENTIALLY GENERALIZING CELL THERAPY IN THE CONTEXT OF THE DONOR LIVER TRANSPLANTATION. EXPERIMENTAL ANIMAL STUDIES HAVE SHOWN ADMINISTRATION OF DEN RIT RIT -- DENDRITIC CELLS POST TRANSPLANT AND SURVIVAL BEING ACHIEVED IN ANIMALS GIVEN THE CELL THERAPY COMPARED WITH APPROPRIATE CONTROLS. THERE'S INTEREST IN THE POSSIBILITY OF REGULATORY DENDRITIC CELL TESTING AND LIVER TRANSPLANTATION AND EXPERIMENTAL ANIMAL MODELS SUGGEST THAT REGULATORY DENDRITIC CELL THERAPY COULD BE POTENTIALLY EFFICACIOUS IN THE CONTEXT OF HUMAN STEM CELL TRANSPLANTATION. SO THE LAST FEW MINUTES ARE MECHANISTIC STUDIES ARE DESIGNED TO GAIN ADDITIONAL INSIGHTS IN PARTICULAR THE IN VIVO FATE AND INFLUENCE OF INFUSION OF THE DC REGS IN REGULATION TO HOST IMMUNE RESPONSE. AND THESE STUDIES WE HOPE WILL GUIDE FUTURE INNOVATION DEVELOPMENTS AN IMMUNOGENIC THERAPIES AND LEAD TO IDENTIFY ANY SAFETY CONCERNS SICH AS THE POTENTIAL RISK OF ANTI-DONOR SENSITIZATION TO DETECT EARLY EF CAS -- EFFICACY SIGNALS AND LOOK AT THE ISSUES DETAILED ON THE SLIDE. THIS IS THE PRODUCT GENERATED GMCSF AND IL4 AND IL0 AND THE VALIDATED DC REG PRODUCT IS INFUSED ONE WEEK PRIOR TO TRANSPLANTATION. THE FIRST THREE PATIENTS HAVE RECEIVED DOSES RANGING FROM 2.9 TO 7 MILLION DENDRITIC CELLS PER KILOGRAM BODY WEIGHT. THE SECOND DONOR UNDERWENT TWO LEU LEU LEU LEU LEUKAPHERESIS AND THERE WAS THE INFUSED CELL PRODUCT SHOWS A RELATIVELY HIGH RATIO AND BIOACTIVE PRODUCTION IS HEAVILY SKEWED AS YOU CAN SEE IN FAVOR OF IL10 PRODUCTION. THIS IS CONSISTENT FOR ALL THE CELL PRODUCTS. THE REGULATORY DENDRITIC CELLS ARE NOT SIMPLY IMMATURE DENDRITIC CELLS AS TRANSCRIPTIONAL ANALYSIS CLEARLY SHOWS THE NUMBER OF GENE PRODUCTS UPREGULATED IN THE CELLS COMPARED TO MATURE DENDRITIC CELLS. WE IDENTIFIED DIFFERENCES IN LAB 3S100R34 AND CD18 AND EXPRESSION OF THE GENE PRODUCTS CONSISTENT WITH REGULATORY CELL FUNCTION AND PROPERTIES OF THE CELLS. WE'VE ALSO BEEN ABLE TO VISUALIZE THE CELLS AFTER THEIR INFUSION AND DISCRIMINATING BETWEEN DONOR AND RECIPIENT AND YOU CAN SEE IMMEDIATELY POST-INFUSION THE PRESENCE OF THE DONOR-DERIVED CELLS IN THE CIRCULATION BY FOUR DAYS AFTER INFUSION ONE CAN NO LONGER DETECT THE CELLS IN THE CIRCULATION BY ANALYSIS BUT THERE IS ANALYSIS WE BELIEVE IS INDICATIVE OF CROSS-DRESSED CELLS RECIPIENT AND DONOR CLASS 1 EXPRESSING CELLS SUGGESTING IN HUMAN AS IN THE MOUSE MODEL THE IN FLUGS -- INFUSION OF THE CELLS PRESENT CROSS-DRESSED CELLS AND HERE'S A DEMONSTRATION OF AT THE TIME OF TRANSPLANT THE SEVEN DAYS AFTER THE INFUSION OF THESE CELLS, EVIDENCE THAT THESE RECIPIENT ANTIGEN-PRESENTING CELLS IN THIS CASE DENDRITIC CELLS ARE CROSS-DRESSED WITH THE CELLS OF DONOR ORIGIN. HERE'S ANOTHER EXAMPLE OF CROSS-DRESSING HERE IN THE RECIPIENT LYMPH NODE SHOWING EVIDENCE OF CROSS-DIRECTION OF THE RECIPIENT DENDRITIC CELLS IN THE LYMPH NODE BY CLASS C AT THE TIME OF TRANSPLANTATION. WE FOUND IN THE MOUSE MODEL CROSS-DRESSING OF RECIPIENT DENDRITIC CELLS IS ASSOCIATED WITH REGULATORY FUNCTION OF THE HOST PRESENTING CELLS AND IF THEY'RE