>> A BRIEF DESCRIPTION OF THE PROGRAM, AND THEN INTRODUCE THE SPEAKERS. SOME DETAILS OF THE PROGRAM HAVE EVOLVED OVER THE YEARS SINCE IT BEGAN IN 1999, THE PURPOSE AND APPROACH REMAIN THE SAME, ACCELERATE DISCOVERY AND TRANSLATION, THERAPIES FOR AUTOIMMUNE, CONDUCT COLLABORATIVE CLINICAL TRIALS OF MECHANISMS OF ACTION FOR NEW AND APPROVED THERAPIES AND ADVANCE STUDIES OF FUNDAMENTAL HUMAN IMMUNOLOGY, TWO DIFFICULT THINGS, CLINICAL TRIALS AND IMMUNOLOGY, ADDING A THIRD COLLABORATION, LIKE CHURCHILL SAID ABOUT FIGHTING WITH ALLIES, WE THINK THAT THE ONLY THING HARDER THAN DOING GREAT RESEARCH WITH COLLABORATORS, TRY TO DO IT WITHOUT. HERE ARE THE CENTERS ACROSS THE UNITED STATES. ELEVEN OF THEM, FOUR FOCUSED ON CLINICAL TRIALS, AND THE OTHER SEVEN IN ASSISTING THEM IN PERFORMING THESE FUNDAMENTAL INVESTIGATIONS. EACH CENTER PROPOSED A THEME IN THEIR APPLICATION, AND THOSE ARE LISTED HERE. ALTHOUGH THEY DID NOT KNOW WITH WHOM THEY WOULD BE COLLABORATING AFTERWARDS, THERE ARE CERTAIN SHARED THEMES, SUCH AS THE PHASING THAT IS PRE-CLINICAL, DURING DISEASE FLARES, JUDITH JAMES WILL REFER TO, SUBSETS OF DEVELOPS AND EPIGENETICS, I MIXED THOSE UP, TWO CENTERS FOCUSED ON EPIGENETICS, AND SEVERAL OF THE CENTERS LOOK AT THE PARTICULAR CELL SUBSETS, DR. SANDS WILL TALK ABOUT THOSE. TODAY WE HAVE JUDITH JAMES AND IGNACIO SANDS FROM EMORY, CHIEF OF RHEUMATOLOGY, DIRECTOR OF THE CENTER OF HUMAN IMMUNOLOGY, AND IMMINENT SCHOLAR, EDUCATED IN SPAIN, AND AT THE COLLEGE AND ALSO UNIVERSITY FOR MEDICAL TRAINING, TRAINED IN MADRID AND MOVED TO TEXAS, DALLAS, AND THEN SAN ANTONIO. APPOINTED ASSOCIATE ASSISTANT PROFESSOR AT SAN ANTONIO AND THEN TO BEING CHIEF AND PROFESSOR AT UNIVERSITY OF ROCHESTER. IT SOUND LIKE A PERSONAL THING BUT HE REPRESENTED SPAIN AT TWO OLYMPICS IN JUDO, AND I THINK THAT'S A TOTAL SIDE ISSUE BUT JUDO TRANSLATES ACTUALLY AS GENTLE LAY, IT MEANS RECOGNIZING AND TAKING ADVANTAGE OF THE OTHER'S STRENGTHS, WHICH IS EXCELLENT FOR COLLABORATING. 194 PUBLICATIONS AS OF LAST MONTH, 23 FROM THE CURRENT ACE AND 30 FROM THE ROCHESTER ACE. HERE JUST VERY SMALL NUMBER FROM HIS PUBLICATIONS, FOCUSING ON THE TOP B CELLS, L LYMPHOCYTES AND SYSTEMIC LUPIS, ERYTHEMATOSUS, CHROMATIN ASSAY BEING IMPORTANT IN EPIGENETICS, AND THE OTHER ONE RECENTLY LAST YEAR WAS IN THE DIVERSITY OF B CELL POPULATIONS IN LUPUS, AND THEN I ALSO LISTED THIRD ONE HERE, CRUCIAL PAPER, EVEN BEFORE ROCHESTER ACE BEGAN, SHOWING THE BENEFIT OF RITUXIMAB IN LUPUS. DR. JAMES IS THE BLUE CARE CHAIR IN BIOMEDICAL RESEARCH DEPARTMENT HEAD, ARTHRITIS AND CLINICAL IMMUNOLOGY, MEMBER OF THE OKLAHOMA MEDICAL RESEARCH FOUNDATION, PROFESSOR OF MEDICINE, AND GEORGE CROSS RESEARCH PROFESSOR OKLAHOMA UNIVERSITY. EDUCATED IN OKLAHOMA, AT THE OKLAHOMA BAPTIST UNIVERSITY, ONE OF THE TOP COLLEGES IN THE COUNTRY, FRANKLY, AND THEN AT THE UNIVERSITY OF OKLAHOMA, ALSO VERY FINE. SHE WAS RESIDENT AND FELLOW IN OKLAHOMA, AND THEN APPOINTED TO OMRF SENIOR RESEARCH SCIENTIST, ASSISTANT RESEARCH ASSOCIATE PROFESSOR AT OKLAHOMA UNIVERSITY. I WILL POINT OUT THE STATE SHE'S BEEN ASSOCIATED WITH, THERE'S MYRIAD REASONS WHY YOU WOULD WANT TO COLLABORATE WITH DR. JAMES BUT SUBLIMINALLY THERE MAY BE TWO, THE STATE IS ABBREVIATED O K, THEY ARE KNOWN AS THE SOONERS, NOT FOR EXAMPLE THE LATERS, OR THE NEVERS. [LAUGHTER] SHE HAS OVER 300 PUBLICATIONS, AND 118 FROM THE OKLAHOMA ACE. AGAIN, LESS THAN 1% OF THOSE PUBLICATIONS HERE. BUT CHOSEN TO REFLECT THE THEME, BIOLOGY OF AUTOIMMUNE DISEASE FLARES. THE MIDDLE ONE DOES NOT ASSOCIATE WITH THE THEME BUT IT'S COOL, AND THE BOTTOM ONE IS ABSOLUTELY SEMINAL PAPER SHE WAS A SENIOR AUTHOR ON, ON THE STAGING OF DISEASE IN A HUGE CORD -- COHORT OF ARMED FORCES SUBJECTS. WITHOUT FURTHER ADO, WE'RE GOING TO REORDER WHAT WAS IN THE LIST AND DR. JAMES WILL START. >> I'M GLAD HE NEVER GAVE THAT PRODUCTION AT THE ACE CONSORTIUM MEETING, BECAUSE EVERYBODY FEELS LIKE I DO SEND SAMPLES TO EVERYONE AND NOW HE WILL SAY IT'S ALWAYS OK. [LAUGHTER] ALL RIGHT. WELL, THANK YOU VERY MUCH. I APPRECIATE THIS OPPORTUNITY TO TALK ABOUT OUR EXPERIENCE AS PART OF THE ACE CONSORTIUM. AND SO THE GOOD THING IS THAT I KNEW WHO MY CO-SPEAKER WAS GOING TO BE, AND SO I KNEW HE WOULD TALK ABOUT HIS BASIC PROGRAM. THERE WE GO. SO I'M GOING TO FOCUS A LITTLE BIT ABOUT KIND OF ALL THE REST OF THE ACE. AND SO, YOU KNOW, ONE OF THE EXCITING THINGS ABOUT THE ACE CONSORTIUM, IT BRINGS TOGETHER DIFFERENT COMPONENTS AND MAKES US ALL THINK ABOUT AUTOIMMUNITY FROM DIFFERENT PERSPECTIVES. SO WHEN I THINK ABOUT THE ACE CENTERS, WE THINK OF COURSE ABOUT CLINICAL TRIALS, AND THESE ARE CLINICAL TRIALS THAT HAVE TO BASICALLY BE SOMETHING UNIQUE, THAT COULD REALLY ONLY BE DONE AT THE NIH. AND SO I'LL TALK ABOUT SOME DATA FROM ONE OF THOSE CLINICAL TRIALS AND A COUPLE OTHER TRIALS CURRENTLY UNDERWAY. IN ADDITION, THE PART THAT I'M THE MOST EXCITED ABOUT IS IT ACTUALLY PARTNERS MECHANISTIC STUDIES WITH THESE CLINICAL TRIALS. AND SO THIS NOT ONLY ALLOWS US TO BETTER UNDERSTAND HOW THE DRUGS WORK, OR DON'T WORK IN OUR PATIENTS, BUT ALSO ALLOWS US TO UNDERSTAND WHICH PATIENTS SHOULD WE POTENTIALLY BE USING FOR DIFFERENT THERAPEUTIC APPLICATIONS. AND SO THE OTHER GREAT THING IS THAT THE ACE CONSORTIUM RIGHT NOW HAS AN INVESTIGATORS FROM A NUMBER OF INSTITUTIONS WHO BRING TOGETHER VARIED TECHNICAL SUPPORT AND DIFFERENT TECHNICAL APPROACHES SO WE BROUGHT STANFORD BROUGHT IN MULTIPLE DIFFERENT PLACES, WE'VE SEEN EPIGENETICS, WE DO A LOT OF GENETICS IN OKLAHOMAS, AND SO YOU BRING TOGETHER A LOT OF DIFFERENT TECHNOLOGIES TO THINK ABOUT HOW CAN WE ANSWER QUESTIONS WITH CLINICAL TRIALS. IN ADDITION WE HAVE THE PRIMARY PROJECTS, AND AS YOU ALREADY HEARD THOSE WENT ALONG WITH THE DIFFERENT THEMES THAT YOU SAW FROM THE DIFFERENT CENTERS, EPIGENETICS PLAYING A BIG ROLE AS WELL AS GLYCOSYLATION, VACCINATION RESPONSES, AND PROBABLY THE PART THAT'S MOST UNIQUE WITH COLLABORATIVE PROJECTS, BUILDING ON THE STRENGTHS AND DIFFERENT CENTERS AND GET US WORKING ON DIFFERENT THINGS TOGETHER. AND SO I'LL PRESENT A LITTLE BIT ABOUT THAT AS WELL. AND THEY KIND OF HAVE COALESCED AROUND SYNOVITIS, FIBROSIS, IMMUNE CELL DISTANCE MAPPING ACROSS AUTOIMMUNE DISEASES. WHY IS IT IMPORTANT FOR US TO THINK ABOUT HOW WE CAN BETTER APPROACH CLINICAL TRIALS AND AUTOIMMUNITY AND DEVELOP NEW THERAPEUTICS FOR LUPUS? AND RHEUMATOID ARTHRITIS AND OTHER THINGS. SO I WENT BACK AND JUST QUICKLY TRIED TO PULL OUT THE NUMBER OF NEW FDA-APPROVED DRUGS AND AUTOIMMUNE RHEUMATIC DISEASES OVER 20 YEARS. TO PUT THIS IN CONTEXT, THE NUMBER OF NEW DRUGS THAT HAVE BEEN APPROVED FOR HYPERTENSION IN THE LAST 20 YEARS IS 53. AND SO THEN I KNEW I WOULD HAVE SOME ALLERGY AND ASTHMA PEOPLE, 23 AND 29. RHEUMATOID ARTHRITIS HAS HAD ABOUT 15. OF THOSE 15, 9 HAVE BEEN APPROVED IN THE LAST 10 YEARS, SO WE'RE SEEING THIS KIND OF EXPLOSION IN RHEUMATOID ARTHRITIS, AND I THINK ALL OF US HOPE THAT WE WILL START TO SEE THIS HAPPENING IN OTHER SYSTEMIC AUTOIMMUNE RHEUMATIC DISEASES. PSORIASIS, SOREATIC ARTHRITIS HAS SEEN THIS EXPLOSION OF THERAPEUTIC TARGETS IN THE LAST TEN YEARS, BUT YOU CAN SEE SYSTEMIC LUPIS IS STILL WOE FLU LAGGING BEHIND WITH ONE NEW FDA-APPROVED DRUG IN THAT TIME. I LOOKED TO SEE, THERE IS ONE IN SJOGREN'S IN 20 YEARS, NOT THE LAST 20, TO MAKE MORE OF THE TEARS AND SALIVA, NOT TO ADDRESS THE BIOLOGY. WE'RE NOT DOING WELL IN SCLEROSIS, SCLERODERMA, OR THINGS LIKE UNDIFFERENTIATED CONNECTIVE TISSUE DISEASE WHICH IS THIS BIG BASKET OF PATIENTS THAT GET THROWN IN WITH THE POSITIVE ANA AND CLINICAL SYMPTOMS, NO CLINICAL TRIALS DONE IN UCTD. WE NEED NEW APPROACHES, NEW DRUGS THAT ACTUALLY WORK, AND SO WE WERE EXCITED THAT THE ACE CHOSE TO ACTUALLY SUPPORT A SJOGREN'S CLINICAL TRIAL, AND SO THIS WAS -- I WAS PROTOCOL CHAIR ON, LYMPHOTOXIN RECEPTOR PROTEIN, THE GOAL TO INHIBIT THE INFILTRATION OF IMMUNE CELLS INTO SALIVARY GLANDS, LACRIMAL GLANDS, ANIMAL DATA LOOKED GOOD, SAFETY DATA LOOKED FINE IN RHEUMATOID ARTHRITIS, THIS WAS TRIED. WE ENROLLED 52 SJOGREN'S PATIENTS, PRIMARY, 2/3 RECEIVED TREATMENT, 1/3 PLACEBO, AND WE HAD MATCHING CONTROLS, DETAILED IMMUNOPHENOTYPING AND A HOST OF DIFFERENT KIND OF MECHANISTIC STUDIES TO TRY AND BETTER DEFINE WHAT'S GOING ON IN SJOGREN'S SYNDROME, AND HOPEFULLY TO UNDERSTAND HOW THIS DRUG WORKED. AND SO THIS HAS BEEN PRESENTED AT THE AMERICAN COLLEGE OF RHEUMATOLOGY MEETING, AND THE PAPER'S NOT OUT YET BUT UNFORTUNATELY THIS TRIAL DID NOT MEET PRIMARY CLINICAL OUTCOME OR MAIN SECONDARY CLINICAL OUTCOMES. HOWEVER, WHAT WE DID FIND WAS THAT THERE'S INTERESTING MECHANISTIC ISSUES THAT COME TO PLAY. IF YOU TALK TO RHEUMATOLOGISTS, I'M A PRACTICING RHEUMATOLOGIST WHO SEES PATIENTS ONCE A WEEK, MY JUNIOR CLINICIANS WOULD SAY THAT'S NOT ALL THE TIME, BUT I STILL SEE PATIENTS EVERY WEEK. AND ONE OF THE THINGS THAT WE WOULD TELL YOU IS COMPARED TO LUPUS, SJOGREN'S SEEMS A LOT MORE HOMOGENOUS, PEOPLE GET DRY EYES, DRY MOUTH. SOME HAVE JOINT PAIN, MOST HAVE FATIGUE. SOME GET REALLY BAD LEUKOCYTE VASCULITIS BUT COMPARED TO LUPUS IT'S HOMOGENOUS. IF WE LOOK AT GENERAL EXPRESSION PROFILING THERE'S A LOT OF WORK IN THE FIELD AT INTERFERON SIGNATURE AND INTERFERON ACTIVATION IN LUPUS, AND SO THERE'S BEEN SOME BEAUTIFUL WORK THAT HAS SHOWN WE ALWAYS WONDERED WHY LUPUS PATIENTS MAKE THE AUTOANTIBODIES THEY DO. SEEMS LIKE MANY OF THOSE AUTOANTIBODIES ARE A PROTEIN RNA COMPLEX OR PROTEIN DNA COMPLEX, AND SO THEY CAN STIMULATE ADAPTIVE AND INNATE IMMUNE SYSTEM. SOME WORK THAT'S BEEN DONE IN OKLAHOMA HAS SHOWN THE SJOGREN'S PATIENTS ALSO A SIGNIFICANT SUBSET HAVE INTERFERON SIGNATURE. YOU HAVE A HOST OF INTERFERON RESPONSIVE GENES AT THE BOTTOM, AND YOU HAVE YELLOW IS UP EXPRESSION, BLUE IS DOWN. WE HAVE A GROUP OF PATIENTS DOWN HERE THAT ARE CLEARLY INTERFERON HIGH, AND THEN A LARGE SECTION OF THESE PATIENTS THAT ENDED UP NOT HAVING THE INTERFERON SIGNATURE. AND SO THIS STARTED TELLING US, WELL, MAYBE THERE'S SOME HETEROGENEITY EVEN WITHIN THIS POPULATION OF PRIMARY SJOGREN'S PATIENTS. SO THIS WAS HAPPENING ABOUT THE TIME THAT VIRGINIA