Confirmation Number:303209 Event Started: 12/16/2004 8:16:50 PM Event Ended: 1/1/0001 12:00:00 AM

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DR. DELUKE KARCHLS I THINK THE RESOURCES, VERY NICE, YOU DID A VERY NICE JOB. ONE OF THE THINGS I THINK THAT NEEDS TO BE CONSIDERED AND MAYBE YON OUR CONTROL IS WE'RE SUBMERGING AGENCIES SUCH AS AVION FLU, IT'S NOT NATURALLY EMERGING. BUT IT'S EMERGING, SARS AND SO ON. VOLUMES LIKE THE BMA AND NHA GUIDELINES MAY HAVE TO REVOLVE. THAT'S WHERE THEY GET A LOT OF INITIAL INFORMATION. IF YOU GO TO SOME OF THOSE APPENDIX, IF YOU CLICK ON THEM, THEY WOULDN'T HAVE THESE VIRUSES IN THEM, RIGHT? THEY WOULD HAVE INFLUENCES ZA BSO TWO.

WHAT I'M SAYING THESE VIRUSES DON'T OFTEN CONSIDER THE BMBL'S TIMELINE WHEN THEY EMERGE SO THERE HAS TO BE A MECHANISM TO GET THAT DON A LITTLE BIT IN A TIMELY MATTER AND ONCE ALL THE IBC'S HAVE A THE VIRUS THEN THEY CAN GO THROUGH THE RISK ASSESSMENT USING THE LATER PARTS OF THE NH GUIDELINES WHICH IS A LINK ON YOUR WEB PAGE AS WELL.

YEAH, BUT WHAT WE TRY TO DO TO COLLECT THE MORE REPEAT THE UPDATES THAT COME OUT IS TO COLLECT, TO GO TO THE SITES LIKE THE CDC AND WHO AND HEALTH CANADA AND THEY, LIKE, LET'S SEE, IF YOU GO DOWN TO THE FLOUNZ ZA SECTION WE TRY TO PICK UP WHAT WAS CURRENTLY BEING POSTED SO IT'S NOT WAITING FOR THE NEXT REVISION OF NBL BUT THE WHO HAS GUIDELINES FOR HANDLING SARS SPECIMENS AND I'M NOT UP ON THE SLIDE ANY MORE BUT WE TRY TO GO OUT THERE AND COLLECT THE MORE RECENT UPDATES THAT COME OUT AND HAVE THEM AT LEAST ON ONE PAGE FOR PEOPLE SO THEY'RE NOT SPENDING A LOT OF TIME GOOGLELING AROUND SO THAT'S OUR STOP GAP.

WHAT I'M CONCERN ABOUT THOUGH WHAT APPEARS TO BE SMALL DISAGREEMENTS LIKE B SL-3 PLUS DEFINED IN A CERTAIN WAY VERSUS B SL-3 AG. NOW THE GOVERNMENT HAS PUT OUT A LOT OF MONEY TO BUILD SOME OF THESE THINGS AND THE DIFFERENCE BETWEEN FULFILLING THOSE TWO, THOSE TWO CONDITIONS IN TERMS OF THE IF IT'S IS GREAT AND PEOPLE NEED TO KNOW, THERE HAS TO BE SOME ESTABLISHED GUIDELINES AND THAT'S WHAT I THINK -- AND WE CAN'T -- WE'RE -- YOU'RE DOING THE BEST YOU CAN BUT WHAT I'M SAYING IS THERE HAS BEEN MORE TIMELY WAY OF ESTABLISHING WHAT THOSE, -- WHAT THE GUIDELINES ARE GOING TO BE FOR CERTAIN AND IT HAS TO BE AGREED UPON.

YEAH, WE TRIED TO BRING ALL THE PLAYERS TO THE TABLE SO -- SO AT LEAST WE HAVE PRESENTATIONS FOR WHAT THE INFORMATION IS AND GOT IT SHARED, BUT --

WE HAD TALKED AT ONE POINT ABOUT POSSIBLY HAVING EXPERTS IN THE FIELD LIKE FOR BIRD FLU OR SOMETHING LIKE THAT GET TOGETHER AND MAKE SOME GUIDELINES THAT COULD BE PUT UP ON A WEBSITE BEFORE PERHAPS BMBL WOULD HAVE TIME TO COME OUT WITH A ISSUE ON THAT. IS THERE ANY POSSIBILITY OF THAT BEING DONE?