SORTED AND THEIR FUNCTION IS TESTED, THEY WILL REGULATE ANTI-DONOR T CELL REACTIST ASSOCIATED WITH SENESCENCE OF T CELLS AND WE HAVE PRELIMINARY EVIDENCE THAT THE INFUSION OF THE REGULATORY DENDRITIC CELLS MAY BE CAUSING AN INITIAL REDUCTION IN EFFECTER MEMORY AND MEMORY CELL POPULATIONS. THESE ARE PRELIMINARY STUDIES AND OBVIOUSLY WE'LL BE CONTINUING OUR MECHANISTIC STUDIES TO FURTHER EXTEND THESE S. -- OBSERVATIONS AND OUR RENAL TRANSPLANTATION WILL BEGIN SHORTLY AND IS BY CONTRAST WITH THE LIVER STUDIES NOT DRUG WITHDRAWAL STUDY AND ALSO BUY -- BY CONTRAST THIS IS A DOSE ESCALATION STUDY IN ORDER TO FIRST OF ALL ASSESS SAFETY WHERE MHC INCOMPATIBILITY WITH A DONOR DERIVED REGULATORY IMMUNE CELL POPULATION COULD PRESENT A POTENTIAL RISK OF POST-SENSITIZATION GIVEN BETWEEN THE TIME OF IN FLUGS AND RENAL TRANSPLANT AND THE IMMUNOSUPPRESSIVE DRUGS THAT WILL BE USED ARE STANDARD OF CARE. AND WE'RE VERY INTERESTED IN LOOKING AT THE COMBINED IMMUNE CELL THERAPY WHETHER THEY CAN BE USED FOR REDUCTION AND IN THE SAME RECIPIENT REGULATORY T CELLS FOR LIMITED EXPRESSION. THESE STUDIES ARE NOW BEING EVALUATED BY US IN OUR NON-HUMAN PRIMATE MODEL. SO FINALLY, LET ME FINISH BY ACKNOWLEDGING THE INVALUABLE SUPPORT OF MANY COLLEAGUES AT THE UNIVERSITY OF PITTSBURGH PARTICULARLY MY COLLEAGUES DR. LATKIS AND DR. HUMAR IN THE LIVER TRANSPLANT PROGRAM. MY COLLEAGUES IN THE PRE-CLINICAL STUDIES AND THE STUDIES OF THE NON-HUMAN PRIMATE MODEL AND STUDIES IN THE REGULATION OF YUM MONTGOMERY AND OF COURSE OUR COLLABORATORS OF THE NATIONAL INSTITUTES OF HEALTH FOR EVOLUTION OF OUR CLINICAL INVESTIGATIONS. SO THANK YOU VERY MUCH INDEED FOR YOUR ATTENTION. [APPLAUSE] >> SO WHEN YOU ARE INFUSING THESE THINGS AS AN UNDERSTAND IT, THERE'S PIECES OF THE INTACT CELLS OF THE DENDRITIC CELLS SO BY THAT PROCESS DO YOU EXPECT TO TARGET T CELLS IN THE DIRECT AND INDIRECT PATHWAYS? >> YOU CAN TARGET INDIRECT AND VIA ACQUISITION OF INTACT DONOR MHC IN THE FORM OF EXOSOMES FROM THE DONOR. >> IF THE EXOSOMES MELTED INTO THE MEMBRANE OF THE DENDRITIC CELLS WOULD THEY BE FACED -- PHASED OUT? >> I THINK WE CAN TEST THAT BY INVESTIGATING WHETHER THE CELLS WILL ACTIVATE A T CELL CLONE REACTIVE TO A2 CLASS 1 AND THAT'S A STUDY WE PROPOSE IN OUR MECHANISTIC INVESTIGATIONS BUT IT'S GOING TO BE DIFFICULT ISOLATING ADEQUATE NUMBERS OF THE CROSS-DRESSED CELLS FOR FUNCTIONAL ANALYSIS. >> NOW WE'VE MOVE ON TO A TIGHT TIME LINE FOR SEVEN CONCEPT PROPOSALS AND ASK EACH OF OUR STAFF AT THE CLOSE OF THEIR DISCUSSION TO COME UP AND INTRODUCE THEMSELVES. FIRST IS WENDY DAVIDSON TALKING ABOUT DEVELOPMENT OF SAMPLE SPEARING ASSAYS FOR RENEWAL OF AN EXISTING PROGRAM AND PLEASE BE BRIEF BUT ALLOW TIME FOR WHATEVER DISCUSSION IS NECESSARY. FIRST, WHAT IS THE EARLIEST TRAIN FOR A COUNCIL MEMBER? ANGUS? SO WE'RE OKAY IF WE GO A LITTLE BIT OVER. FEEL FREE TO SPEND AS MUCH AS TIME AS WE NEED. NONE OF US ARE GOING ANYWHERE. >> THANK YOU. I'LL TRY TO BE BRIEF HERE. SO THIS SAY RENEWAL AS DAN SAID OF THE SAMPLE SPARRING ASSAY RFA. THIS WAS