WAS PRESENTING HER WORK AND PUBLISHED HER PAPER IN "CELL" LAST YEAR AND VIRGINIA HAS ANOTHER ONE OF THE ACES, THE BAYLOR ACE, BY HISTORICAL THINGS. NOW IT'S PROBABLY A NEW YORK ACE. AND SO SHE HAS LOOKED AT MODULES, AND THE DIFFERENT GENE EXPRESSION MODULES THAT SHE IDENTIFIED IN PEDIATRIC LUPUS PATIENTS. SO WE WENT BACK AND LOOKED AT THESE SJOGREN'S PATIENTS, LOOKING AT THE SAME MODULES THAT HAVE BEEN IDENTIFIED IN PEDIATRIC DISEASE. AND SO YOU CAN SEE DIFFERENT MODULES WITH EACH ONE OF THE DIFFERENT LINES, DIFFERENT PATIENTS, ONE OF THE COLUMNS, YOU CAN SEE AT THE TOP WE HAVE KIND OF CLUSTER 2 WHICH UNFORTUNATELY DOESN'T LINE UP WITH LINES IN THE WALL, BUT YOU CAN SEE WE HAVE THREE DIFFERENT CLUSTERS, CLUSTER 1 TENDS TO HAVE YELLOW UP TOP, PURPLE IN 2, 3 YOU SEE SOME YELLOW. BUT CLUSTER 2 IS REALLY OBVIOUS. CLUSTER 2 HAS HIGH EXPRESSION OF INTERFERON, WHICH IS KIND OF THE SECOND GROUP DOWN. AND THEN A STRONG SIGNAL IN INFLAMMATION. OPPOSING THAT YOU SEE IN CLUSTER 1 ALMOST NO INTERFERON SIGNATURE, A LITTLE BIT OF INFLAMMATION, CLUSTER 3 INTERFERON AND NO INFLAMMATION. IF YOU START TRYING TO PUT THIS TOGETHER GRAPHICALLY AND LOOK AT THIS, KIND OF IN CONTEXT, YOU CAN SEE EACH OF THE DIFFERENT MODULES IS ONE OF THESE LINES ON THE SPIDER PLOT. YOU CAN SEE CLUSTER 2 IS BLUE, CLUSTER 3 IS GREEN, STRONG INTERFERON IN THOSE TWO, HOWEVER CLUSTER 1 HAS NO INTERFERON AND THEN DOWN HERE AT THE BOTTOM YOU CAN SEE SOME INFLAMMATION. WE SEE NEUTROPHIL SIGNATURE IN THE GROUP CLUSTER 2 AND THEN CLUSTER 3 ACTUALLY HAS MONOCYTE SIGNATURE. AND SO THIS STARTS TELLING US WE MAY REALLY HAVE DIFFERENT GROUPS OF PATIENTS. WE FELT MAYBE THIS IS JUST A REALLY EXPENSIVE WAY TO SAY THEY HAVE AUTOANTIBODIES VERSUS NOT HAVING AUTOANTI-BODIES. CLUSTER 1, 2, AND 3, THE RESPONSE YOU CAN SEE, PRESENT IN ALL THREE CLUSTERS. ANTIBODIES ALONE WOULD NOT HAVE HELPED YOU MAKE THIS DISTINCTION. PROBABLY GENE-EXPRESSION PROFILING WOULD HAVE HELPED BUT WE LOOKED AT SOLUBLE MEDIATORS, CYTOKINES, CHEMOKINES, SOLUBLE RECEPTORS, AND WE ALSO LOOKED AT LIGHT BECAUSE LIGHT WAS PART OF THE PATHWAY, AND WE KNEW THE PATIENTS WITH SJOGREN'S HAD ELEVATED LEVELS OF LIGHT AND THAT THIS MIGHT BE THE MOST HELPFUL BUT YOU CAN SEE LIGHT IS VERY HIGH IN CLUSTER 2, LOWER IN CLUSTER 3, AND BASICALLY LOWER THAN WHAT WE SEE IN CONTROLS IN CLUSTER 1. AND SO YOU CAN SEE WE ALSO HAVE IP 10 AND OTHER ADHESION MOLECULES, AND OTHER RECEPTORS. WE SEE SOME SUBTLE DIFFERENCES THAT UP HAD US TEASE OUT WE HAVE DIFFERENT GROUPS WITHIN THE SJOGREN'S PATIENTS. AND SO, YOU KNOW, THAT'S NOT THE TOTAL END OF THE STORY, BUT IT DOES HELP US AS WE THINK ABOUT HOW WOULD WE DESIGN THE NEXT SJOGREN'S TRIAL. SHOULD WE BE REACHING FOR CERTAIN KINDS OF PATIENTS, WE CAN'T DO THAT JUST BASED ON -- WE LOOKED AT COULD WE LOOK AT JOINT PAIN, COULD WE LOOK AT FATIGUE LEVELS, WAS THERE SOMETHING CLINICALLY THAT WOULD HAVE HELPED US MAKE THE THREE SUBSETS, AND WE COULDN'T FIND ANYTHING. SO IT MAY BE WE NEED TO START THINKING MOLECULARLY HOW CAN WE DEFINE THESE DIFFERENT GROUPS SO THAT WE CAN ENRICH FOR PATIENTS WE NEED FOR A SPECIFIC TARGET FOR A SPECIFIC PATHWAY. AND SO I JUST HAVE ONE SLIDE ON TWO ADDITIONAL TRIALS THAT ARE ONGOING WITH THE ACE CONSORTIUM RIGHT NOW, BOTH OF WHICH ARE REALLY NOVEL BUT NEVER COULD HAVE HAPPENED ANYPLACE ELSE SO THIS IS STOP R.A. WHICH I LIKE THAT NAME. AND SO YOU CAN TELL I CAN'T BE A CLINICAL TRIALIST BECAUSE I COULD NEVER COME UP WITH COOL NAMES. THIS COMES OUT OF UNIVERSITY OF COLORADO WITH KEVIN DEAN AND MIKE HOLIERS, STRATEGY TO PREVENT CLINICAL CON SET OF RHEUMATOID ARTHRITIS, PLACEBO CONTROLLED DOUBLE BLIND, LOOKING AT ANTIBODY-POSITIVE INDIVIDUALS TO SEE IF WE CAN DELAY ONSET OF CLINICALLY APPARENT RHEUMATOID ARTHRITIS USING A BIOMARKER, YOU HAVE TO HAVE GREATER THAN 40 TO BE ENROLLED INTO THE TRIAL AND BECAUSE WE KNOW THOSE INDIVIDUALS HAVE A SIGNIFICANTLY ENHANCED RISK OF DEVELOPING RHEUMATOID ARTHRITIS IN THE NEXT TWO YEARS. THIS HAS BEEN A VERY INTERESTING TRIAL. IT IS REALLY HARD TO FIND PATIENTS WHO AREN'T PATIENTS, AND SO IT'S GIVING US LOTS OF THOUGHT ABOUT HOW DO WE FIND AND ENRICH FOR HIGH RISK INDIVIDUALS. WE THOUGHT ABOUT FAMILY MEMBERS, AND ARE SCREENING FAMILY MEMBERS WITH ANTI-CCP THAT'S POSITIVE IN THE MEDICAL RECORD BUT NO DOCUMENTATION OF R.A. AND ALSO DOING A NOVEL PARTNERSHIP WITH THE OKLAHOMA BLOOD INSTITUTE. AND HAVE USED THAT AS A SCREENING PLATFORM BECAUSE WE HAVE VERY GUNG HO DONORS, VOLUNTEERS WHO ARE OVER 275,000 MULTIPLE DONORS, 275,000 PEOPLE WHO DONATED MULTIPLE TIMES TO THE OKLAHOMA BLOOD INSTITUTE WHICH IS THE ONLY BLOOD INSTITUTE IN THE REGION. AND WE SCREENED, OFFERED PEOPLE TO HAVE ANTIBODIES TESTED AND WE'VE BEEN ABLE TO IDENTIFY PEOPLE WHO HAVE THIS POSITIVE ANTI-BODY WHO OTHERWISE WOULD HAVE NEVER BEEN ENROLLED AND THERE WILL BE LOTS OF OTHER NOVEL WAYS TO FIND THESE INDIVIDUALS. IN ADDITION, WE HAVE A TRIAL IN LUPUS INSTEAD OF STARTING A NEW MEDICATION, OR LOOKING AT A NEW THERAPY, IT'S ACTUALLY A WITHDRAWAL TRIAL SO CLINICALLY MANY TIMES IN LUPUS WE HAVE PATIENTS WHO HAVE SIGNIFICANT DISEASE, SOMETIMES EVEN RENAL DISEASE THAT WILL GET STARTED ON A MEDICATION MMF, AND THEY GET STARTED ON THIS MEDICINE AND THEY DO WELL AND WE KEEP THEM ON THE MEDICINE AND KEEP THEM ON THE MEDICINE AND WE KEEP THEM ON THE MEDICINE BECAUSE AS CLINICIANS WE MIGHT BE NERVOUS ABOUT TAKING THEM OFF, THE PATIENT MIGHT BE NERVOUS, WE'VE NEVER KNOWN WHEN WE COULD ACTUALLY STOP THE MEDICINE. UNFORTUNATELY, AUTOIMMUNE DISEASES ARE NOT LIKE STREP THROAT. YOU CAN'T CLEAR THE INFECTION AND BE DONE WITH IT YET. THIS IS A TRIAL THAT TAKES PATIENTS WITH LUPUS WHO HAVE SUPPRESSED DISEASE AND BASICALLY WATCHES THEM VERY CLOSELY AS WE STOP MMF IN WELL-CONTROLLED LUPUS PATIENTS. THE INTERESTING PART IS IT'S ANSWERING AN IMPORTANT CLINICAL QUESTION AND GETTING INTERESTING SAMPLES FROM PATIENTS WITH SUPPRESSED DISEASE WHILE ON THERAPY, AS THEY TAPER OFF THERAPY, AS DISEASE FLARES OCCUR AND DISEASE FLARES WHETHER OR NOT MAJOR IMMUNOSUPPRESSED MEDICATION, THIS TRIAL ENROLLED 90 OUT OF 120 INDIVIDUALS, STILL UNDERWAY. I'LL SPEND THE LAST BIT OF TIME TALKING MORE IN DEPTH ABOUT SYSTEMIC LUPUS ERYTHROMITOSIS, INCREDIBLY CLINICAL HETEROGENEOUS DISEASE. SOME MAY HAVE RENAL INVOLVEMENT, JOINT INVOLVEMENT, OTHERS SEEM TO HAVE EVERY CRITERIA THAT THERE IS FOR LUPUS. BUT EVEN THE CLASSIC RASH IS ONLY FOUND IN MAYBE 40% OF LUPUS PATIENTS. WE'VE SPENT A LOT OF TIME WORKING ON AUTOANTIBODIES WHICH ARE FOUND IN 99% OF LUPUS PATIENTS, BUT THE AUTOANTIBODIES BY THEMSELVES CAN UP HAD US PUT YOU INTO PROGNOSTIC CLASSES BUT CAN'T HELP US IDENTIFY WHETHER OR NOT YOU'RE GOING TO HAVE A MAJOR CLINICAL FLARE. AND SO WHEN YOU THINK ABOUT THE CLINICAL COURSES OF LUPUS, THERE'S A SUBSET, PROBABLY 10 OR 15% OF PATIENTS WHO HAVE PERSISTENTLY DISEASE, SO A SMALL PERCENTAGE HAVE PERSISTENTLY ELEVATED DISEASE, MAYBE 5 TO 10% COME IN WITH THIS EXPLOSIVE DISEASE, WE THINK IT'S BECAUSE WE AGGRESSIVELY IMMUNOSUPPRESS THEM AND THEN STAY STRESSED. WE'VE BEEN FOCUSING ON WHAT ARE THE MECHANISMS OF DISEASE FLARE. SOME SAY THE FIRST TIME YOU COME IN FOR YOUR CLINICAL PRESENTATION IS YOUR FIRST FLARE OF LUPUS, THE FLARE IS IMPORTANT IN INITIATION AND WAXING AND WANING, ASSOCIATESED WITH INCREASED DAMAGE. IF YOU HAVE DAMAGE IN THE FIRST SIX MONTHS THAT'S ASSOCIATED WITH EARLY MORTALITY AND SIGNIFICANTLY INCREASED MORBIDITY, TWICE AS EXPENSIVE AS PATIENTS WHO EVEN HAVE PERSISTENTLY ELEVATED DISEASE. IT'S BECAUSE A LOT OF TIMES PATIENTS ARE DOING WELL AND COME IN WITH EXPLOSIVE FLARE, TREAT WITH HIGH DOSES OF PULSE IV STEROIDS, MANY TIMES LEADING TO COMPLICATION AND DAMAGE FROM UNDERLYING DISEASE. OUR KIND OF RATIONALE WAS IF WE COULD IDENTIFY PATIENTS WHO WERE ABOUT TO FLARE, WE COULD POTENTIALLY PREEMPTIVELY TREAT WITH LESS AGGRESSIVE THERAPY AND DECREASE CUMULATIVE TOXICITY OVER TIME. AND SO PARTS OF THIS HAVE BEEN LOOKED AT SO THEY WENT BACK AND LOOKED AT THE LARGE CLINICAL TRIALS FOR POLIO AND TOOK PLACEBO GROUPS, 562 LUPUS PATIENTS TREATED WITH STANDARD OF CARE OVER 52 WEEKS, STANDARD OF CARE YOU GET AS PART OF THE CLINICAL TRIAL. AND SO THAT MEANS YOU HAVE FREQUENT MONITORING, MANY WERE ON STEROIDS, ALMOST ALL ON SOME DEGREE OF STEROIDS, FLARE RATES WERE 25 TO 32% MODERATE AND SEVERE FLARES HAPPENING, DURING THOSE 52 WEEKS. AND THE FLARE PREDICTORS WITH THE MULTI-VARIED ANALYSIS WERE REALLY MORE CONSISTENT IN PEOPLE WHO HAD RENAL INVOLVEMENT, HIGH LEVELS OF DOUBLE-STRANDED DNA, HIGHER LEVELS OF BLISS, TWICE NORMAL, LOW COMPLEMENT AND THEN VASCULAR OR NEUROLOGIC INVOLVEMENT. THIS IS SOMETHING WE COULD ADDRESS, FROM A MOLECULAR PERSPECTIVE? AND THOSE THIS IS AN M.D./ PH.D. IN MY LAB TWO LED THE STUDIES, COULD WE ASK THE CLINICALLY IMPORTANT QUESTION, SOMETHING WE COULD MEASURE IN THE SERUM TO HELP IDENTIFY PATIENTS AT THE HIGHEST RISK FOR FLARE, AND SO THIS IS OUR DYSREGULATED, TO UP HAD US IDENTIFY THE BEST WAY TO INTERCEDE. AND SO THESE PLASMA SAMPLES CAME FROM THE VACCINATION COHORT, A GIFT FROM NIAID, SO THANK YOU. I TOLD CONRAD I WANTED TO MAKE SURE HE WAS AWAKE FOR THE SLIDE BECAUSE THIS CAME FROM THE NIAID SPECIAL POPULATIONS CONTRACT, NOW THAT'S BEEN CLOSED FOR SEVERAL YEARS, MANY YEARS, WE ENROLLED 100 LUPUS PATIENTS, MANY WERE STUDIED IN MULTIPLE YEARS OF FLU CONTRACT AND MATCH CONTROLS FOR MATCHED ON AGE, RACE AND GENDER, AND WEIGHED 53 PATIENTS THAT HAD MILD OR MODERATE OR SEVERE FLARE, 6 OR 12 WEEKS AFTER THE VACCINATION. SO WE DID NOT SEE AN INCREASED RATE OF FLARE RIGHT AFTER VACCINATION, BUT WE HAD PATIENTS THAT WE WERE FOLLOWING BASELINE TWO WEEKS, SIX WEEKS, 12 WEEKS AND THEN THE NEXT YEAR WHERE WE WOULD HAVE SAMPLES AVAILABLE FROM BEFORE THEY HAD A CLINICAL FLARE. ALL OF THESE WERE FROM DAY ZERO BASELINE, THIS IS NOT LOOKING AT A VACCINATION RESPONSE. BUT THIS WAS THE DAY THEY CAME IN TO GET THEIR VACCINATION. WE HAVE TWO DIFFERENT GROUPS, GROUP 1 IS EUROPEAN-AMERICAN AND GROUP TWO IS AFRICAN-AMERICAN. AND EVEN WITHIN THESE GROUPS, WE HAD 28 PRE-FLARE LUPUS PATIENTS, THESE ARE