FIRST APPROVED BY COUNCIL IN 2015 AND THE MAIN GOALS OF THE PROGRAM WERE TO DEVELOP CUTTING EDGE ASSAYS TO LABEL IMMUNE COMPLEX MONITORING USING SMALL SAMPLE VOLUMES DERIVED FROM HUMAN SUBJECTS AND MANY INVOLVED PEDIATRIC POPULATIONS. SO WE'RE ALWAYS STRUGGLING TO BE ABLE TO DO IN DEPTH IMMUNE ANALYSIS WITH A SMALL VOLUME. THE WHOLE PURPOSE OF THE RFA IS TO DEVELOP SAMPLE SPARRING ASSAYS. SO IT'S BEEN A VERY SUCCESSFUL PROGRAM SO FAR. WE'VE HAD 55 PUBLICATIONS. THESE AND THIS IS HIGHLIGHTING SOME OF THE WORK WE'VE BEEN DOING AND DEVELOP THE TECHNOLOGY USING BAR CODING TECHNOLOGY SO WE CAN NOW USING IMMUNE CELLS. WE DEVELOPED SMART TUBES IN PARTICULAR FOR ANALYSIS USING PEDIATRIC SAMPLES. WE CAN GET DOWN TO 200 MICROLITERS NOW USING 30 TO 60 FREE AGENT. WE CAN SAMPLE MANY DIFFERENT IMMUNE CELL SUBSETS IN ONE TUBE USING 200 MICRO LITERS. WE HAVE SMART LITERS FOR BASAL FILL ASSAYS AND CAN DO THOSE AT ONE TIME AND SO IT'S A ONE-STEP ASSAY. WE ALSO HAVE SMART TUBES NOW BEING USED IN THIRD-WORLD COUNTRIES AND LOOKING AT VARIOUS DISEASE AND SMART TUBES ARE BEING INCORPORATED IN INFECTIOUS DISEASE AND BEING USED IN THE CLINICAL TRIALS INVOLVING INFANTS. AND WE'RE LOOKING AT INDIVIDUAL CELL POPULATIONS. THESE HAVE BEEN DONE AT MIT, BRIGHAM AND WOMEN'S AND COLUMBIA AND WE'RE DEVELOPING NOVEL APPROACHES FOR ASSAYS ON INDIVIDUAL CELLS AND HAVE PROTOCOL FOR SINGLE-CELL RNA EXPRESSION AND NAL -- ANALYSES OF RECEPTORS AND ANOTHER DEVELOPMENT IS AN AUTOMATED SYSTEM WHICH IS INTERESTING GIVEN THE PRESENTATIONS. WE'RE HOPING TO RENEW THE RFA. THE GOAL IS TO DEVELOP CUTTING-EDGE ASSAYS TO ENABLE COMPLEX IMMUNOMONITORING USING SMALL SAMPLES DERIVED FROM HUMAN SUBJECT. WE'RE FOCUSSING ON HIGH RESOLUTION AND STATE OF THE ART MONITORING SOLUTIONS. FOR A PERIOD OF FIVE YEARS. FUNDING MECHANISM WILL BE A $5 MILLION BUDGET AND ONE DIFFERENCE THE PREVIOUS RFAs WE'RE GOING INTRODUCE AN OPPORTUNITY FUND OF HALF A MILLION DOLLARS PER YEAR. WE BROUGHT THIS IN TO FURTHER ENCOURAGE SIDE PROJECTS AND INVESTIGATORS POSSIBLE YO TO EXPAND UP THE WORK WE'VE BEEN DOING AND INTRODUCE NOVEL IDEAS AND BETTER COLLABORATIONS AN INTERACTIONS WITH SOME OF OUR CONSORTIA AND THE GOAL IS TO INCREASE PROGRAM OUTREACH AND ENABLE TRAINING OF INVESTIGATORS. I WANTED TO POINT OUT ALREADY THE PROGRAM HAS BEEN SUCCESSFUL IN GENERATING COLLABORATIVE INTERACTIONS. AND WE'VE HAD A NUMBER OF PATENTS IN ADDITION. THANK YOU AND ANY QUESTIONS? >> THIS IS STEVE GALWAY. WHAT IS THE ONE-STEP ASSAY SUPPORTED BY THIS? >> THAT'S A NEW ASSAY CECILIA BARON DEVELOPED AT MOUNT SINAI. >> IT'S A SITE-OFF BASED ASSAY. >> AND IT HAS THREE AGENT FOR DOING STIMULATION AS WELL AS SOME OF THE ANTIBODIES FOR DOING THE SURFACE STAINING. SOME ARE FIXATION RESISTANT SO SHE THEN FIXES THE CELLS THAT COULD BE FROZEN AWAY AND GENERALIZED BACK AT MOUNT SINAI AND THE FIXATION AGENTS CAN BE ADDED TO FINISH THE ANALYSIS. >> THANK YOU. I'M FAMILIAR WITH THE METHOD. >> GREAT. >> SO I WAS GOING TO START BY INTRODUCING MYSELF AS JEFF RICE IN THE TRANSLATIONAL BRANCH