PATIENTS WHO HAD A SAMPLE AND THEN CAME IN 6 WEEKS LATER AND HAD A FLARE, MATCHED TO 28 PATIENTS WHO CAME IN AND 6 WEEKS LATER HAD NOT HAD A FLARE. IN ADDITION, WE HAVE TWO SUBSETS WHERE PATIENTS SERVED AS THEIR OWN CONTROLS. WE COULD STUDY SOMEONE IN A YEAR THEY HAD A FLARE AND SOME SUBSEQUENT YEAR WHERE THEY HAD A SAMPLE FROM BEFORE NOT HAVING A FLARE. WE HAD THAT IN OUR EUROPEAN-AMERICANS AND OUR AFRICAN-AMERICANS. YOU CAN SEE THAT WE LOOKED AT 52 DIFFERENT SOLUBLE MEDIATORS, DIFFERENT KINDS OF BLISS AND TNF RECEPTOR 1 AND 2 AND CYTOKINES AND CHEMOKINES, IL-12, INTERFERON GAMMA. DOWN HERE IS AFRICAN-AMERICAN. TOP IS EUROPEAN-AMERICAN, COMPARED TO BLUE NON-FLARE. WE SEE QUITE A BIT HIGHER IN THE PRE-FLARE IL-12 AND INTERFERON GAMMA COMPARED TO MATCHED NON-FLARE. BUT EVEN MORE STRIKING ARE THE SAME INDIVIDUALS IN TWO DIFFERENT YEARS, 6 WEEKS BEFORE HAVING THEIR FLARE, USUALLY OF ARTHRITIS, MUCO CUTANEOUS, HIGHER THAN THEIR SELF NON-FLARE, FOR IL-12, INTERFERON GAMMA AND FOR IL-17 AS WELL AS IL-21, NOT QUITE AS MARKED IN THE AFRICAN-AMERICANS FOR IL-21. WE ALSO SEE THIS FOR IL-1 BETA, WHICH IS ON THE PANEL THE FARTHEST FROM ME. WE ALSO LOOKED AT IL-1 RECEPTOR ANTAGONIST, AND IL-IS RECEPTOR ANTAGONIST WAS HIGHER IN THE SAMPLES FROM BEFORE THE PATIENT, WHEN THE PATIENT WAS NOT GOING TO HAVE A FLARE, WHETHER IT WAS A NON-FLARE MATCHED MANY OR SELF NON-FLARE SAMPLE. YOU CAN SEE THAT THAT RATIO OF IL-1 RECEPTOR ANTAGONIST, IL-1 BETA WAS HIGHER IN SAMPLES FROM PEOPLE NOT GOING TO HAVE A CLINICAL FLARE. IN ADDITION, WE LOOKED AT IP 10, YOU CAN SEE THE SAME THING, SIGNIFICANTLY ELEVATED IN THE PRE-FLARE VISIT. PROBABLY EVEN MORE MARKED IN THE AFRICAN-AMERICAN PATIENTS. SELF NON-FLARE, IP 10 IS HIGHER IN LUPUS PATIENTS THAN WE SEE IN HEALTHY CONTROLS, WHETHER THEY ARE FLARING OR GOING TO FLARE OR NOT. AND SO WE STILL SEE THE STAIR-STEP, AND THEN PROBABLY ONE OF THE OTHER THINGS WE FOUND THAT WAS REALLY INTERESTING, TGF-BETA LEVELS, SIGNIFICANTLY HIGHER IN THE NON-FLARE COMPARED TO THE PRE-FLARE VISIT, COMPARED TO HEALTHY CONTROLS, AND WE ALSO SAW THIS IN THE YEARS THAT THE PERSON DID NOT HAVE A FLARE VISIT. AND SO WE THINK THIS IS VERY EXCITING AND WE'RE WORKING ON THIS FOR MECHANISTIC REASONS, AND LOOKING AT WHAT TYPES OF REGULATORY PATHWAYS ARE IN PLAY, HELPING PREVENT PATIENTS FROM FLARE. FROM A CLINICAL PERSPECTIVE WHAT WE'D LIKE TO DO IS WE WOULD LIKE TO BE ABLE TO ACTUALLY MEASURE IN THE CLINIC, CAN THIS HELP US IDENTIFY PATIENTS THAT NEED MONITORING OR CHANGES IN IMMUNOTHERAPEUTIC BEFORE WE SEE MAJOR CLINICAL FLARES. AND SO WE WITH THE HELP OF THE COLORADO ACE WHO TRIED TO LOOK AT THIS IN RHEUMATOID ARTHRITIS APPLIED SAME STATISTICAL ALGORITHMIC BUILDING METHOD AND WENT THROUGH THE SAME KIND OF APPROACH TO COME UP WITH SOLUBLE MEDIATOR SCORE. WHAT YOU CAN SEE ON THE TOP AGAIN ARE EUROPEAN-AMERICAN PATIENTS GROUPS, BOTTOM AFRICAN-AMERICAN PATIENT GROUPS, THE FIRST COMPARE FLARE TO PEOPLE, THE PRE-FLARE VISIT, TO NON-FLARE, SIGNIFICANTLY HIGHER IN PEOPLE WHO ARE ABOUT TO FLARE COMPARED TO NON-FLARE, MORE PRONOUNCED IN THE FLARE VERSUS SELF NON-FLARE. BECAUSE AFRICAN-AMERICAN PATIENTS TEND TO HAVE MORE SEVERE DISEASE, AND TEND TO HAVE MORE AGGRESSIVE ORGAN INVOLVEMENT I WAS AFRAID THIS WOULDN'T BE AS HELPFUL IN AFRICAN-AMERICANS AND IT'S ACTUALLY TIGHTER IN THE AFRICAN-AMERICANS THAN IT IS IN THE EUROPEAN-AMERICAN PATIENTS AND SO YOU CAN SEE THAT CLEARLY IF YOU HAVE A POSITIVE SCORE IN YOUR SAMPLE THEN THAT MEANS YOU'RE MUCH HIGHER RISK FOR FLARE THAN IF YOU HAVE A NEGATIVE SCORE WHICH IS WHAT WE SEE WITH THE NON-FLARE AND SELF NON-FLARE. WE ALSO SHOW OVER HERE EACH PATIENT, AND COMPARED TO THEIR OWN SAMPLES IN A DIFFERENT YEAR VERSUS EACH PATIENT COMPARED TO MATCHED PATIENT WHO DID NOT HAVE A FLARE. WE SEE THIS AS A CLINICAL TEST, BUT WE ALSO FEEL THAT THE DATA ARE HELPING US THINK ABOUT WAYS TO START THINKING ABOUT HOW THE IMMUNE SYSTEM IN LUPUS PATIENTS WHICH IS ALREADY DYSREGULATED BECOMES EVEN MORE DYSREGULATED RIGHT BEFORE THEY HAVE A CLINICAL FLARE. AND SO IN RED ARE THINGS ELEVATED COMPARED TO HEALTHY CONTROLS, BLUE ARE THE ONES THAT ARE ELEVATED IN THE PATIENTS WHO ARE NOT GOING TO FLARE COMPARED TO LUPUS PATIENTS WHO ARE GOING TO FLARE. RED IS UP IN THE ONES WHO ARE GOING TO FLARE. YOU CAN SEE IT FITS MANY DIFFERENT PARTS OF THE PATHWAYS. AND SO WE THINK THAT THIS IS PART OF WHAT OUR GROUP IS WORKING ON. YOU'LL HEAR THAT THIS HAS LED TO LOTS OF COLLABORATIONS WITHIN THE ACE CONSORTIUM AND MADE US THINK ABOUT IS THERE A DIFFERENT WAY TO THINK ABOUT CLINICAL TRIALS. AND SO IN A PAPER PUBLISHED EARLIER THIS YEAR ONE OF THE CHALLENGES THAT WE'VE HAD IN SJOGREN'S WE HAVE NOT VERY MANY CLINICAL TRIALS BEING DONE. IN LUPUS, WE HAVE LOTS OF CLINICAL TRIALS BEING DONE, UNFORTUNATELY MANY, MANY IF NOT ALMOST ALL OF THEM ARE FAILING. AND SO WHY ARE LUPUS CLINICAL TRIALS FAILING? AND SO ONE OF THE CHALLENGES THAT WE HAVE IS THAT IN PLACEBO ARMS WE SEE SIGNIFICANT IMPROVEMENT. AND THAT'S PARTIALLY BECAUSE THOSE PLACEBO ARMS AROUND COMPLETELY AND TOTALLY REALLY PLACEBO, BECAUSE WE ALLOW PATIENTS TO STAY ON THEIR BACKGROUND MEDS, AND KIND OF STANDARD OF CARE, APPLAUSE MOST OF THOSE PATIENTS RECEIVING STEROIDS. AND SO THEY ARE GETTING SOME KIND OF REGIMEN OF STEROIDS THROUGHOUT THE CLINICAL TRIAL. AND SO THIS WAS THE NAME OF THIS TRIAL WAS BOLD, I DID NOT COME UP WITH THAT, WHICH IS BIOMARKERS OF LUPUS DISEASE, THE BRAINCHILD OF JOHN MERRILL SHOWN HERE AND BASICALLY ALSO KIND OF A BOLD STUDY DESIGN BECAUSE THE QUESTION WAS CAN WE SAFELY TAKE PATIENTS WHO HAVE SOME ELEVATED DISEASE ACTIVITY, NOT LIFE-THREATENING, NOT ORGAN THREATENING DISEASE, NO MAJOR KIDNEY INVOLVEMENT, NO CNS LUPUS BUT HAVE ARTHRITIS, MUCOCUTANEOUS ACTIVE DISEASE, CAN WE GIVE THEM STEROID SHOTS UNTIL DISEASE IS SUPPRESSED, STOP BACKGROUNDS MEDS, FOLLOW AND WATCH AND SEE IF THEY FLARE. THIS IS KIND OF THE STUDY DESIGN, 41 INDIVIDUALS IN THE SMALL PILOT STUDY, THE GOOD NEWS IS WE SAW NO MAJOR SAFETY SIGNALS. 40 OUT OF 41 PATIENTS FLARED WITHIN ABOUT -- EARLY TO FLARES, 21 FLARES WITHIN 2 MONTHS, 13 MORE THAT FLARED BUT ALMOST -- BEEVERYBODY FLARED, 40 OUT OF 41 FLARED WITHIN THE 160 DAYS. AND SO IF YOU TAKE PATIENTS AND GIVE THEM STEROIDS THEY WILL GET BETTER, AND WHEN THEY FLARE THEY DON'T FLARE TO AN INCREASED DISEASE ACTIVITY AT THE FLARE VISIT IS NO HIGHER THAN WHEN THEY CAME INTO THE TRIAL, NOT LIKE WE'RE TAKING THEM OFF BACKGROUND MEDS, WHEN THEY FLARE NOW THEY HAVE, YOU KNOW, MAJOR BRAIN INVOLVEMENT AND HEART AND LUNGS, USUALLY THEY FLARE IN MANY WAYS THE SAME WAY THEY CAME INTO THE TRIAL USUALLY WITH ACTIVE ARTHRITIS, MUCOCUTANEOUS ET CETERA. WE HAVE A GROUP THAT CLEARLY RESPOND TO STEROIDS, DISEASE ACTIVITY GOES DOWN AND THEY FLARE QUICKLY AS THE STEROID SHOTS WEAR OFF. WE HAVE OTHERS THAT SEEM TO DO REALLY WELL FOR THREE MONTHS, FOUR MONTHS, FIVE MONTHS, OFF BACKGROUND MEDS, SOME ON METHOTREXATE, SOME WERE ON MMF, WE DIDN'T THINK IT WAS ETHICAL TO STOP THE HYDROXY. WE HAD THE OTHER GROUP LATER TO FLARE. NOW WE'RE DISSECTING ARE THE FLARES DIFFERENT IN THE PEOPLE WHO ARE EARLY TO FLARE COMPARED TO LATE. AND SO THE CLINICAL TRIAL PART OF THIS WAS PUBLISHED BUT THE MOLECULAR PHENOTYPE PART IS STILL A WORK IN PROGRESS. WE'VE LOOKED AT THE DIFFERENT MOLECULAR SIGNATURES BASED UPON GENE EXPRESSION PROFILES FOLLOWING PASCUAL'S PAPER, AND YOU CAN SEE WE HAVE CERTAIN THINGS WHERE THE RED COMES UP, YOU CAN SEE INCREASED EXPRESSION IN CERTAIN MODULES, ESPECIALLY IN EARLY FLARE COMPARED TO THE CONTROLS, AND THEN IN THE LATE TO FLARE YOU CAN SEE WE HAVE THE BIG BLUE DOTS WHERE WE HAVE DOWNREGULATION, IF YOU PUT THIS INTO A GESTALT, BLUE IS EARLY TO FLARE, INCREASED INFLAMMATION HERE, INCREASE BY PLASMA CELLS AND A NUMBER OF DIFFERENT UNDETERMINED MODULES, WHICH WE THINK ARE INTERESTING AND WE'RE DISSECTING THIS IN A COUPLE WAYS. AND THEN YOU CAN SEE THE INTERFERONS ARE ACTUALLY ELEVATED IN EARLY TO FLARE AND LATE TO FLARE, AND THAT THE LATE TO FLARE DIDN'T REALLY HAVE A SIGNAL THAT WAS COMPLETELY ITS OWN EXCEPT MAYBE THE TWO THINGS THAT ARE OVER HERE IN UNDETERMINED AREAS. AND SO WE'RE STILL TRYING TO TEASE OUT WHAT'S GOING ON WITH THE PATHOGENESIS OF THE LATE TO FLARE. BUT THE SURPRISING THING IS SO IF WE TAKE ALL OF THE CLINICAL INFORMATION WE HAVE ON THESE INDIVIDUALS, WE TAKE THEIR GENE-EXPRESSION PROFILING, AUTO ANTIBODIES AND TAKE SOME IMMUNE PHENOTYPING, FLOW CYTOMETRY DATA, CAN WE USE RANDOM FORCE MODELING TO IDENTIFY EARLY TO FLARE VERSUS LATE FLARE GROUPS, WE FIND WE DON'T JUST HAVE LATE TO FLARE VERSUS EARLY TO FLARE, BUT EARLY TO FLARES THAT THREE GROUPS IN THEM. LATE TO FLARE DEFINITELY CAN BE DIFFERENTIATED AWAY FROM EARLY TO FLARE BUT EVEN WITHIN THE EARLY TO FLARE GROUP, SMALL SAMPLE SIZES NEED TO BE LOOKED AT IN DIFFERENT STUDIES BUT WE SEE THAT THERE ARE DIFFERENT WAYS YOU COME TO FLARE. THIS IS QUITE A BIT OF DATA SUMMARIZED ON SLIDE NOT PROJECTING WELL, I'M SORRY, BUT YOU CAN SEE WE HAVE DIFFERENT PATHWAYS THAT ARE SHOWING US RED IS HIGHER IN COMPLEMENT CELL ACTIVATION, WE HAVE RED TWO DIFFERENT EARLY TO FLARE BUT ARE HIGHER IN THOSE COMPARED TO OTHERS, WE HAVE DOWN HERE MONOCYTES MAY BE IMPORTANT IN CERTAIN KINDS OF EARLY TO FLARE, IF YOU BREAK THIS OUT AND ACTUALLY LOOK AT THE NUMBERS YOU CAN SEE THAT EARLY TO FLARE WE HAVE QUITE A FEW THAT HAVE HIGHER NUMBERS OF ACTIVATED CD11 B MONOCYTES, A DIFFERENT GROUP WITH HIGHER NUMBERS OF CD8 6 HIGH B CELLS. I THINK THE MORE THAT WE LEARN ABOUT THE UNDERLYING MECHANISMS OF THE DISEASE, ESPECIALLY THE DISEASE AS IT FLARES, WE HAVE DATA ABOUT SECOND FLARES, AND IT DOES LOOK LIKE THE MOLECULAR WAY YOU FLARE MAY BE THE SAME WAY THAT YOU MOLECULARLY FLARE. UH-HUH? >> (INAUDIBE) CAN YOU ANALYZE THE DATA FROM -- (INAUDIBLE). >> A BEAUTIFUL LEAD-IN TO OUR ACE COLLABORATIVE PROJECT BECAUSE WE THINK THAT'S WHERE WE NEED TO GO, WE'VE LOOKED AT MMF, ON AND OFF MMF, WE CAN SEE WHICH PATHWAYS ARE INFLUENCED BY MMF, AND WHICH OF THE THREE FLARES, THAT THEY ARE ACTIVATING IN THE CELLS THAT ARE UP MAY BE TARGETED BY MMF. GROUP 1 LOOKS LIKE IT MAY BE MORE METHOTREXATE. SO I AGREE THAT'S EXACTLY WHERE WE'RE TRYING TO GET TO. AND SO DAVID IS LOOKING AT ME SO I'M GOING TO -- I THOUGHT YOU WERE LOOKING AT ME. HOW CAN WE BETTER SELECT THERAPIES? WE CAN USE THIS INFORMATION TO TAKE AUTOIMMUNE DISEASES, CLINICALLY MIXED BAG, MOLECULARLY MAYBE DIVERGENT PATHWAYS, PROBABLY BOTH. THEY DON'T LINE UP. IF WE USE MOLECULAR INFORMATION CAN WE ENRICH FOR PATIENTS HOMOGENUS FOR PATHWAYS AND INTERVENE WITH TARGETS WE KNOW AFFECT THAT SPECIFIC PATHWAY, NOT NECESSARILY A NEW BIOLOGIC BUT SOME OF THE OLDER ONES WE HAVE OR EVEN SOME OF THE NEWER BIOLOGICS BUT ONLY IN A SUBSET OF PATIENTS. WE THINK THIS WILL BE CRITICAL FOR PERSONALIZED TREATMENT, MEDICINE, IN AUTOIMMUNE DISEASES, ALSO FOR CLINICAL TRIAL SUCCESS. AS WE KNOW WHICH PATHWAY AND ENRICH FOR THAT PATHWAY WE THINK THAT'S THE WAY THAT WILL SEE IMPROVED SUCCESS IN CLINICAL TRIALS IF WE CAN GET RID OF BACKGROUND MEDS USING NOVEL DESIGN AND ALLOWING PATIENTS THAT WE KNOW ARE GOING TO FLARE INTO THE TRIALS. IN ADDITION, WE'RE STARTING TO LEARN THERE ARE PATHWAYS THAT ARE CLEARLY COMMON ACROSS DIFFERENT AUTOIMMUNE DISEASES, AND SO SOME SJOGREN'S LOOK IKE OTHERS, COULD WE PICK A THERAPY THAT COULD WORK ACROSS INSTEAD OF DOING CLINICAL TRIALS BASED ON HISTORICAL CLINICAL PHENOTYPE. THE FINAL IS PARTNERSHIPS OF WELL-DEFINED PATIENT COLLECTIONS WITH CUTTING EDGE APPROACHES OFTENTIMES ACROSS FIELDS, ACROSS DISCIPLINES CAN ACCELERATE DISCOVERIES IN ADVANCED CLINICAL CARE. THE SECTION AT THE END WAS BETWEEN US AND STANDARD ACE WHICH LOOKS AT LUPUS PATIENTS WITH SUPPRESSED DISEASE ACTIVITY AND FURTHER SPLITTING LOOKING AT PATIENTS ON AND OFF MMF WHERE WE CAN MATCH FOR DISEASE ACTIVITY. I THINK I WILL TAKE QUESTIONS THERE, THAT WILL CATCH US BACK UP. I DON'T WANT TO MAKE ANYBODY MISS THEIR FLIGHT. I'D BE HAPPY TO TAKE QUESTIONS IF WE HAVE TIME. IGNAKIR ON YOU THE PHONE? >> YES, I AM. >> WONDERFUL. ANY QUESTIONS? OTHERWISE WE'RE MOVING TOWARD YOUR TALK, IGNAKI. >> OKAY. LET ME FIRST ASK ABOUT THE SCREEN THERE. >> THERE'S AN UPDATED ONE. >> (INAUDIBLE) (INAUDIBLE CONVERSATION) >> WE STARTED TO LOOK AT PATIENTS WITH MULTIPLE AUTOIMMUNE DISEASES. >> EVENTUALLY THAT WOULD BE REALLY NICE. >> IGNAKI, I THINK YOU -- (INAUDIBLE). >> AS FAR AS I KNOW, I AM. >> (INAUDIBLE) THAT I HAD NOT HEARD BEFORE. ALSO SORRY I CANNOT BE THERE. I WAS GETTING READY TO DO THE PRESENTATIONS, HEARD FROM HOME WE JUST LOST POWER THERE, SO THINGS ARE HAPPENING HERE AS WELL. IT'S GOOD TO BE WITH EVERYBODY. AND WHAT I WANTED TO DO, DAVID AND JUDITH HINTED AT BEFORE, TO GIVE YOU A SENSE OF WHAT WE ARE DOING WITHIN THE EMORY (INDISCERNIBLE) EXCELLENCE, THE SEC PART OF THE PRESENTATION I'LL CONCENTRATE MORE ON COLLABORATIVE STUDIES ACROSS THE ACES. TRY TO UNDERSTAND HUMAN B CELLS AND DYSREGULATION. AND THE MAIN MESSAGE OF THE FIRST PART OF THE PRESENTATION IS THAT WE CANNOT IDENTIFY WITH THE IMMUNE EFFECTOR PATHWAY FOR B CELLS THAT ARE VERY PROMINENT AND ARE EXPANDED BECAUSE OF THE EFFECTIVE RELATION OF THE PARENT SIGNALING. YOU SEE WHERE I'M GOING. ALTERNATIVE VIEW WOULD BE NAIVE VIEW OF CELLS, PATHOGENESIS -- >> (INAUDIBLE). >> WOULD EVERYBODY ELSE MUTE THEIR MICS. >> (INAUDIBLE) A COUPLE YEARS AGO, A COMBINATION (INAUDIBLE) NAIVE CELLS IN SLE, DISTINCT PHENOTYPE CHARACTERIZING LACK OF EXPRESSION OR LOSS BECAUSE IT'S EXPRESSED BEFORE ACTIVATION, ALSO EXPRESSION OF THE GRID, CONTAINING A LARGE ABUNDANCE, A SUBSET OF SLE INDICATING BEFORE. THEY ALSO (INDISCERNIBLE) CELLULAR COMPARTMENT, SERUM ANTIBODIES THEMSELVES. THESE ANTIBODIES ACTUALLY DISPLAY OTHER REACTIVITY IN THE ABSENCE OF MUTATION WHICH SUGGESTS ACTUALLY THEY DIVIDE AND ALSO INDICATING THAT ALTHOUGH MUTATIONS CAN BE IMPORTANT IN MANY DIFFERENT WAYS, PATHOGENIC (INDISCERNIBLE) DOES NOT REQUIRE ACTUALLY MUTATION TO ACTUALLY HAPPEN. THESE ARE SOME ORIGINAL DATA WE PUBLISHED CONTRIBUTING TO THIS MODEL, BY FLOW CYTOMETRY, INACTIVE SLE, THIS POPULATION OF ACTIVATED NAIVE CELLS IN THE COMPARTMENT, ABSENT IN (INDISCERNIBLE). THAT POPULATION IF YOU LOOK HERE, A LARGE SEGMENT OF EXPANSION HERE AND THEY ARE HIGHLY INTERCONNECTED WITH PLASMA CELLS IN THE SAME WAY IN THE PATIENT. SO THEY ARE HIGHLY (INDISCERNIBLE) GENERATE PLASMABLAST AND PLASMA CELLS. THE COMPONENT IS HIGHLY ENRICHED AS YOU CAN SEE HERE AND HERE IN REACTIVE CELLS WE CAN IDENTIFY WITH CORRESPONDING (INDISCERNIBLE) AND THAT EXPRESSED 34. I'M TAKING ADVANTAGE OF THAT REAGENT, WE WERE ABLE TO FACILITATE IN 94 FRACTION, AND THEN BY DOING SERUM PROTEOMICS AND MATCHING AND SEQUENCING WE WERE ABLE TO MATCH, IT'S IN THE BLOOD, ACTUALLY MATCHED ACTIVATED NAIVE CELLS, (INDISCERNIBLE) HIGHLY AUTOREACTIVE WHICH WE SHOWED IN THE PAPER IN DIFFERENT WAYS, MORE RECENTLY WE EXPANDED IN COLLABORATION WITH STANFORD BY USING HIS EXTENSIVE MICROARRAYS SHOWING SOME OF THESE ARE MUTATED, DERIVED FROM NAIVE B CELLS, NOT ONLY HIGHLY REACTIVE AGAINST ANTIGENS, IN SOME CASES REACTIVE AS WELL, WE WANTED TO UNDERSTAND CONTRIBUTION OF B CELL PATHWAYS TO SLE AND WE DISPLAYED THE PERMUTATION PATHWAYS COMING TO ACTIVATE NAIVE CELLS, PLASMABLASTS, OR REACTION THAT WE MAKE MEMORY B CELLS ALONG WITH PLASMA CELLS. FIRST TIME WE ACTIVATED NAIVE CELLS ARE GOING TO FIND (INDISCERNIBLE) REACTION. WE FIND THIS COMPONENT IN THE PREVIOUS PAPER, NOW WHAT WE WANTED TO DO WAS PLACE IN PATHWAYS AND CELL POPULATIONS WE HAVE REPORTED ACTUALLY ALMOST TEN YEARS AGO BY NOW AND THOSE ARE THE B CELLS THAT ABSENCE OF IGV AND CD37, MAINLY MARKER, AND INACTIVE FOR SEVERE SLE, THEY ACTUALLY BECOME THE MAJOR POPULATION IN THE (INDISCERNIBLE) OF THESE YOU BARELY IDENTIFY THEM.ECTS- IN FACT, THEY HAVE BEEN IGNORED FOR QUITE A TIME. WE WANTED TO UNDERSTAND WITH THE POPULATION FOR WHICH AN OVERLAPPING PHENOTYPE HAS BEEN REPORTED IN HIV AND MALARIA, REPORTED IN (INDISCERNIBLE) MEMORY OR WHETHER WE CAN ACTUALLY PLACE IT HERE IN THE EXTERNAL REGULAR REACTION AS A PROGENY OF NAIVE CELLS AND PRECURSOR OF PLASMABLASTS. THIS IS A SUMMARY THAT WE USE IN EMORY, IN PARTICULAR LUPUS WITH COLLABORATIONS WITH INTEGRATED ANALYSIS, IMMUNOPRECIPITATION (INDISCERNIBLE) AND B CELL POPULATION WE ANALYZE BY NEXT GEN SEQUENCING TO IDENTIFY B CELL BY MULTI-DIMENSIONAL FLOW CYTOMETRY AND SORT THOSE POPULATIONS OF INTEREST AND PERFORM AN INTEGRATED ANALYSIS OF THE TRANSCRIPTOME AND GENOME, AND THESE ARE DIFFERENT COLLABORATORS, EITHER EMORY DIFFERENT NETWORKS AND THEN PROTEOMICS. USING THAT APPROACH STARTING WITH MULTI-DIMENSIONAL FLOW CYTOMETRY WE CHARACERIZE THE POPULATION MORE RECENTLY IN MORE COLLABORATIVE WAY. IF YOU FOLLOW COMPLICATED SLIDES, IF YOU LOOK AT THE HEALTHY CONTROLS, YOU WILL SEE SO-CALLED NAIVE CELLS, (INDISCERNIBLE) MEMORY, RATHER A SMALL FRACTION HERE. YOU WILL SEE NO MORE B CELLS IN THE COMPARTMENT (INDISCERNIBLE) ALSO CD19 AT HIGHER LEVELS. ACTIVE LUPUS, ON THE OTHER HAND, YOU WILL SEE THE POPULATION NOW IS HIGHLY ENRICHED, (INDISCERNIBLE), THE OTHERS WE CALL THE N 1. SOMETHING SIMILAR HAPPENS IN THE COMPARTMENT, NOW YOU HAVE THE EXPANSION OF THE ACTIVATED NAIVE CELLS THAT WE IDENTIFIED BEFORE THAT NOW WE CHARACTERIZE, THE EXTENDED PHENOTYPE OF CELLS FOR THOSE THAT MIGHT BE INTERESTED, BUT I WILL COUNTER THAT IN MORE DETAIL AS WE GO. SO LET ME DO THAT. ONE OF THE FIRST THINGS I WANTED TO POINT OUT IS THESE CELLS, THE POPULATION, B CELL POPULATION CAN BECOME GREAT INTEREST IN BIOLOGY THE LAST FEW YEARS TO SOME EXTENT THE DESCRIPTION OF THE B CELLS IN THE GROUP AND LABEL THEM AGE ASSOCIATED B CELLS OR ABCs, AND WENT ON TO DEMONSTRATE THEIR (INDISCERNIBLE) AS WELL AS BIOCLEARANCE IN THE MOUSE. SO IN HUMANS THERE'S BEEN A LOT OF WORK RECENTLY IN DIFFERENT POPULATIONS THAT HAVE BEEN REPORTED EITHER POSITIVE OR ALTERNATIVELY CD19 LEVEL, OVERLAP BETWEEN THE POPULATIONS THAT I'LL SHOW YOU IN A MOMENT. I THINK THAT CONFUSION, WHERE PEOPLE ARE (INDISCERNIBLE) BY ANALOGY TO ANOTHER POPULATION. AND I THINK THAT'S AN IMPORTANT POINT IN B CELL BIOLOGY. WITHIN THE B CELLS, THE POSITIVE FRACTION AND NEGATIVE FRACTION, WHAT YOU CAN SEE IS THAT THE NEGATIVE HAS NORMAL DISTRIBUTION FOR POPULATIONS, POTENTIALLY A FRACTION OF NAIVE CELLS AND WHEN YOU LOOK AT THEM BY THE OTHER MARKERS YOU GET HERE (INDISCERNIBLE) AND YOU WILL SEE IN A POSITIVE POPULATION IS ESSENTIALLY ONLY THE VAST MAJORITY WITHIN THAT (INDISCERNIBLE) ESSENTIALLY ACTIVATED NAIVE CELLS, SHOWING HERE HISTOGRAMS, SUMMARIZED HERE PERHAPS BY LOOKING, YOU'LL SEE THE PHENOTYPE POPULATION IS REALLY LIMITED OR CONCENTRATED IN THE NAIVE CELL, AND EVEN IN THE NEGATIVE, SWITCH MEMORY, (INDISCERNIBLE) THERE IS NOT HIGH, CERTAINLY NOT AT THE LEVEL OF THESE POPULATIONS. I THINK THAT WOULD BE IMPORTANT œTO KEEP IN MIND MOVING FORWARD AS WE TRY TO MAKE SENSE OF PLETHORA OF LITERATURE NOW ABOUT POSITIVE OR CD21 NEGATIVE B CELLS DESCRIBED IN MANY WAYS HIGHLIGHTED HERE, WHETHER IN HUMANS OR IN MICE IN RED AND THEN IN MICE ONLY IN DIFFERENT SITUATIONS. WE THINK THESE ARE THE POPULATIONS HIGH CD31, 11 C POSITIVE, AND (INDISCERNIBLE) NEGATIVE. WHEN YOU LOOK IN THE LUPUS POPULATION, I'M GOING TO SUMMARIZE THIS IN THE INTEREST OF TIME. (INDISCERNIBLE) THAT'S SHOWN HERE, HERE SHOWING THE NORMAL POPULATION, THEY ARE VERY, VERY EXPANDED IN ANY LUPUS COHORT THAT WE HAVE LOOKED AT HERE, WE HAVE ONE FROM ROCHESTER AND HOPKINS, ALSO FUNDED AT THE TIME, THIS IS THE ONE FROM EMORY, THE AFRICAN-AMERICAN PATIENTS, AND IN FACT THAT POPULATION WE SEE HIGHER LEVELS, THEY ARE ALSO EXPANDED THAT THE ABSOLUTE NUMBER IS NOT THE PERCENTAGE, AND THERE'S NOW A CORRELATION WITH AGE WHICH HAS BEEN REPORTED FOR THE ABCs, A STUDY IN LUPUS THAT DID NOT FIND ACTUALLY EXPANSION OF ABCs IN LUPUS FOR REASONS UNCLEAR TO ME BUT A VERY SMALL STUDY, DIFFERENT POPULATION, IT WAS ACTUALLY ARGUED THAT MIGHT HAVE BEEN BECAUSE LUPUS PATIENTS ARE YOUNGER AND ABCs ARE -- THIS IS THE MOUSE, THAT IS CERTAINLY NOT THE CASE AS YOU CAN SEE HERE, NOT THE RELATION BETWEEN THE PERCENTAGE AND IN FACT WE HAVE FOUND PATIENTS AS YOUNG AS 5 YEARS OF AGE ON SLE, HUGE EXPANSIONS, POTENTIALLY REPRESENTING