BUT IN THE INTEREST OF BRANCH I'LL SKIP THAT. I'M LOOKING TO RENEWAL OF THE COOPERATIVE GROUP AND THE HLA HERE REGIONS ARE THE MOST GENE-DENSE AND POLY MORPHIC REGIONS AND PLAY ROLES IN REGULATION OF THE ADAPTIVE AND INNATE IMMUNE RESPONSES AND THEY'RE ASSOCIATED WITH IMMUNE REGULATED DISEASES INCLUDING TRANSPLANTATION OUTCOME AND AUTOIMMUNITY AND DUE TO THEIR HIGHLY POLY MORPHIC AND DENSE NATURE THE SEQUENCING REQUIRES SPECIALIZED TECHNIQUES INCLUDING EXTENSIVE BIOINFORMATICS EXPERTISE. THE SCOPE OF THIS INITIATIVE IS TO ADDRESS FUNDAMENTAL QUESTIONS IN HUMAN IMMUNOLOGY AND DEFINE ASSOCIATIONS IN IMMUNE MEDIATED DISEASES SUCH AS DISEASE PHENOTYPE AND STUDY DISEASES THAT EFFECT SPECIFIC GENDER OR ETHNIC GROUPS AND DEVELOP TOOLS FOR ANALYSIS. THIS GROUP WAS INITIALLY ESTABLISHED IN 2005 AND WE'VE UNDER GONE RENEWABLE SINCE 2010 AND 2015 AND IN EACH OF THESE CYCLES WE'VE BEEN JOINED BY NIAIDS WHO SUPPORTED ONE AWARD EACH ROUND AND WILL CONTINUE THEIR SUPPORT SHOULD WE DECIDE TO CONTINUE THIS. THE GROUP HAS BEEN HIGHLY PRODUCTIVE AND COLLABORATIVE. IN THE LAST FIVE YEARS THERE'S BEEN OVER 120 RESEARCH PUBLICATIONS AN MANY OF THESE ARE THE RESULT OF COLLABORATIONS WITHIN THE GROUP. THEY'VE MADE SIGNIFICANT CONTRIBUTION THOSE DEVELOPMENT OF NEXT GENERATION CONSEQUENCING AND BIOINFORMATICS TECHNIQUES AND TOOLS HAVE AVAILABLE ONLINE FOR USE FOR ANYBODY AND THERE'S LOTS OF WHAT THEY CALL HACKATHONS WHERE THEY GET TOGETHER TO ADAPT AND MODIFY THESE FOR BETTER USE. THEY'VE IDENTIFIED VARIANTS FOR IMMUNE DISEASES AND LOOKED AT TRANSPLANTATION OUTCOME AND THE PROJECT LEADERS PLAY A PROMINENT ROLE IN THE RESEARCH COMMUNITY THROUGH THEIR SPECIFIC LEADERSHIP AND COLLABORATION WITH NATIONAL AND INTERNATIONAL TRANSPLANTATION AND IMMUNOGENICS PROGRAMS. SO WE ARE NOT PLANNING A CHANGE IN SCOPE. WE'LL CONTINUE AS UL1 AND UL19 COOPERATIVE AGREEMENTS AND CONTINUE IN IMMUNE-MEDIATED DISEASE AND TRANSPLANTATION AND THE EXCEPTION TO THAT STATEMENT ABOUT NO CHANGE IN SCOPE IS WE ARE LOOKING TO SEE IF NCI WILL JOIN US ON THIS INITIATIVE AND IF THEY ARE INTERESTED IN JOINING THEN WE WOULD ALLOW LIMITED STUDIES WITH SUSCEPTIBILITY TO COUNCIL. >> IS -- HAS THE GROUP MADE PROGRESS IN REDUCING THE COST AND GETTING A FOUR-DIGIT MLA TYPE? >> I THINK THE PRICE OF THE SEQUENCING HAS CONSISTENTLY GONE DOWN THAT WOVE SEEN BUT THEY'RE NOT AS FAR AS BEING ABLE TO QUANTIFY THAT, THEY'RE NOT REALLY INVOLVED IN SO MUCH THE DEVELOPMENT OF TECHNOLOGY LIKE THE MACHINERY BUT ADAPTING TO THE REGION. THERE'S A SIGNIFICANT BIOINFORMATICS LOAD WHICH CARRIES EIGHT OF COST. >> GOOD AFTERNOON. MY NAME IS NASRI NABAVI AND LOOK AT IMMUNOBIOLOGY OF XENO TRANSPLANTATION COOPERATE RESEARCH PROGRAM AND LOOKING AT SURVIVAL AND FUNCTION. AND ALSO THE FOCUS WAS TO DEVELOP AND STUDY SWINE TO NON-HUMAN PRIMATE XENOTRANSPLANTING MODELS FOR HART, LUNG AND LIVER. OUR GOAL OF THE PROGRAM IS TO USE XENOTRANSPLANTATION TO SHOW AN ALTERNATIVE AND THE RATIONAL IS IT'S A COLLABORATIVE PROGRAM TOPROMOTE SYNERGY IN A SMALL GROUP OF SPECIALIZED