THE B CELLS THAT PROLIFERATE, (INDISCERNIBLE) AT LEAST NOT IN OUR COMMUNITY. VERY INTERESTING IN PARTICULAR (INDISCERNIBLE) IN THE SERUM PHENOTYPES AS WELL, WHEN YOU LOOK AT HIGHLY QUANTITYATED ASSAY, (INDISCERNIBLE) COMPARED TO LESS ACTIVE OR HEALTHY CONTROLS. LOOKING AT B CELLS, THIS IS JUST LOOKING AT B CELLS, HERE IS THE NAIVE CELLS, ALL OF THEM, NOT ONLY ACTIVATED NAIVE CELLS, DN 1, 2, SWITCH MEMORY, YOU CAN SEE ALL OF THEM ARE SEPARATED FROM THE HEALTHY COUNTER PARTS BY COMPONENT 1, WHICH IS SUMMARIZING HERE FOR GENES AND YOU CAN SEE THAT THEY ARE THE DIFFERENT CODE INTERFERON REGULATED GENES, EXPRESSED IN ORANGE, MANY OF THEM SUMMARIZED HERE, LOOKING AT INCREASING THE INTERFERON, TYPE 1 INTERFERON BACK TO MODULES. YOU CAN SEE A LOT OF DNA AND RNA SENSORS HERE, DIFFERENT COLOR CODE, AND I'M NOT GOING TO GO IN DETAIL OVER THEM BUT A LOT OF THEM ARE ACTUALLY HIGHLY INCREASED IN (INDISCERNIBLE) RELATIVE TO HEALTHY CONTROLS IN ALL THE DIFFERENT POPULATIONS. YOU CAN ALSO SEE INTERESTING SET OF GENES DOWNREGULATED, POORLY EXPRESSED IN LUPUS B CELLS, AND THEY SEEM TO IMPACT THE SAME PATHWAYS IN THE SAME LIKE (INDISCERNIBLE) NEGATIVE REGULATORS, INFLAMMATORY PATHWAYS, THEY SEEM TO BE DEFECTIVE IN THE B CELL. NOW WHEN YOU START LOOKING FROM BIRTH TO THE OTHER B CELLS, YOU CAN SEE HERE A NUMBER OF RNA SEQUENCING, FIRST THEY SHOW A SIGNIFICANT DIFFERENCE WITH ALL THE DIFFERENT POPULATIONS, AS YOU CAN SEE HERE, AND IN CONTRAST YOU CAN SEE THE DN 1 AND SWITCH MEMORY ARE ESSENTIALLY IDENTICAL, RNA SEQUENCING LEVEL, WITH ONLY 22 DIFFERENTIALLY EXPRESSED GENES SO THEY ARE PRETTY MUCH THE SAME FROM THAT POINT OF VIEW. AND YOU CAN SEE HERE AN INTERESTING SET OF GENES THAT ARE EXPRESSED IN DIFFERENT DIRECTIONS, HIGHLIGHTS THE ONES TO UNDERSTAND WHAT THE CELLS MAY DO AND COME FROM. THERE ARE SEVERAL GENES ONLY HIGHLY EXPRESSED, RATHER THAN ANOTHER SUBSET, THE ONES YOU MIGHT EXPECT BECAUSE THEY WERE OVEREXPRESSED BY THE MARKERS PD11C AND AS YOU MIGHT EXPECT, (INDISCERNIBLE) AND I'LL TALK ABOUT THESE IN A SECOND AND A NUMBER OF MARKERS, A MARKER OF ACTIVATION, HIGHLY EXPRESSED BY PLASMA CELLS, A NUMBER OF SIGNALING OR INHIBITORY RECEPTORS, AND THEN AS SAID TRANSCRIPTION FACTORS, THERE'S OVEREXPRESSED RELATIVE TO OTHER CELLS. THERE'S A NUMBER OF MARKERS THAT ARE SPECIFICALLY LOW INCLUDING WHAT I SHOWED YOU BEFORE, A20 AND FRET 5 AND I'LL GET BACK TO THAT IN A SECOND AS WELL. BUT LET ME SAY THIS IS THE CENTRAL REGULATOR OF B CELLS (INDISCERNIBLE). THOSE ARE CONSISTENT WITH EXTRACURRICULAR PATTERNS OF MIGRATION AND TRANSCRIPTION FACTORS, AND I'LL GET BACK TO THAT IN A SECOND AS WELL. AND THEN YOU HAVE A NUMBER OF HIGH MARKERS THAT ARE ONLY ON NAIVE CELLS, IN PARTICULAR BACK TO FOX 1 THAT MAINTAIN NAIVE B CELL IDENTITY ESSENTIALLY THROUGH THE DIFFERENTIATION AND THOSE ARE DOWNREGULATED, AND FINALLY THERE'S A NUMBER OF TRANSCRIPTION FACTORS, HIGHLY EXPRESSED ON THE SWITCH MEMORY, BUT NOT IN NAIVE OR BM2s. AS YOU CAN SEE BM1 MEMORY ARE ESSENTIALLY THE SAME. NOW, YOU CAN SEE HERE THAT ACTUALLY THE ONLY NAIVE POPULATION OR SAMPLE IS THIS PARTICULAR ONE THAT CO-RESPONDS TO A PATIENT GROUP OF (INDISCERNIBLE) ABOUT 40% OF THE NAIVE CELLS WITH NAIVE -- ACTIVE NAIVE PHENOTYPE AND OUR SPECULATION WAS THAT IT WAS INDUCES, REFRACTING A SIMILAR TRANSCRIPTIONAL PROGRAM IN THE ACTIVATED NAIVE CELLS. IN FACT WHEN WE DID ANOTHER (INDISCERNIBLE) PATIENTS AND SORTED THE NAIVE CELLS AND RNA SEQUENCING, YOU CAN SEE THAT BY COMPONENT ANALYSIS, ACTIVATED NIH CELLS CLOSE TOGETHER, AND SO WE BELIEVE THAT'S THE EXPLANATION FOR THAT. HERE IS WHAT WE THINK THE CELLS COME FROM AND LOOK LIKE. THEY HAVE A PROGRAM THAT IS VERY SIMILAR TO CD8 CELLS, MEMORY B CELLS, (INDISCERNIBLE) AS I SAID BEFORE REFER TO DIFFERENTIATION OF NAIVE B CELLS, THEY DO NOT EXPRESS THE (INDISCERNIBLE) WHICH IS CRITICAL TO MAINTAIN MEMORY PROGRAM AND SURVIVAL AND THEY DO NOT EXPRESS (INDISCERNIBLE) THAT FAVORS (INDISCERNIBLE), THEY EXPRESS IL-4, RATIOS ARE MORE POISED TO BECOME PLASMA CELLS AND I'LL SHOW YOU THE EVIDENCE FOR THAT LATER. THEY OVEREXPRESSED AND CONTRIBUTE WITH DISCERN (INDISCERNIBLE) THEY ARE ALSO CONTROLLED. SO WE THANK POTENTIALLY THAT WAS AN ANALOGY WITH MEMORY CELLS AND PLASMA PHENOTYPE, I'LL PRESENT EVIDENCE IN THE NEXT FEW SLIDES, INCLUDING THIS ONE. YOU SEE HIGHLY ENRICHED ON THAT. THIS IS THE IL-4 RATIO I SHOWED YOU BEFORE, AND INDICATING IT IS THE ACTIVE CELLS THAT WERE LOWER IN THE SAME DIRECTION AS PLASMA CELLS, AND THESE ARE NOT THE MARKERS THAT WE FIND VERY INTERESTING, OUR MARKER OF B CELL ACTIVATION, (INDISCERNIBLE) PREFERENTIALLY UPREGULATED INACTIVATED NAIVE CELLS, HIGHLY UPREGULATED IN PLASMA CELLS. THIS IS WHY (INDISCERNIBLE) HAVE SHOWN TO BE HIGHLY ACTIVE AGAINST AGAINST MYELOMA, FDA APPROVED RECENTLY FOR THAT PATIENT. LET ME SHOW YOU THAT ALTHOUGH I DIDN'T MENTION THAT BEFORE, IT'S NOT TRANSCRIPTIONALLY OVEREXPRESSED (INDISCERNIBLE) YOU LOOK AT ACCESSIBILITY, ATTEMPTING TO OPEN ( INDISCERNIBLE) OR IN LUPUS, ALREADY OFFERING THOSE CELLS ARE THERE FOR TRANSCRIBE AND BECOME PLASMA CELLS. THEN IN FACT DOING CULTURE, THEY DO IT WHEN YOU INCUBATE THEM, IL-21 CONDITIONS, THEY PRODUCE AS MUCH AS (INDISCERNIBLE) MEMORY POPULATIONS, SHOWN IT'S HIGHLY IL-21 DEPENDENT, RELATIVE TO SWITCH MEMORY, AND THAT'S KNOWN TO BE A PROPERTY OF NAIVE T CELLS IN HUMANS. WE DIDN'T HAVE CELLS HERE (INDISCERNIBLE) FIND THEM IN LUPUS, AND THEREFORE THERE WAS NO CELLS. THE CELLS IN THE CULTURES PRODUCE LUPUS ANTIBODIES, RMP, IL-60, NOT SPECIFICALLY TO LUPUS, HIGHLY ENRICHED AT THE SAME LEVEL OR MORE MEMORY CELLS FOR ANTIBODIES. THE FINAL PROOF ON PLASMA CELL DIFFERENTIATION SHOWING IN THE BLOOD IN PATIENTS WITH FUTURE EXPANSIONS OF PLASMA CELLS, YOU'VE BEEN SEEING HERE BY FLOW CYTOMETRY AND HUGE EXPANSIONS THAT WHEN YOU DO NEXT GENERATION SEQUENCING OF THE REPERTOIRE THERE'S A HUGE AMOUNT OF CONNECTIVITY, BULK ANALYSIS OR SINGLE CELL LEVEL, BETWEEN THE COMPARTMENTS SHOWING THAT IN FACT THOSE CELLS ARE BECOMING PLASMA CELLS, A VERY LARGE PLATE. IN TERMS OF FUNCTIONALITY THE CELLS THAT WERE DEFICIENT IN FRET 5, THE EXPECTATIONS THEY SHOULD HAVE SIGNALING, THESE WOULD BE THE NEGATIVE OF THE PATHWAY, IN FACT THEY DO AS YOU CAN SEE HERE, ACTIVATED WITH IL-4A, (INDISCERNIBLE) LEVELS OF PHOSPHORYLATION AND THEN IN FACT THAT'S SUMMARIZED HERE. YOU CAN SEE THE PROPERTIES AS MANY MARKERS AND THE TRANSCRIPTOME IS SHARED BETWEEN INACTIVATED CELLS, AND THIS IS THE SIGNALING. ALTHOUGH NAIVE CELLS RESPOND WELL TO CD4 LIGAND, THESE DO NOT, THAT REFLECTS THE FRET 5 DEFICIENCY. THEY RESPOND, GOING TO SUMMARIZE THIS, ALSO TO INTERFERON (INDISCERNIBLE) I MAY HAVE NOT POINTED THAT OUT IN THE HEAT MAPS BEFORE FOR TRANSCRIPTOME, DEFINED IN NAIVE CELLS EXPRESS HIGH LEVELS OF INTERFERON LAMBDA RECEPTOR, THOSE ARE THE TWO POPULATIONS THAT ACTUALLY RESPOND AT HIGHER LEVEL. THAT'S IMPORTANT BECAUSE INTERFERON LAMBDA IS GAINING FROM BIOLOGY AND CERTAINLY LUPUS, WHERE IT HAS BEEN SHOWN IN THE KIDNEYS OF PATIENTS WITH LUPUS, ONE OF THE THINGS THAT (INDISCERNIBLE) EXPRESSION. SO WE THINK THAT INTERFERON LAMBDA ARE SYNERGISTIC FOR EXPANSION OF CELLS. TO SUMMARIZE THIS PART OF THE TALK, WHAT WE THINK GOING BACK TO THE DIFFERENTIATION, WE THINK OUR DATA INDICATES THAT IN FACT THE CELLS ARE SO PROMINENT IN LUPUS ACTUALLY BELONG IN THE DIFFERENTIATION PATHWAY, THE PROGENY OF ACTIVATED NAIVE CELLS AND PRECURSOR OF PLASMA, PRECURSOR OF LATE MEMORY CELLS, AND WE THINK THAT THESE AGENTS ACTUALLY CAN WIPE OUT ACTUALLY THE EXTRACURRICULAR PATHWAY KNOWN TO BE IMPORTANT IN HUMAN LUPUS AND ALSO THE PLASMA CELLS ARE SHOWN FOR MULTIPLE MYELOMA. WE WERE JUST APPROVED TO AT LEAST PAY FOR THE DRUG, PERFORMANCE STUDY, AND HOPEFULLY WE WILL BE ABLE TO GUESS THE PATHWAYS AND MAKE ACTION BASED ON THESE. SO FOR THE SECOND PART OF THE TALK, I WANT TO EMPHASIZE SOME MORE MULTIPLE COLLABORATIONS TO THE COLLABORATIVE AGENDA OF THE CENTERS, AND SUMMARIZING HERE WITH DATA USED IN THE BEGINNING, THESE ARE THE ANALYZED PERIPHERAL ADAPTIVE IMMUNITY RELATED TO DISEASE FLARE WITH US AND THERE ARE MULTIPLES WHICH I'M GOING TO EMPHASIZE ONE THING, EPIGENETICS, WE DO ACTUALLY PARTICIPATE ACTIVELY IN MANY OF THEM THAT ARE HIGHLY INTERACTIVE BETWEEN THE MULTIPLE CENTERS. EPIGENETIC IS LED BY JEREMY BOSS IN COLLABORATION WITH (INDISCERNIBLE) AT UCSF, IN COLORADO, AND MDH. ONE OF THE GREAT ABUNDANCES IS NOT ONLY COLLABORATION BETWEEN THE CENTERS WHICH IS OBVIOUSLY CRITICAL TO US AND TO THE NETWORK BUT I'D SAY IT'S ALSO A GREAT TOOL TO RECRUIT GREAT SCIENTISTS THAT WERE NOT WORKING IN OUR COMMUNITY, AND I THINK IT'S A VERY GOOD EXAMPLE OF THAT BECAUSE JEREMY BOSS HAS NOT REALLY THOUGHT ABOUT THAT COMMUNITY BEFORE HE GOT INVOLVED WITH OUR COMMUNITY CENTERS AND NOW CATEGORIES HAS THE PROGRAM ON IT, MAJOR CONTRIBUTIONS TO THE FIELD SO I THINK THIS IS ONE OF THE (INDISCERNIBLE) WITHIN THE DIFFERENT SAMPLE. SO THIS IS SUMMARIZING HERE THE EPIGENETIC COLLABORATIONS THAT I JUST MENTIONED WITH DIFFERENT CENTERS, FOR DIABETES, FOR EYE DISEASE, RELATED DISEASE, PLASMABLASTS, AND MENTIONED THIS MORNING WITH COLORADO THROUGH JEFF BANNER FOR THE B CELLS, (INDISCERNIBLE). I SHOULD SAY WE ALSO COLLABORATE IN SIMILAR PROGRAMS WITH SOME OF THE STUDIES, AND WE ARE NOW LOOKING AT THE EPIGENETICS OF B CELL TOLERANCE IN KIDNEY TRANSPLANTATION AS WELL AS IN DIFFERENT DISEASES, IN PARTICULAR LUPUS AS WELL AS PHENOTYPE NEPHROPATHY WHERE CELLS GET ELIMINATED AND TRY TO UNDERSTAND WHETHER THEY CAN BE REPROGRAMMED AFTER B CELL REPOPULATION. FIRST PIECE OF RESULT THAT WE FOUND THIS LAST YEAR WHICH MENTIONED FIRST PART OF THE PRESENTATION I THINK HIGHLY INFORMATIVE. WE ARE LOOKING AT THE EPIGENETICS OF B CELLS IN LUPUS, VERSUS HEALTHY CONTROS, WHAT WE FOUND WAS ACTUALLY THE RESTING NAIVE CELLS ARE THE ONES THAT HAVE THE MAJOR EPIGENETIC DISTANCE IN TERMS OF DIFFERENTIAL REACTIVE REGIONS VERSUS HEALTHY CONTROLS, T CELLS HAVE DIFFERENCES, RESTING NAIVE CELLS ARE THE MOST DIFFERENT FROM THAT POINT OF VIEW, AND WHEN WE LOOK AT WHICH GENES AND TRANSCRIPTION FACTORS ARE AT