INVESTIGATORS. ALSO TO ENSURE THE NIH AND FDA STANDARDS AND REGULATORY CONSIDERATION IN INTERNATIONALLY WORK AND MAINTAIN THE INVOLVEMENT IN TRANSITION FROM PRE-CLINICAL STUDIES TO FUTURE CLINICAL STUDIES APPLICATION. THIS WAS CO-FUNDED AND THE PROGRAM WAS RENEWED IN 2010 AND 2015 BY NIAID AND THE CURRENT PROGRAM FOR THE GRANTS ADDRESSING KIDNEY HEART, LUNG AND XENOTRANSPLANTATION. THE PROGRAM WAS VERY SUCCESSFUL AND ACCOMPLISHED MANY RESEARCH OBJECTIVES INCLUDING PUBLISHING 175 RESEARCH ORIGINAL PUBLICATIONS SINCE 2005 AND ABOUT 48 TO 50 PUBLICATIONS. THEY IDENTIFIED ANTIGENS AND AMONG THEIR ACHIEVEMENT WAS OTHER MOLECULES AND PATHWAYS INVOLVED IN XENOPATHIC DONORS AND USE DEVELOPMENT OF THE GENE MODIFICATION. SINCE 2005 SINCE THE PROGRAM STARTED MANY ADVANCES WERE MADE IN THE FIELD. PLEASE PRESS ANY KEY ON THE TELEPHONE TOUCH PAD. >> AS YOU SEE, 2005 FOR EXAMPLE THERE WAS 26 OR 27 TO 70 DAYS. NOW IT'S OVER 31 MONTHS OR YEARS AND THE ISLETS SURVIVED FOR 84 DAYS AND NOW IT'S 32 MONTHS OR BEYOND. SO PHOR -- FOR THE RENEWAL OF THIS PROGRAM THERE WERE NEW CHANGES IN THE SCOPE. NO CLINICAL TRIALS WERE INCLUDED IN THIS PROGRAM AND SO THE FOCUS IS GOING TO REMAIN ADDRESSING REMAINING CHALLENGES SUCH AS COAGULATION AND INFLAMMATION FOR REJECTION AND DRUG TOXICITY AND INFECTION IN THE RECIPIENT AND TOLERANCE IS ANOTHER GOAL OF THE PROGRAM. THANK YOU. I'LL BE HAPPY TO TAKE ANY QUESTIONS. >> JUST ONE. THE STUDIES IN SWINE TO PIG, WHAT IS THE RATIONALE? IS IT BECAUSE IT'S PRE-CLINICAL MODEL IN THERE'S A BROAD RANGE OF ORGANS SELECTIVELY FUNDING ONE OR TWO ORGANS. THERE'S A BROAD RANGE OF ORGANS BEING ENTERTAINED. HOW FEASIBLE CURRENTLY IS IT TO DO LIVER TRANSPLANT AND LUNG TRANSPLANT IN A PIG TO PRIMATE MODEL? >> WELL, WITH THE XENOTRANSPLANTATION IS MORE CHALLENGING THAN OTHER ORGANS BUT THE INVESTIGATOR MANAGED TO HAVE DIFFERENT PATHWAYS AND USING DIFFERENT TRANSGENIC TO SURVIVE THE FUNCTION OF THE ORGAN FOR EXAMPLE IN 2005 THERE WAS SURVIVAL [MULTIPLE DISCUSSIONS] >> IT'S A DIFFICULT AND CHALLENGING ORGAN BUT OTHER ORGANS AND -- [MULTIP [MULTIPLE DISCUSSIONS] >> EACH ORGAN HAS ITS OWN CHALLENGES. >> WE CAN HEAR YOU. >> GOOD AFTERNOON. I'M FROM THE SPECIFIC TECHNOLOGY FELLOW IN THE RADIATION AND COUNTER MEASURES PROGRAM. TODAY I'LL PRESENT ON THE RENEWAL OF THE RADIATION AND NUCLEAR COUNTERMEASURE PRODUCT DEVELOPMENT SUPPORT CONTRACT ON BEHALF OF MY COLLEAGUE DAVID CASSATT. FIRST I'D LIKE TO START WITH BACKGROUND FIRST ON OUR OFFICE. OUR OFFICE HAS BEEN TASK WITH THE MISSION OF DEVELOPING ADVANCED MEDICAL COUNTERMEASURES TO BE USED IN THE CASE OF A RADIATION NUCLEAR EMERGENCY AND TO INCLUDE THESE IN THE STRATEGIC NATIONAL STOCKPILE FOR THE EMERGENCY PREPAREDNESS OF OUR COUNTRY. ONE IMPORTANT PART IS THE SUPPORT SERVICES CONTRACT WHICH ALLOWS US TO TEST POTENTIAL CANDIDATES FOR MEDICAL COUNTERMEASURES BY DOING PROOF OF CONCEPT STUDIES AND EFFICACY TESTING TO MOVE THE PRODUCTS DOWN. THE CONTRACT WE'VE HAD THREE ITERATIONS PREVIOUSLY. THE FIRST 10 YEARS IT WAS AWARDED TO THE UNIVERSITY