THE TOP OF THE DIFFERENCES YOU SEE VERY IMPORTANT ONES, BLING 1, IL-4 AND NFKAPPAB AND AP 1 TRANSCRIPTION FACTORS. I DON'T REALLY HAVE THE TIME TO GO INTO THESE BUT AGAIN THESE ARE EXTREMELY IMPORTANT REGULATORS OF B CELLS DIFFERENTIATION ON FACE AND ACTIVATION ON PROLIFERATION AND SO IN FACT EVEN BEFORE THEY GET ACTIVATED BY ANTIGENS LUPUS B CELLS ARE QUITE AS ABNORMAL IN THE RESTING STATE ARE OVERLY POISED TO DIFFERENTIATE AND FOLLOW DIFFERENTIATION FATE INTO THE PATHWAY THAT I SHOWED YOU BEFORE. THE WAY WE LOOK AT THESE IN A COMPREHENSIVE WAY, INTEGRATED ANALYSIS OF METHYLATION, DNA ACCESSIBILITY, ChIP-SEQ TO LOOK AT T CELL MODIFICATION, THAT'S A MUCH HARDER THING TO DO BECAUSE IT REQUIRES A NUMBER OF CELLS THAT OFTENTIMES WE DON'T GET IN HUMANS AND THEN RNA SEQUENCING. SO I'M GOING TO JUST SHOW SOME RESULTS. THESE ARE HUGE AMOUNT OF EFFORT THAT IS BEING PERFORMED THROUGH THE COLLABORATIVE AGENDA, WITH THE COMMUNITY CENTERS, ALREADY OUTDATED BUT AS YOU CAN SEE A HUGE AMOUNT THAT WE'RE ANALYZING NOW FOR THE DIFFERENT TYPES OF ASSAYS. THIS IS SUMMARY OF THE MAJOR MESSAGE HERE, UNDER ANALYSIS NOW, GIVING YOU DIFFERENT ANSWERS THAT ARE COMPLEMENTARY. IT'S VERY IMPORTANT TO DO THEM IN INTEGRATED FASHION TO GET COMPREHENSIVE PICTURE. LOOK AT METHYLATION, THERE'S A LINEAL PROGRESSION PATTERN OF LOSS OF METHYLATION ALTERING THE CELLS THAT WE BELIEVE IN FACT THEY ARE ACTIVATED NAIVE CELLS AS WELL, I REALLY DON'T HAVE THE TIME TO GET INTO THIS ARGUMENT. ACTIVATED NAIVE CELLS, INTRODUCED AND THEN SWITCH MEMORY. SO THEY ESSENTIALLY FOLLOW THAT DIAGONAL, SEEMS TO REFLECT THAT THEY LOSE METHYLATION AS THEY DIFFERENTIATE. LOOK AT RNA SEQUENCING YOU SEE MORE COMPLICATED PATTERNS, AND THE COMPONENTS SEPARATE, ALSO AS I SHOWED YOU BEFORE ACTUALLY THE DCA OF LUPUS VERSUS NORMAL FOR RNA SEQUENCING, AND ALSO SHOWING HERE THEY DO NOT SUPERIMPOSE SO YOU CANNOT SEE IT HERE BUT THAT'S THE WAY IT GOES. (INDISCERNIBLE) BY RNA SEQUENCING. YOU CONCENTRATE HERE ON THE APAC STATE, THE IMPORTANT MESSAGE IS WHEN WE LOOK AT THE ELEMENT YOU GET A DIFFERENT PICTURE WHEN YOU ONLY LOOK AT PROMOTERS, PHYLOGENETIC MAP THAT SHOWS DISTANCE BETWEEN DIFFERENT POPULATIONS AND TELLS YOU HOW CLOSELY RELATED THEY ARE OR NOT IN TERMS OF OPENNESS OF THE DISTAL PART AND YOU CAN SEE HERE THERE'S A MAJOR CHANGE BETWEEN HEALTHY CONTROLS WHERE WE GET CELLS INCLUDING PLASMABLASTS, SEVEN DAYS, NOW YOU CAN SEE HERE HOW THE ACTIVATED NAIVE CELLS MOVE MUCH CLOSER TO THE PLASMABLAST IN KEEPING WITH MANY OF THE DATA THAT WAS SHOWN BEFORE. THIS IS A SUMMARY FOR METHYLATION. I WILL NOT GO IN DETAILS OVER THESE IN THE INTEREST OF TIME. JUST TO SAY THAT THE FINDING THAT WE'RE TRYING TO UNDERSTAND ALTHOUGH ALL THE POPULATIONS LOSE PROGRESSIVELY METHYLATION AS THEY DIFFERENTIATE IN BOTH STATES, LUPUS PATIENTS ACTUALLY HAVE MORE METHYLATED LOCI THAN HEALTHY CONTROLS, AND SO THAT'S SOMETHING THAT WE'RE TRYING TO UNDERSTAND, YOU CAN SEE THAT AS WELL. RNA SEQUENCING DATA THAT I WAS ALLUDING TO. YOU CAN SEE THE ORIGINAL COMPONENTS SEPARATE LUPUS FROM NORMALS, ALL CELL TYPES, AND THEN COMPONENTS TO ACTUALLY SEPARATE THE CELL TYPES WITHIN EACH DISEASE OR HEALTHY CONTROLS. THIS IS NOW PERFORMED WITH A LARGER NUMBER OF SAMPLES, SEPARATING ACTIVE NAIVE CELLS AS WELL, YOU CAN SEE ONCE AGAIN FOR ALL THE LUPUS CELLS THOUGH WE RUN INTO THE SAME TYPE OF TRANSCRIPTION FACTORS THAT ARE HIGHLY ACCESSIBLE IN LUPUS OVER NORMAL. YOU CAN SEE THIS IS HIGHLY OVERLAPPING WITH WHAT I SHOWED YOU BEFORE, WITH RESTING NAIVE CELLS, ONE EXAMPLE FOR AP 1 AND A MAJOR GROUP OF TRANSCRIPTION FACTORS, WHICH IS VERY IMPORTANT FOR THE CONTROL OF PROGRAMS AS WELL AS B CELL ACTIVATION, PROLIFERATION AND ACTUALLY (INDISCERNIBLE) AND THEN INTERFERON REGULATORY FACTORS, AP 1 FAMILY AND NFKAPPAB FAMILY. (INDISCERNIBLE) THAT I WAS TELLING YOU BEFORE. AND THIS IS TO SHOW HOW THE INTEGRATION OF RNA SEQUENCING AND THE APAC 6 IS HIGHLY INFORMATIVE, OTHERWISE YOU DON'T KNOW WHICH ACTUAL TRANSCRIPTION FACTOR GOT OVEREXPRESSED, JUST TO SHOW SOME OF IT, IN THIS PARTICULAR CASE ARE AP 1 FAMILY, FRY 1 IS HIGHEST ONE, MOSTLY UPREGULATED IN RECOGNIZED CELLS AND IN LUPUS, APS 3 IS UPREGULATED IN ALL THE LUPUS B CELLS ACCESSIBLE OVER THE CONTROLS. IT'S TRUE FOR (INDISCERNIBLE). YOU CAN SEE WHEN YOU COMBINE THE TRANSCRIPTION LEVEL TO IDENTIFY WHICH ONES ARE ACTUALLY UP, VERSUS IL-2 FOR INSTANCE IS DOWN, IT'S INTERESTING BECAUSE IL-2 INHIBITS THE IL-1 UPREGULATION OR POSITIVE REGULATION OF THE INTERFERON ALPHA AND BETA PATHWAY, SO THIS REALLY TELLS YOU EVERYTHING IS GOING IN THE RIGHT DIRECTION TO UPREGULATE THOSE RESPONSIVE PATHWAYS. SO LET ME JUST FINISH HERE BEFORE I RUN OUT OF TIME, AND NOW I LOST -- MY APOLOGIES. I WANT TO MAKE A POINT AND SHOW YOU A COUPLE OF SLIDES. A COUPLE OF SLIDES ABOUT THE COLLABORATION WITH T-REGS AND UCSF. I THINK THE STUDIES ARE THE WAY WE'RE DOING THEM, I THINK THAT PROVIDES A LOT OF INTERESTING INFORMATION BUT THE IMPORTANCE OF REALLY SEPARATING CELL SUBSETS CAREFULLY. I THINK YOU COULD GET THIS INFORMATION JUST BY GETTING WHOLE B CELLS OR EVEN CONVENTIONAL SUBSET SO I THINK THAT STARTING WITH AN UNDERSTANDING OF CELL DYNAMICS AND PHENOTYPES IT'S VERY IMPORTANT. AS I WAS SAYING, INTEGRATING THE TRANSCRIPTIONAL AND EPIGENETIC ANALYSIS IS HIGHLY IMPORTANT AS WELL. BY DOING THAT, I THINK THAT WE'VE BEEN ABLE TO ORDER ACTUALLY THE DIFFERENT SUBSETS THAT WE IDENTIFY BY FLOW CYTOMETRY INTO PATHWAYS AND ALSO DEFINE I BELIEVE THE PROBLEM (INDISCERNIBLE) FOR B CELLS TO ACTUALLY FOLLOW THE DIFFERENTIATION PATHWAYS, TRANSCRIPTION FACTORS AND SIMULATIONS THAT I WAS SHOWING YOU. SO THAT WAS MY REMINDER THAT AT LEAST BY MY CALCULATION I HAVE FIVE MINUTES, I HOPE. I'M NOT RUNNING LATE. A COUPLE SLIDES, THIS IS A COLLABORATION WITH JEFF, AND UCSF, WHERE THEY HAVE TWO CLINICAL TRIALS, ALSO A GOOD EXAMPLE OF MECHANISTIC APPLICATION OF OUR STUDIES AND COLLABORATION BETWEEN THE ACES TO APPLY TO CLINICAL TRIALS. UCSF HAS TWO CLINICAL TRIALS, USING IN VITRO, EX VIVO EXPANDED (INDISCERNIBLE) TO PATIENTS, ONE FOR (INDISCERNIBLE), THE OTHER FOR SLE. ONE OF THE STUDIES THAT WE ARE DOING WITH THEM IS TO TAKE EXPANDED EX VIVO FROM TYPE 1 DIABETES PATIENTS OR HEALTHY SUBJECTS, AND STUDY THEM TO SEE HOW THEY MAY DIFFER FROM HEALTHY CONTROLS, OR FROM BASELINE THROUGH ISOLATION AND BEFORE EXPANSION. SO THIS IS VERY PRELIMINARY BUT JUST TO SHOW YOU BY THESE TWO ASSAYS THAT THEY ARE VERY SIMILAR, HEALTHY CONTROLS EX VIVO OF A EXPANSION I BELIEVE FOR TWO TO FOUR WEEKS BEFORE INFUSION. THEY ARE VERY SIMILAR I'M HIGHLIGHTING DIFFERENCES WE'RE ANALYZING, SOME DIFFERENCES, ONE OF THE INTERESTING POINTS IS THERE'S NO INTROSPECTION SO THERE IS A NUMBER OF GENETICALLY POISED TO OPEN LOCI THAT ARE NOT OVERTRANSCRIBED AT THIS POINT BUT WE WONDER WHAT MAY HAPPEN ONCE THEY ARE IN VIVO. WE INFUSE. THIS WILL BE SOMETHING QUITE INTERESTING, IS IT JUST AN EXAMPLE OF IT FOR BRE 7 WHICH CONTROLS A NUMBER OF RESPONSES TO CYTOKINES AS YOU CAN SEE THAT THEY ARE DIFFERENT AREAS ACTUALLY THAT ARE MORE ACCESSIBLE IN SOME CASES FROM HEALTHY CONTROLS IN SOME CASES ACTUALLY FOR THE TYPE 1 DIABETES. THE DISCREPANCIES ARE SOMETHING WE NEED TO UNDERSTAND BETTER BUT THEY BECOME OBVIOUSLY -- AND THE LAST SLIDE IS JUST TO SHOW YOU THAT IN FACT THE EX VIVO EXPANSION IMPACT (INDISCERNIBLE) YOU HAVE THE SUMMARY HERE, YOU CAN SEE THIS ABOUT 300 -- I'M SORRY, 3,000+ LOCI THAT ARE OPEN IN THE TYPE 1 DIABETES OF HEALTHY CONTROLS OF A -- AFTER EXPANSION RELATIVE TO BASELINE, YOU CAN FIND EXAMPLES OF SOME GENES GOING DIFFERENT DIRECTIONS, FOXP3, FOLLOW THE CELLS IN GREEN THAT REMAIN, ONE OPEN, T-REGS, EX VIVO, HEALTHY CONTROLS OF TYPE 1 DIABETES BUT NOT IN THE OTHER T CELLS. YOU CAN'T GET TWO WHICH REGULATE RESPONSE TO MULTIPLE FACTORS IN IL-2 AND YOU CAN SEE ACTUALLY IT REMAINS ALSO OPEN IN THE EX VIVO T-REGS AND HERE RELATIVE TO ALL THE OPEN SUBSETS SO YOU WANT RESPONSE TO IL-2 AND THEN THE IL-7 RECEPTOR IS HARDER TO UNDERSTAND, AS YOU CAN SEE THAT ACTUALLY IS MUCH MORE OPEN IN MANY OF THE OTHER B CELLS. AND THE (INDISCERNIBLE) THAT ARE IN THE EX VIVO AFTER EXPANSION T-REG, AND DOWNREGULATION IS ONE OF THE MARKERS FOR THE MORE EFFECTIVE T-REGS FOR EXPANSION SO THIS IS PROBABLY MEANINGFUL BUT WE WILL HAVE TO CONTINUE THESE STUDY. BUT WE THINK ALL TOGETHER THEY GIVE US THE ABILITY TO COLLABORATE AND PROVIDE INFORMATION AS TO WHETHER WE CAN PREDICT ANY PLASTICITY OR SUSTAINMENT OF T-REG EXPANSION FROM THE DIFFERENT DISEASES AND BEFORE THE INFUSION. SO THESE ARE THE COLLABORATORS, MULTIPLE PEOPLE AT EMORY IN MY LAB THAT HAVE DONE A LOT OF THE WORK THAT I JUST PRESENTED. JEREMY AND HIS GROUP AS WELL DOING THE EPIGENETICS, AND MULTIPLE COLLABORATORS FROM THE FIRST PART OF THE WORK. AND THEN OF COURSE SUITABLE FROM THE H2-19. THANK YOU VERY MUCH. I'LL TAKE ANY QUESTIONS THAT YOU MIGHT HAVE. >> THIS IS (INDISCERNIBLE). I HAVE A QUESTION. IN YOUR EARLIER SLIDES WHEN YOU WERE SHOWING THE INCREASE IN THE POPULATION, SLE PATIENTS, IT WAS CLEAR THERE WAS A DECREASE IN UNSWITCHED MEMORY CELL POPULATION IN THE SLE PATIENTS COMPARED TO HEALTHY CONTROLS. I WAS WONDERING IF THAT'S ANYTHING F INTEREST OR IS IT JUST BECAUSE PEOPLE ARE CHRONICALLY ACTIVATED SO IT'S MOVING OVER TO THE SWITCHED MEMORY VERY QUICKLY OR DOES THAT -- >> SO YOU'RE POINTING TO ONE VERY INTERESTING FINDING, NOT ONLY IN LUPUS BUT IN ALMOST ALL THE COMMUNITY DISEASES THAT WE'VE LOOKED AT, WITH THE EXCEPTION OF RHEUMATOID AT LEAST IN THE BLOOD, THAT UNSWITCHED MEMORY GOES DOWN, COVERING VERY WELL WITH ANY MANIPULATION OR T CELL DEPLETION ALTHOUGH THERE ARE REPORTS WHERE IT GOES DOWN AND (INDISCERNIBLE) SO WE DON'T UNDERSTAND THAT VERY WELL, BUT IT CERTAINLY IS A VERY COMMON FINDING IN OUR COMMUNITY. WE ALSO SHOW IT IN PRE-SJOGREN'S, INCOMPLETE SJOGREN'S AND WE PUBLISHED THAT, BUT IT GOES DOWN EVERY ARM, SO WE COULD DISCUSS WHY THAT MIGHT BE BUT THAT'S THE OBSERVATION. WE HAVE TO MAKE CLEAR THE EXPANSION IS NOT AT THE EXPENSE OF THE UNSWITCHED MEMORY, RELATIVELY SMALL TO START WITH BUT AS I MENTIONED (INDISCERNIBLE) ALSO INCREASE MASSIVE NUMBERS. YES, THEY GO TOGETHER, UNSWITCHED MEMORY IS EARLY SITUATION, UNSTABLE ONE I BELIEVE IN LUPUS. >> THANK YOU. >> THANK YOU. I DON'T THINK WE HAVE ANY OTHER QUESTIONS RIGHT NOW. >> IT DOESN'T SEEM LIKE IT. THIS IS DAN. THANK YOU BOTH, JUDITH AND IGNACI, FOR WHO STELLAR PRESENTATIONS. WE HAVE FOUR CONCEPT CLEARANCES THAT I MENTIONED EARLIER, AND THE FIRST IS FOR THE COOPERATIVE CENTERS ON HUMAN IMMUNOLOGY, AND LACKSHMI IS COMING UP. IN THE INTEREST OF TIME WHEN QUESTIONS ARE THROUGH I'LL ASK THE OTHER STAFF TO COME UP AND INTRODUCE THEMSELVES SO WE CAN MOVE ALONG WITH THIS. >> WE JUST CAN'T FIND THE BUTTON TO MAKE THIS A SLIDE SHOW. >> IGNACI, COULD YOU STOP SHARING THE CONTROLLING OF THE SCREEN? I THINK YOU'RE CONTROLLING OUR SCREEN. VERY GOOD. WELL DONE. [LAUGHTER] >> THAT'S REAL POWER. [LAUGHTER] >> WHAT DO YOU WANT TO GIVE US BACK CONTROL? >> OKAY. I'M TRYING. >> I THINK I COULD START AND STILL MOVE MY SLIDES. SO MY NAME IS LACKSHMI, PROGRAM OFFICER IN THE BASIC IMMUNOLOGY BRANCH. I'LL BE TALKING ABOUT RENEWAL OF THE COOPERATIVE CENTERS IN HUMAN IMMUNOLOGY, CCHI, WE'VE GOT ACRONYMS FOR EVERYTHING. OKAY. CCHI WAS ESTABLISHED IN 2004 AND HAS SUBSEQUENTLY BEEN RENEWED TWICE, ONCE IN 2009, AND THEN IN 2014. NOW, THE BASIC THREE MAIN OBJECTIVES, TO SUPPORT RESEARCH, LOOKING AT THE MOLECULAR MECHANISMS OF HOW THE HUMAN IMMUNE SYSTEM IS ACTIVATED AND REGULATED, AND THE FOCUS HERE HAS BEEN ON INFECTION AND/OR VACCINATION. IT DOESN'T MATTER. I DON'T THINK IT IMPACTS THE PRESENTATION. AND CCHI HAS ALSO SUPPORTED CENTRALIZED INFRASTRUCTURE TO COORDINATE THE MULTI-DISCIPLINARY RESEARCH WHICH IS REQUIRED FOR HUMAN IMMUNOLOGY, AND ANOTHER THING WE'RE PROUD OF IS IT'S ALSO SUPPORTED THE DEVELOPMENT OF NEW AND INNOVATIVE TECHNOLOGIES TO FACILITATE IMMUNOLOGY RESEARCH IN HUMANS. WE CURRENTLY HAVE SIX AWARDS, THESE ARE U 19s, AND THEY DO SORT OF SPAN THE SPECTRUM OF THE IMMUNE STUDIES. THEY INCLUDE SYSTEMIC AND MUCOSAL INNATE AND ADAPTIVE IMMUNITY, STUDIES LOOKING AT IMMUNE RESPONSES TO CHILDREN AND ADULTS. THE SIX PROGRAMS ALSO SPAN A LOT OF PATHOGENS AND VACCINES, WE'VE GOT STUDIES LOOKING AT RESPONSES TO FLAVIVIRUSES, HEPATITIS C, INFLUENZA VIRUS AND VACCINES, AND BACILLUS AND SALMONELLA. OKAY. SO CCHI HAS BEEN VERY PRODUCTIVE AND SINCE 2014 TO PRESENT SO WE'RE TALKING 3 1/2 YEARS, IT HAS SUPPORTED STUDIES THAT HAVE BEEN INCLUDED IN 262 RESEARCH ARTICLES, MAYBE A FEW MORE SINCE I LAST LOOKED. AND MANY OF THESE HAVE BEEN IN VERY HIGH IMPACT JOURNAL, AND I'VE JUST SORT OF SELECTED A FEW TO HIGHLIGHT, THE SECOND ONE PUBLISHED IN "CELL" LOOKED AT COMPARED IMMUNE RESPONSES TO VACCINATION AND INFECTION, IN IDENTICAL VERSUS FRATERNAL TWINS AND SAID ENVIRONMENTAL FACTORS EXPLAINED MUCH OF THE VARIATION ONE SEES IN THE IMMUNE RESPONSE. AND PAPERS THAT JUST CAME OUT IN 2015 IN "CELL," ONE THIS YEAR IN "SCIENCE" EXAMINED FC MODIFICATION AND IgGs, ABLE TO SHOW YOU CAN IMPACT VACCINE RESPONSES TO INFLUENZA AND ALSO DETERMINE SEVERITY OF DENGUE INFECTION. SO IN TERMS OF TECHNOLOGY DEVELOPMENT, I KNOW DR. JAMES JUST LEFT BUT WHEN SHE SHOWED A SLIDE SHE TALKED ABOUT USING CYTOF MANY AND ATAC-SEQ TO DO MECHANISTIC STUDIES, I FEEL LIKE A PROUD MAMA WHO CAN SAY CCHI HAS HELPED TO SUPPORT DEVELOPMENT OF THE TECHNOLOGY. AND WE ALSO -- CCHI SUPPORTS IMMUNE MONITORING COURSE OFFERED IN STANFORD, OPEN TO CCHI AND OTHER INVESTIGATORS, IT FOCUSES ON ALL THE NEW TECHNOLOGIES THAT IS AVAILABLE FOR HUMAN STUDIES. THE OTHER THING THAT CCHI HAS DONE IS SUPPORT SOME COMPUTER TOOLS, FOR EXAMPLE JUST THIS YEAR THERE'S A PAPER IN "NATURE" WHICH SHOWED -- IN WHICH AN ALGORITHM WAS DEVELOPED, SHOWN IT CAN AUTOMATICALLY GROUP TCR SEQUENCES ACCORDING TO THOSE LIKELY TO HAVE THE SAME SPECIFICITY. SO THIS IS MY LAST SLIDE. SO WHAT DO WE HAVE IN MIND? WHY DO WE NEED TO CONTINUE AND WHAT DO WE HAVE IN MIND FOR THE RENEWAL? SO WHAT WE HAVE MADE INROADS INTO UNDERSTANDING THE MECHANISMS THAT REGULATE HUMAN RESPONSES, THERE ARE A LOT OF KNOWLEDGE GAPS AND WE THINK THAT IT'S IMPORTANT TO CONTINUE TO FUND PROGRAMS SUCH AS CCHI TO LOOK AT MECHANISMS REGULATING HUMAN IMMUNE RESPONSES. SO THE IDEA IS TO CONTINUE TO FOCUS ON DEFINING MOLECULAR MECHANISMS OF HUMAN IMMUNE REGULATION, TO CONTINUE TO SUPPORT CENTRALIZED INFRASTRUCTURE, AND BASED ON THE SUCCESSES WE'VE HAD IN DEVELOPMENT OF NEW AND INNOVATIVE TECHNOLOGIES, WE WOULD LIKE TO CONTINUE TO DEVELOP -- ALLOW CCHI TO SUPPORT DEVELOPMENT OF NEW TECHNOLOGIES TO SUPPORT HUMAN RESEARCH. THE MECHANISM WILL REMAIN A CORPORATE OF AGREEMENT U19, BUT SO IN TERMS OF SCOPE WE WERE THINKING OF BROADENING SCOPE TO INCLUDE IMMUNE MEDIATED DISEASES, ENCOURAGE STUDIES WHICH ARE GOING TO BE ANALYZING TISSUE AND ORGAN-SPECIFIC RESPONSES. WE'D LIKE TO ENCOURAGE STUDIES LOOKING AT IMPACT OF COMORBIDITIES ON THE IMMUNE RESPONSE, TRAINED IMMUNITY, EFFECT IDENTIFY MICROBIOME, THERE'S BEEN A LOT OF INROADS BEING MADE IN EPIGENETIC AND METABOLIC REGULATION, I'D LIKE TO ENCOURAGE STUDIES ANALYZING THIS AS IMMUNE EXHAUSTION AND LOOKING AT IMMUNE REGULATORY PATHWAYS. SO THE PROPOSALS NEED TO REALLY FOCUS ON USING PRIMARY HUMAN CELLS, TISSUES, FLUIDS, ET CETERA. ANIMAL STUDIES WILL BE PERMITTED. THEY HAVE TO BE STRONGLY JUSTIFIED. AND THEY NEED TO REALLY GUIDE MECHANISTIC ANALYSIS OF THE HUMAN SAMPLES. SO WITH THAT WE -- I'M READY TO TAKE QUESTIONS THAT ANY OF YOU MIGHT HAVE. OKAY, WELL, THANK YOU VERY MUCH. >> JUST KEEP GOING THE SAME WAY? OKAY. WITH THIS. HOW DO WE ADVANCE THE SLIDE? OKAY. EXCUSE ME. MY NAME IS CONRAD, ALSO FROM THE BASIC IMMUNOLOGY BRANCH. I'M GOING TO TALK ABOUT A NEW INITIATIVE WE ARE PROPOSING, THE TITLE IS MAINTAINING IMMUNITY AFTER IMMUNIZATION. I'M GOING THE SAME WAY AS THE PREVIOUS ONES. I DIDN'T SEE A PRESENTAION MODE. OKAY. THERE WE GO. THAT'S BETTER. OKAY. THIS INITIATIVE, THE BACKGROUND IS THAT WE KNOW THAT THERE ARE VACCINES THAT ARE PROTECTIVE FOR VERY LONG PERIODS OF TIME SUCH AS SMALLPOX VACCINE. AND WHILE THERE ARE OTHERS, SUCH AS PERTUSSIS AND NEWEST SALMONELLA VACCINE THAT ARE ONLY PROTECTIVE FOR A FEW YEARS. SO THE IDEA IS THAT A BETTER UNDERSTANDING OF HOW THESE -- THE MECHANISMS THAT CAUSE THIS SUSTAINED IMMUNITY OR DURABLE IMMUNITY THAT OCCURS WITH VACCINES THAT ARE EFFECTIVE FOR LONGER PERIODS OF TIME COULD HELP IN THE DESIGN OF FUTURE VACCINES THAT TARGET THESE SPECIFIC IMMUNE COMPONENTS. SO THE PURPOSE OF THIS INITIATIVE IS -- WOULD BE ULTIMATELY TO DETERMNE WHAT COMPONENTS AND MECHANISMS OF A PERSISTENT DURABLE IMMUNE RESPONSE ARE TO VACCINATION. SO JUST SOME IDEAS ABOUT WHAT COULD BE DONE UNDER THIS INITIATIVE, YOU COULD COMPARE THE IMMUNE RESPONSES BY VACCINE THAT PRODUCE SUSTAINED IMMUNE RESPONSES VERSUS THOSE THAT DON'T AND THEN IDENTIFY THE COMPONENTS OF THE INNATE AND ADAPTIVE IMMUNE RESPONSES THAT ARE REQUIRED TO PROVIDE THE DURABLE PROTECTIVE IMMUNE RESPONSE. YOU CAN COMPARE EVEN THE IMMUNE MECHANISMS THAT ARE TRIGGERED BY NATURAL INFECTION, WHICH OFTEN PRODUCE LIFELONG IMMUNITY AND COMPARE TO VACCINATIONS THAT DON'T PROVIDE LIFELONG IMMUNITY. AND IDENTIFY WHAT IMMUNE COMPONENTS ARE THERE. IN ADDITION TO UNDERSTANDING INNATE AND ADAPTIVE IMMUNE COMPONENTS, WHAT RELATIONSHIP BETWEEN THOSE COMPONENTS IS ESSENTIAL TO PROVIDE DURABLE IMMUNITY, AND ALSO NEW AREAS BEING EXPLORED THAT AFFECT HOW THE IMMUNE SYSTEM RESPONSES ARE EPIGENETIC CHANGES THAT OCCUR TO THE IMMUNE SYSTEM OR METABOLIC CHANGES THAT OCCUR TO THE IMMUNE SYSTEM. IN FACT THERE'S RECENT RESEARCH THAT SHOWS METABOLIC STATE OF T CELLS MAY AFFECT EPIGENETIC MODIFICATIONS WHICH FURTHER AFFECT T CELL MEMORY SO THAT CORRECTION, ALL THAT THERE IS AN EXAMPLE OF ANOTHER FIELD THAT'S POSSIBLE FOR EXPLORATION AND LOOKING AT HOW DURABLE IMMUNITY IS ACHIEVED. THIS MECHANISM, PROPOSED MECHANISM IS A COOPERATIVE AGREEMENT, U01, IT IS A DATE-LED PROGRAM BY DMID IS A CO-SPONSOR, THERE'S ABOUT 7 TO 10 AWARDS IS WHAT WE ANTICIPATE MAKING. ARE THERE ANY QUESTIONS ABOUT THIS? OKAY. >> GOOD AFTERNOON, I'M ALSO FROM THE BASIC IMMUNOLOGY BRANCH AND I WILL INTRODUCE THE CONCEPT FOR THE RENEWAL OF THE VACCINE DISCOVERY PROGRAM. BEFORE I TALK ABOUT THE SPECIFICS OF THE PROGRAM, I WANT TO SHOW YOU HOW IT FITS INTO THE OVERALL PORTFOLIO OF DATE. ALL THREE SCIENTIFIC DIVISIONS HAVE AN INTEREST IN VACCINE ADJUVANTS, FOCUSING MORE ON APPLICATION AND CONNECTION WITH A SPECIFIC VACCINE WHEREAS DATE COVERS THE EARLY STAGES OF VACCINE ADJUVANT RESEARCH. SHOWN HERE ARE THE DIFFERENT STAGES OF VACCINE ADJUVANT RESEARCH FROM DISCOVERY THROUGH LICENSURE. THE VACCINE ADJUVANT DISCOVERY PROGRAM WAS INITIATED IN FISCAL YEAR 2003, CURRENTLY IN ITS THIRD ITERATION AND COVERS THE VERY EARLY STAGES WHICH INCLUDE DISCOVERY ALL THE WAY UP TO VERY EARLY DEVELOPMENT. ACTUAL VACCINE DEVELOPMENT OF PREVIOUSLY IDENTIFIED AND VALIDATED COMPOUNDS ALL THE WAY THROUGH IND ENABLING STUDIES IS SUPPORTED BY ADJUVANT DEVELOPMENT PROGRAM, THROUGH THE SBIR FUNDING MECHANISM TO REACH DIFFERENT SET OF INVESTIGATORS WITHIN SMALL BUSINESSES. THERE'S INCREASING INTEREST IN COMBINING VACCINE ADJUVANTS, AND TO SUPPORT MECHANISTIC STUDIES INTO HOW THE COMBINATION OF TWO COMPOUNDS ENHANCING IMMUNE RESPONSES SYNERGISTICALLY. WE STARTED MOLECULAR MECHANISMS OF VACCINE -- COMBINATION ADJUVANTS LAST YEAR, MMCA PROGRAM. IN ADDITION TO THESE SOLICITED MECHANISMS WE USED THE UNSOLICITED GRANT MECHANISM TO SUPPORT VACCINE ADJUVANT RESEARCH. DURING THE PREVIOUS ITERATIONS A LARGE NUMBER OF PROMISING COMPOUNDS WERE DISCOVERED, I DON'T HAVE TIME TO GO THROUGH THEM. I WANT TO SHOW AN OVERVIEW OF CATEGORIES. TRADITIONALLY VACCINE ADJUVANT DISCOVERY FOCUSED ON TOLL-LIKE RECEPTORS AND THE PROGRAM HAS YIELDED A NUMBER OF EXCITING NOVEL TYPES OF TLR AGONISTS, BUT IN ADDITION WE'RE SEEING AN EXPANSION INTO OTHER AREAS, INTO OTHER TYPES OF RECEPTORS, NON-TRADITIONAL TARGETS OF VACCINE ADJUVANTS, FOR EXAMPLE INTERFERON REGULATORY FACTORS SUCH AS IR 1, 3, 5 AND 7, THESE ARE NOT UPSTREAM RECEPTORS BUT TRANSMITTERS OF SIGNALS FROM INNATE IMMUNE RECEPTORS. WE ARE SEEING MORE FOCUS ON NON-TRADITIONAL