OF MARYLAND IN 2005 AND 2010 AND TO SRI INTERNATIONAL IN 2015. SO SUMMARIZE THE ACCOMPLISHMENTS WE'VE HAVE BEEN ABLE TO DEVELOP A VARIETY OF ANIMAL MODELS FOR LATE RADIATION THERAPIES IN DIFFERENT SPECIES. THESE MODELS HAVE ALLOWED US TO TEST A VARIETY OF PRODUCTS FOR MITIGATION OF THE VARIOUS SYNDROMES AND ACUTE RADIATION SYNDROME AND THESE STUDIES INCLUDING ANIMAL STUDIES HAVE ALLOWED US TO ADVANCE THE PRODUCTS TO INTERACTIONS WITH THE FDA IN COLLABORATION WITH THE OFFICE OF REGULATORY AFFAIRS. WE HAVE SUPPORTED IND AND PRE-IND FILINGS AND ONE OF THE MOST IMPORTANT ACCOMPLISHMENT IS STUDIES DONE TO THE CONTRACT ALLOWED FOR THE APPROVAL OF THE FIRST TWO COUNTERMEASURES THAT WERE INCLUDED IN THE STRATEGIC NATIONAL STOCKPILE FOR 42 TREATMENT OF HEMATOPOIETIC RAID RATION THERAPY AND RECENTLY LED A COLLABORATIVE PROJECT WHERE WE WERE ABLE TO SUPPLY SAMPLES FROM RADIATE AND NON-RADIATED MHP FOR ANALYSIS. SO TO SUMMARIZE IT'S BEEN A SUCCESS PART -- SUCCESSFUL PART OF OUR CONTRACT AND IT ALLOWS US TO DEVELOP IN THE TASK AREAS LISTED THAT RESPOND TO THE DIFFERENT ASPECTS OF DRUG DEVELOPMENT. WE ANTICIPATE TO RECEIVE FOUR TO SIX PROPOSALS AND PLANNING ON AWARDING ONE OR MORE DURING A SEVEN-YEAR DURATION. WITH THAT I'D BE HAPPY TO ANSWER ANY QUESTIONS. THANK YOU. MY NAME IS CARMEN RIOS IN THE COUNTER NUCLEAR COUNTERMEASURE PRODUCT AND THERE'S GUIDANCE AND MONITORING OF SOURCES AND RADIATION PROTOCOLS UNDER THE CONTRACT MECHANISM. WE LOOK TO HAVE ONE AWARD FOR A DURATION OF THREE YEARS AND ANTICIPATE ONE TO THREE PROPOSALS SUBMITTED. AND THE MILESTONES DEVELOPED BY THE AWARDEE IN COLLABORATION WITH NIAID WILL HELP US TO REACH OUR GOAL OF ESTABLISHING THIS CORE THAT WILL SET UP AND ENSURE HARMONIZATION ACROSS THE PORTFOLIO. SO A LITTLE BIT OF BACKGROUND AND AS MENTIONED EARLIER THE PURPOSE OF OUR PROGRAM IS TO DEVELOP MEDICAL COUNTERMEASURES TO TREAT ACUTE NUCLEAR SYNDROME AND THE WAY WE LOOK AT EFFICACY IS TO LOOK AT DIFFERENT RADIATION DOSES BECAUSE THEY ELICIT A DIFFERENT STAGE IN RADIATION SYNDROME. AND THE DIFFERENT LABS WE FUND THROUGHOUT OUR PROGRAM HAVE DIFFERENT RADIATION SOURCES HOWEVER, THOSE MUST BE COMPARABLE. THE WAY WE AS YOU SEE WITH HUMAN RADIO THERAPY, THAT SYMMETRY IS CAREFULLY MONITORED AND WE BELIEVE BY CENTRALIZING THAT INITIATIVE WE CAN HAVE THE SAME KIND OF HARMONIZATION IN THE AREA. SO CURRENTLY WE HAVE A CORE THAT IS SOMEWHAT OF A PROTOTYPE WITHIN THE CENTERS OF COUNTERMEASURES CONSORTIUM OR CMCRC AND OVERSEE THE PROGRAM AND IT'S BEEN VERY SUCCESSFUL. THAT'S HEADED UP BY A DOCTOR WHO DEVELOPED 3-D ANATOMICAL PROGRAMS TO DO THE TESTING TO SEND THEM OUT TO THE UNIVERSITIES THAT PARTICIPATE IN THE CORPS AND EVALUATE THE DISSYMMET DISSYMMETRY YI78 -- IMPLANTS AND WANT TO USE IT FOR THE CORPS PROGRAM. IN ADDITION WE HELD A WORKSHOP WHERE WE OPENED IT UP TO OTHER INSTITUTES WITHIN OUR PORTFOLIO AND WE BROUGHT TOGETHER RADIATION PHYSICISTS AND BIOLOGISTS TO SURVEY THE LANDSCAPE OF THE METHODOLOGY AND THE CHALLENGES AND GAPS IN KNOWLEDGE THEY ARE SEEM. AND WE LOOK TO ENSURE PROCEDURES FOR ALL THE INSTITUTES IN THE PORTFOLIO. THEY'LL WORK WITH INSTITUTE TO EDUCATE OPERATORS OF THE IRRADIATORS TO GET OUT THE INACCURACIES AND DETERMINE HOW TO SOLVE THOSE PROBLEMS AND THEY'LL PROVIDE THE SERVICE ON SITE AT THE VARIOUS INSTITUTES AND THEN IN YIN HOUSE TO DO THE -- IN-HOUSE AND DO THE EVALUATION OF THE PHANTOMS FOR RADIATION AND EVENTUALLY HARMONIZE HOPEFULLY ALL THE INSTITUTES ACROSS THE PORTFOLIO WITH INITIATIVE. THAT'S IT. I'LL TAKE ANY QUESTIONS. THANK YOU. >> HI, GOOD AFTERNOON. I'M KETNER SINGLETON LOOKING TO MOVE FORWARD WITH THE VACCINE OF OPIOID VACCINE. WE'VE SEEN GROWTH IN DEATHS CAUSED BY ACCIDENTAL OVERDOSE DUE TO DRUG USE AND IN THE PAST 10 YEARS IT'S BEEN LARGELY DRIVEN BY THE USE OF OPIOIDS INITIALLY BY PRESCRIPTION OPIOIDS AND THEN HEROIN AND NOW THE TREND IS BEING DRIVEN BY SYNTHETIC OPIOIDS SUCH AS FENTANYL. IN 2017 THE TRUMP ADMINISTRATION DECLARED THIS A PUBLIC HEALTH EMERGENCY AND CHARGED THE NIH WITH SOLVING THE OPIOID EPIDEMIC. BECAUSE OF THAT IN 2018 THE NIH CREATE THE HEAL INITIATIVE HELPING TO END ADDICTION LONG TERM. THIS IS PART OF THAT COORDINATED EFFORT WHICH IS TRANS-NIH AND REALLY A TRANS-FEDERAL INITIATIVE TO ADDRESS THE OPIOID CRISIS. SO ANTI-OPIOID VACCINES ARE A PROMISING COMPLIMENTARY APPROACH FOR THE INDIVIDUALS FOR THE TREATMENT OF OPIOID USE DISORDERS. A RELAPSE IS A VERY SIGNIFICANT PROBLEM WITH PEOPLE IN TREATMENT PROGRAMS. WE'RE DEPENDING ON THE STUDY TO LOOK AT ANYWHERE FROM 70% TO 90% OF THE PEOPLE IN THE TREATMENT PROGRAMS RELAPSE AND GO BACK TO OPIOIDS. NOW, THESE PEOPLE ARE AT VERY HIGH RISK FOR AN OPIOID EVENT BECAUSE THEY'VE LOST THEIR TOLERANCE. THE IDEA IS THE ANTI-OPIOID VACCINE WOULD CREATE A SAFETY NET TO HELP PREVENT THESE PEOPLE FROM ENCOUNTERING AN OVERDOSE SITUATION IF THEY WERE TO HAVE A SINGLE-USE EVENT AND TO PREVENT A SINGLE-USE EVENT FROM SPIRALLING TO A FULL RELAPSE SITUATION. THE IDEA ABOUT HOW HE ANTI-OPIOID VACCINES WOULD WORK IS THE ANTIBODIES GENERATED BY THE VACCINES WOULD BIND TO THEIR SPECIFIC TARGET OPIOID THERE BE BE -- THEREBY HAVE CHANGED KINETICS CROSSING THE BLOOD BRAIN BARRIER AND HAVE REDUCED NEUROTROPICECT EFFECTS SUCH AS EUPHORIA. NOW, THE ANIMAL STUDIES HAVE BEEN VERY SUCCESSFUL FOR ANTI-OPIOID VACCINES IN SHOWING THEY CAN INDUCE ANTIBODIES THAT PREVENT OVERDOSE SITUATIONS AND ALSO SHOWN ANIMALS THAT THAT ARE ADDICTED TO OPIOIDS CAN SELF-WITHDRAW OFF THE OPIOIDS POST VACCINATION WHICH IS PROMISING. THERE HAVE NOT BEEN ANY ANTI-OPIOID VACCINES. CLINIC TESTED BUT THERE'S BEEN ENCOURAGING RESULTS WITH VACCINES TO TARGET NICOTINE IN A PHASE 2 TRIALS THOSE WITH THE HIGHEST LEVELS OF ANTIBODIES AGAINST NICOTINE SHOWED CLINICAL BENEFITS DEMONSTRATED AS REDUCED NICOTINE USE. PROPOSING FOR PHYSICAL YEAR 20 WOULD BE TO DEVELOP VACCINES THAT PROTECT AGAINST HEROIN AND FENTANYL. THIS IS A TRANS-NIH INITIATIVE WORK THE RESOURCE INFRASTRUCTURE PROGRAMS. AND THE INITIATIVE WOULD SUPPORT VACCINE DEVELOPMENT SO VACCINE DESIGN AND DEVELOPMENT WHICH WOULD INCLUDE IMMUNO