TARGET CELLS OF ADJUVANTS, SUCH AS NAST CELLS. I'D LIKE TO POINT OUT TYPES OF COMPOUNDS INVESTIGATORS ARE DISCOVERING. TRADITIONALLY ADJUVANT DISCOVERY WAS FOCUSED ON DERIVATIVES OF NATURAL AGONISTS, SO FOR EXAMPLE NPL BEING A DERIVATIVE OF LPS. NOVEL TYPES OF ADJUVANTS FALL INTO TWO CATEGORIES, SYNTHETIC MIMETICS AND DRUG LIKE MOLECULES WHICH HAVE NO SIMILARITY TO STRUCTURAL SIMILARITY TO NATURAL AGONISTS. AND ONE EXAMPLE I WANT TO MENTION IS SYNTHETIC TLR 4ING A AGONIST CHANNELED DOGMA SIGNALING WAS DEPENDING ON LONG THERE WOULD NOT BE SIGNALING, IT WOULD BE AN INHIBITOR. THIS PROGRAM YIELDED THE FIRST SMALL MOLECULE TLR 4 AGONIST. ONE OF THE REQUIREMENTS OF THE PROGRAM IS HIGH THROUGHPUT SCREENING OF COMPOUND LIBRARIES AND IN THE CURRENT PROGRAM INVESTIGATORS HAVE SO FAR SCREENED MORE THAN 1 1/2 MILLION COMPOUNDS BY IN VITRO ASSAYS, IN ADDITION WE'RE SEEING A TREND TOWARDS INITIAL HIGH THROUGHPUT SCREENING BY IN SILICO METHODS. ONE OF THESE PROGRAMS HAS SO FAR SCREENED MORE THAN 10 TO THE 20th CBG SEQUENCES, HAS YIELDED A NOVEL CpG OLIGO DINUCLEOTIDE IN CLINICAL TRIALS. A LOT OF THESE ACTIVITIES ARE NOT SUITABLE FOR ESPECIALLY HIGH PROFILE PUBLICATIONS, A LOT OF THEM ARE ESSENTIAL ACTIVITIES BUT STILL THESE INVESTIGATORS HAVE SO FAR PUBLISHED MORE THAN 40 PAPERS FROM THE CURRENT PROGRAM AND MORE THAN 75 IN THE LAST 5 YEARS. SO WHAT ARE WE TRYING TO ACHIEVE WITH THE RENEWAL OF THIS PROGRAM AND THE ADJUVANT DISCOVERED PROGRAM IN GENERAL. WE WANT TO CONTINUE TO SUPPLY THE PIPELINE OF NOVEL ADJUVANTS. THE ULTIMATE GOAL IS TO BUILD A LARGE -- BUILD AND EXPAND A TOLL BOX OF COMPOUNDS THAT ARE NOT ONLY SAFE AND EFFECTIVE BUT THAT HAVE VERY DEFINED MECHANISMS OF ACTION AND CAN BE COMBINED WITH VACCINES IN A RATIONAL MANNER, DEPENDING ON THEIR MECHANISM OF ACTION. WE ALSO HAVE A STRONG INTEREST IN THESE COMPOUNDS BEING USED FORUM KNOW THERAPY OF ALLERGY AND AUTOIMMUNE DISEASES IN ADDITION TO BEING VACCINE ADJUVANTS FOR INFECTIOUS DISEASE VACCINES. THE INVESTIGATORS IN THIS PROGRAM ARE EXPLORING NOVEL TYPES OF TARGETS. THESE ARE BOTH CELLULAR AND MOLECULAR TARGETS FOR ADJUVANTS, I MENTIONED BEFORE IRFs AS NOVEL TARGET MOLECULAR TARGET AND MAST CELLS AS NON-TRADITIONAL TARGETS OF ADJUVANTS. AS WE'RE GAINING MORE INSIGHT INTO NEW MECHANISMS, MORE OF THESE TARGETS BECOME AVAILABLE AS POTENTIAL TARGETS FOR NOVEL VACCINE ADJUVANTS. THIS PROGRAM TOGETHER WITH THE ADJUVANT DEVELOPMENT PROGRAM ARE NOT REALLY PRODUCT, PURE PRODUCT DEVELOPMENT PROGRAMS. THEY ARE BASIC RESEARCH PROGRAMS. THEY ARE PROVIDING A LOT OF INSIGHTS INTO THE MECHANISM OF ADJUVANTS. BY CONDUCTING MEDICINAL CHEMISTRY MODIFICATION OF COMPOUNDS INVESTIGATORS ARE GAINING INSIGHT INTO THE STRUCTURAL REQUIREMENTS OF THESE INNATE IMMUNE RECEPTORS, NOT JUST AN ACADEMIC EXERCISE BUT THIS PROVIDES COMPOUNDS THAT ARE MORE EFFECTIVE BUT ALSO COMPOUNDS THAT CAN BE USED TO TWEAK THE SIGNALING THAT'S COMING FROM A RECEPTOR TO TUNE THE IMMUNE RESPONSE THAT IS TRIGGERED BY A PARTICULAR VACCINE ADJUVANT TARGET. WHAT ARE WE PROPOSING TO CHANGE IN THE RENEWAL OF THE INITIATIVE? OVERALL THE STRUCTURE OF THE PROGRAM HAS WORKED VERY WELL SO WE ONLY PROPOSE A FEW MINOR TWEAKS TO THE PROGRAM. FIRST OF ALL, IN ORDER TO BE ABLE TO BETTER GAUGE THE EFFECTIVENESS OF NOVEL COMPOUNDS INVESTIGATORS WOULD BE REQUIRED TO INCLUDE COMMERCIALLY AVAILABLE ADJUVANTS IN KEY EXPERIMENTS, AS A BENCHMARK, AS A REFERENCE. AS CONRAD MENTIONED, A BIG CONCERN NOW IS WEIGHING IMMUNITY, TO ADDRESS THIS THROUGH ADJUVANTS, THE INVESTIGATORS WOULD BE REQUIRED TO INCLUDE STUDIES TO DETERMINE THE ABILITY OF NOVEL COMPOUND THAT ARE BEING IDENTIFIED TO PROMOTE DURABLE IMMUNE RESPONSES, AND FINALLY WE WOULD NOT REQUIRE BUT STRONGLY ENCOURAGE THE DISCOVERY OF COMPOUNDS THAT CAN BE USED AS VACCINE ADJUVANTS FOR VACCINES IN NEWBORNS, FOR ELDERLY, BUT ALSO FOR MUCOSAL ADJUVANTS. NOW, WHY DO WE NEED A SOLICITED PROGRAM FOR THIS TYPE OF THE PROGRAM HAS A LOT OF DIFFERENT -- INCLUDES A LOT OF DIFFERENT TYPES OF ACTIVITIES, THAT RANGE FROM HIGH THROUGHPUT SCREENING OF COMPOUND LIBRARIES THROUGH MEDICINAL CHEMISTRY, TO PRE-CLINICAL TESTING OF THESE NOVEL COMPOUNDS. SO THIS REQUIRES LARGE GROUPS AND MULTI-DISCIPLINARY COLLABORATIONS WHICH ARE NOT EASY TO SUPPORT THROUGH UNSOLICITED GRANT MECHANISMS. ALSO THESE THIS WAS I JUST DESCRIBED ARE NOT NECESSARILY VERY POPULAR WHEN PRESENTED TO STANDING STUDY SECTIONS, REVIEWERS IN STANDING STUDY SECTIONS DO NOT LIKE THESE TYPES OF HIGH RISK ACTIVITIES, WHICH SCREENING IS. THEY DO NOT LIKE SCREENING BY ITSELF. AND THIS PROGRAM INVOLVES SCREENING FOR NOVEL COMPOUNDS, NOVEL FORMULATIONS, MODIFICATIONS, SCREENING THROUGH MODIFICATIONS OF COMPOUNDS, AND THROUGH MEDICINAL CHEMISTRY. THE FUNDING MECHANISM WE'RE PROPOSING TO USE, WE'VE USED BEFORE, IS THE CONTRACT MECHANISM, THIS WOULD BE A DATE-LED PROGRAM. HOWEVER, IF THERE ARE COMPOUNDS THAT MIGHT BE OF INTEREST FOR HIV VACCINES, AIDS, MAY PROVIDE SUPPLEMENTAL FUNDING. AND WE'RE PROPOSING TO AWARD BETWEEN 4 AND 6 OF THESE CONTRACTS. AND I'D BE HAPPY TO TAKE ANY QUESTIONS. >> HI, EVERYONE. WOLFGANG, HOW DID YOU VIEW FULL SCREEN? THERE WE GO. OKAY. GOOD AFTERNOON, EVERYONE. I'M ALLISON AUGUSTINE, CHIEF OF THE BASIC IMMUNOLOGY BRANCH IN DATE, PRESENTING THE JOINT INITIATIVE THAT'S CO-SPONSORED BY DATE AND THEN SISTER DIVISIONS IN DMID AND DAIDS. THIS IS THE IMMUNE MECHANISM OF PROTECTION AGAINST TUBERCULOSIS CONSORTIUM, A MOUTHFUL SO WE'RE CALLING IT IMPACT TB. AND AS DR. FAUCI MENTIONED TODAY, THE GLOBAL BURDEN OF TUBERCULOSIS IS HIGH, TB IS ONE OF THE TOP TEN CAUSES OF DEATH WORLDWIDE, A 10.4 MILLION PEOPLE BECAME ILL, 1.8 MILLION PEOPLE DIED, AND 35% OF HIV DEATHS ARE DUE TO TB, SO TB IS A HUGE BURDEN FOR HIV-INFECTED INDIVIDUALS. BCG IS THE ONLY LICENSED TB VACCINE, PROVIDES PROTECTION AGAINST TB, MENINGITIS AND DISSEMINATED TB IN CHILDREN, LIMITED PROTECTION AGAINST PULMONARY DISEASE IN CHILDREN AND ADULTS. A MAJOR ROAD BLOCK TO INCREASING TB VACCINE EFFICACY IS ACTUALLY OUR LIMITED UNDERSTANDING OF IMMUNE MECHANISMS REQUIRED TO INDUCE AND MAINTAIN PROTECTIVE IMMUNITY. IN RESPONSE TO THIS BOTTLENECK AND LACK OF INFORMATION, WE HAVE A JOINT TRANSDIVISIONAL TUBERCULOSIS VACCINE TEAM, WHICH IS COMPOSED OF PROGRAM STAFF IN DAIDS, DATE AND DMID, TO BETTER UNDERSTAND IMMUNE MECHANISMS THAT ARE REQUIRED TO INDUCE TB IMMUNITY AND HELPING TO PROVIDE FOUNDATIONAL INFORMATION TO IMPROVE TB VACCINE EFFICACY. A GOAL OF THE PROGRAM WILL BE TO DIVINE IMMUNE MECHANISMS REQUIRED FOR PROTECTION AGAINST M. TB INFECTION OR EFFECTIVE TB VACCINEs, INCLUDING UNDERSTANDING THE NATURE, LOCATION AND TIMING OF IMMUNE RESPONSE, THROUGH ALL OF THE DIFFERENT STAGES OF TB INFECTION SO THAT'S PRIMARY, LATENCY AND ACTIVE DISEASE, AS WELL AS IN RESPONSE TO INVESTIGATIONAL OR EXISTING TB VACCINES. WE WANT TO UNDERSTAND THE IMPACT OF HIV INFECTION ON THE IMMUNITY TO TB AND HOW THAT ALSO IMPACTS THE RESPONSE TO VACCINATION AGAINST TB. SO THIS PROGRAM WOULD SUPPORT ITERATIVE STUDIES BETWEEN ANIMALS AND HUMANS TO INCREASE PREDICTED VALUE OF ANIMAL MODELS, AND USING CONTRACT MECHANISM, BROAD AGENCY ANNOUNCEMENT MECHANISM, INVESTIGATOR HAS MORE LATITUDE IN PROVIDING THEIR OWN STATEMENT OF WORK AND SAYING HOW THEY WOULD MEET OBJECTIVES OF THE PROGRAM. WE HOPE TO MAKE ONE TO TWO AWARDS, AND THE AWARD WOULD RESIDE IN DATE BECAUSE OF FOCUS ON IMMUNOLOGY, CO-MANAGED BY PROGRAM STAFF FROM EACH OF THE DIVISIONS THAT ARE INVOLVED BECAUSE WE NEED ALL OF THAT EXPERTISE WHICH HAS THIS PROGRAM DO WELL AND SUCCEED. SO JUST GOING INTO MORE DETAIL ABOUT THE RESEARCH AREAS, WE WANT TO FOCUS ON COMPARISON OF TISSUE-SPECIFIC AND SYSTEMIC IMMUNE RESPONSES, TO M. TB AND TB VACCINES, SO WE WANT INVESTIGATORS TO CHARACTERIZES INNATE AND ADAPTIVE EFFECTOR MECHANISMS TO IDENTIFY THE PROTECTIVE IMMUNE RESPONSES IN TISSUES, AND THEN TAKE THAT INFORMATION TO BE ABLE TO IDENTIFY IMMUNE CORRELATES IN BODY FLUIDS THAT SERVE AS INDICATORS OF THE TISSUE-SPECIFIC PROTECTIVE IMMUNITY. WE ALSO WANT INVESTIGATORS TO BE ABLE TO IDENTIFY FACTORS AND MECHANISMS THAT PREVENT IMMUNE SYSTEM FROM RESISTING OR CLEARING INFECTION, AND UNDERSTAND WHY TB VACCINES BOTH BCG AND INVESTIGATIONAL VACCINES ARE NOT ELICITING DURABLE PROTECTIVE IMMUNITY. A SENSE OF STRUCTURE, A LEADERSHIP GROUP IS MADE OF THE INVESTIGATORS WHO HAVE THE VARIETY OF EXPERTISE, AND ITERATIVE STUDIES BETWEEN SMALL ANIMAL MODELS, NON-HUMAN PRIMATE AND HUMAN, TO GET A CLEAR UNDERSTANDING OF WHAT'S GOING ON IMMUNOLOGICALLY IN THE SPECIES, AND THE OTHER POINT BEING THAT IF WE HAVE A BETTER UNDERSTANDING OF WHAT'S GOING ON IN THE HUMAN AND SMALL ANIMAL AND NON-HUMAN PRIMATE, WE CAN IMPROVE OUR ANIMAL MODELS SO THEY CAN REALLY BE PREDICTIVE AND HELP US IN DEVELOPING BETTER TB VACCINES AND PRE-CLINICALLY IDENTIFY WHICH VACCINES ARE IMPORTANT TO MOVE FORWARD. WE WANT TO LEVERAGE PROGRAMS IN TB RESEARCH AND HUMAN IMMUNOLOGY RESEARCH AS WELL AS ANIMAL MODEL RESEARCH SO WE'RE HOPING THESE EXISTING PROGRAMS WILL BE PROVIDING SAMPLES, EXPERTISE, ET CETERA, TO THE IMPACT TB CONSORTIUM AND THEN THE OUTPUT OF THIS PROGRAM WOULD BE THAT WE HAVE A BETTER UNDERSTANDING OF IMMUNE LANDSCAPE, TISSUE SPECIFIC AND SYSTEMIC COMMUNITY, THAT WILL HAVE CLEAR UNDERSTANDING OF COMPARISONS ACROSS THE DIFFERENT ANIMAL MODELS IN HUMANS, WE'LL HAVE A BETTER HANDLE ON HIV AND SIV IN PATHOGENESIS, RESPONSE TO VACCINES, AND IMPROVED ASSAY DEVELOPMENT ADVANCED TECHNOLOGIES AND ALL DATA FOR THIS PROGRAM WE DEPOSITED IN PUBLIC REPOSITORIES AS MUCH AS WE CAN. SO WITH THAT, I WILL TAKE ANY QUESTIONS. THANK YOU VERY MUCH. WE'RE GOOD? OKAY. THANK YOU. >> OKAY. IF THERE ARE NO QUESTIONS, I GUESS THERE AREN'T, LET'S ASK FOR A MOTION TO PROCEED AND A SECOND FROM COUNCIL WHILE WE STILL HAVE A QUORUM. WE'LL RECORD THAT. AND THANK YOU FOR HANGING THROUGH TODAY, DESPITE THE TECHNICAL PROBLEMS WE HAD, AND FOR DR. SANDS AND DR. BOOK, THANK YOU FOR PARTICIPATING REMOTELY. I HOPE YOU GOT AS MUCH OUT OF IT TODAY AS YOU COULD. AND SAFE TRAVELS TO EVERYBODY. I HOPE NOBODY'S TRYING TO FLY