ANTIBODIES AND PRE CLINICAL IMMUNOGENICITY AND INCLUDE PHARMACOLOGY AND TOXICOLOGY, VACCINE MANUFACTURING AND PHASE 1 CLINICAL TRIALS AND BECAUSE THIS HAS A BASIC SCIENCE COMPONENT WE'D BE UTILIZING THE CONTRACT MECHANISM OF THIS INITIATIVE. IF ANYONE HAS ANY QUESTIONS I'D BE MORE THAN HAPPY TO ADDRESS THEM AT THIS TIME. >> THIS IS SPECIAL PROESHS AND -- APPROPRIATION BY CONGRESS. THANK YOU VERY MUCH. >> I'LL BE SPEAKING TO YOU ABOUT A PROPOSED FISCAL YEAR '20 INITIATIVE ON DEVELOPMENT AND TESTING OF HUMANIZED IMMUNE SYSTEM MOUSE MODELS. WE HELD A WORKSHOP TO DISCUSS THE STATE OF THE SCIENCE OF THE HUMANIZED IMMUNE SYSTEM MOUSE MODELS AND HAD LEADERS COME AND DISCUSS VARIOUS ADVANCES AND THEY TALKED ABOUT THE VARIETY OF ADVANCES MADE USING THE MOUGS -- MOUSE MODELS AND FETAL DERIVED MODELS AND THEY REMAIN THE GOLD STANDARD. AND THE VARIOUS MOUSE MODELS VARE IN THEIR ABUSE TO KEY CAPITULATE ASPECTS OF HUMAN MODEL AND NO SINGLE MODEL IS OPTIMAL FOR ALL APPLICATIONS. AND MOREOVER, THERE HAVE BEEN VERY FEW DIRECT COMPARISONS THAT HAVE BEEN CONDUCTED USING THE MICE THAT HAVE BEEN DRAFTED WITH FETAL AND NON-FETAL HUMAN SOURCES. THE INITIATIVE WE'RE PROPOSING IS TO HAVE STUDIES TO COMPARE THE FETAL TISSUE VERSUS NON-FETAL TISSUE SOURCES WHEN HUMANIZING THESE MICE. WE'D LIKE FOLKS TO OPTIMIZE OR DEVELOP THESE HUMAN MOUSE MODELS WITH EMPHASIS ON ONES MADE WITH NON-FETAL TISSUE SOURCES AND WOULD LIKE FOR THEM TO SHOW THEY MAY CAPITULATE HUMAN RESPONSES AN FUNCTION AND TO SHOW THAT THEY ALSO DEMONSTRATE HUMAN MUCOSAL RESPONSES AND THEY'LL ALSO SHOW SOME RECAPITULATION OF TISSUE DEVELOPMENT AND THEY'LL ALSO LOOK AT COMPARISON OF DEVELOPMENT AS WELL AS FUNCTION TO HUMAN PATHOGENS AND DEVELOPMENT AND PROFESSIONAL DISEASES. AND THE MECHANISM BY WHICH YOU WANT TO DO THIS IS THERE'LL ABE BROAD AGENCY ANNOUNCEMENT OF CONTRACT MECHANISM FOR FIVE YEARS AND WILL HAVE PARTNER SUCH AS THE DIVISION OF AIDS AND WE MAY HAVE OTHER INSTITUTES AND CENTERS WHICH MAY BE JOINING AS WELL. SO IF YOU HAVE ANY QUESTIONS? >> THERE'S BEEN PUBLICITY SURROUNDED THE HHS REVIEW OF THE RESEARCH. THAT'S PROMPTED MANY DISCUSSIONS AT THE NIH RECORDS OFFICE OVER THE SUMMER AND FALL. THERE WAS A NOTICE TO THE NIH GUIDE THAT WE HAVE SEEN WEEKS AGO SEEING THAT NIH IS SPENDING $20 MILLION ON RESEARCH. IT'S A COMBINATION OF MONIES FROM THE NIH DIRECTOR'S OFFICE, NCI, NIAID AND MAINLY HEALTH INSTITUTES. >> IMMUNOLOGICAL DISEASES. >> THIS IS A RESPONSE TO THAT ASSESSING THE STATUS OF THE RESEARCH AND WHAT ALTERNATIVE TO FETAL TISSUE RESEARCH ARE DEVELOPED. >> SO THANK YOU, MERCY. WITH THAT IF THERE ARE REALLY NO OTHER TOPICS FOR DISCUSSION RELATED TO THESE I SHOULD ASK YOU FOR A MOVE TO APPROVE AND THEN A SECOND. CAN WE HAVE THAT? >> I MOF TO A -- MOVE TO APPROVE. >> OKAY. SO WE NEED A SECOND AND WE HAVE THAT AND THEN A REQUEST THAT YOU APPROVE THESE IN THE COUNCIL BOOK AND THE SAME FOR THOSE OF YOU WHO ARE ON BY PHONE. AND IF THERE'S NO QUESTIONS WE'LL CONCLUDE OUR AFTERNOON SO THANK YOU ALL FOR A REALLY INFORMATIVE SESSION