WELL, ALL WE KNOW IS ABSA IS AWARE OF THE RECOMMENDATION THAT CAME OUT WITH THE IBC AND THEY'RE TAKING THAT OUT INTO CONSIDERATION AS THEY'RE REVIEWSING THEIR OWN WEBSITE. SHARING INFORMATION AMONG INVESTIGATORS, IT'S HARD TO DETERMINE EXACTLY WHAT ROLE O BA SHOULD TAKE IN TRYING TO SET THAT UP OR MAYBE THAT SHOULD BE AN EFFORT THAT SHOULD COME OUT OF THE RESEARCH COMMUNITY ITSELF. SO WHAT'S YOUR FEEL ON THAT?

I CAN'T HEAR YOU VERY WELL, I'M SORRY.

DR. O'REILLY, I THINK THE QUESTIONS THAT ARE COMING FROM THE RAC ABOUT THE SAME ISSUE AND THAT IS, WE ALL AGREE THAT SOMEONE SHOULD TAKE THE RESPONSIBILITY FOR PUTTING FOR THE TIMELY GUIDANCE, AND THAT SOMEONE SHOULD TAKE THE RESPONSIBILITY FOR A TRAINING MODULE FOR NEW INVESTIGATORS WHO ARE BEING ASKED TO ESTABLISH AN ADVANCED LAB. THE MEDIUM ADVANCED LAB BECAUSE THERE'S NO WHERE TO GO TO REALLY FOR THAT GUIDANCE. THE QUESTION ISN'T SO MUCH SHOULD OBA OR WHO AT OABA SHOULD TAKE RESPONSIBILITY, MY QUESTIONS SLIGHTLY DIFFERENT, IS HOW DO WE MAKE A PUBLIC STATEMENTS THAT THESE ARE NEEDS THAT CAME OUT OF THE SAFETY SYMPTOM PODIUM AND MUST BE MET. THERE'S A DIFFERENCE.

RIGHT.

-- WE KNOW THOSE TWO COMMENTS OR QUESTIONS.

WHICH WE CAN DEVELOP MAYBE MORE BACKGROUND MATERIALS ON THE FRONT PAGE ON SOME OF THESE RECOMMENDATIONS THAT CAME OUT OF THE MEETING.

YES, IT MAKES SENSE. I WAS GOING TO SAY THAT THIS I THINK IS ALSO HE CAN ECHOING OR SOME OF THE CONCERNS THAT WE'VE HAD WITHIN THE OFFICE ABOUT HOW TO ADVANCE THE UNDERSTANDING AND SEAL FARTHER WHAT MORE CONCRETE GUIDANCE COULD EMERGE. WE REALIZE IN ALL OF THESE INSTANCES THE ULTIMATE DETERMINATION OF THE APPROPRIATE CONTAINMENT LEVEL AND THE RISK ASSESSMENT WILL HAVE TO BE DONE ON A CASE-BY-CASE BASIS, THE PARTICULAR APPLICATION, THE BITE BEING USED. THE ENVIRONMENT BIKE LICK AND THE EXPERTISE OF THE RESEARCHERS HANDLING IT. THAT SAID, I THINK THAT WE WOULD APPRECIATE INPUT FROM THE RAC ON WHETHER OR NOT IT WOULD BE APPROPRIATE FOR US TO MOVE FORWARD IN PARTNERSHIP WITH ABSA, ASN AND OTHERS TO TRY TO PERFORM PERFORM RISK ASSESSMENT IN THIS AREA.

DR. ROSENBERG, I'M GOING TO ASK YOU TO COMMENT ON AMY'S QUESTION. NO?

NO, I'M SORRY. I'M EATING MY POPCORN. IT SEEMS TO ME THAT REALLY THE ISSUE IS THAT SOMEONE NEEDS TO STEP FORWARD AND TAKE THIS RESPONSIBILITY, AND I DON'T KNOW FOR SURE IF THAT SHOULD BE OBA BUT IN ITS SUBABSENCE IS IT SEEMS THAT MAYBE THAT IS A GOOD IDEA, BUT I'M NOT AWARE ASM MAY BE A VERY LOGICAL ORGANIZATION TO TAKE ON THE TRAINING PIECE, BUT I'M NOT AWARE THAT THEY ARE ALTHOUGH MAYBE --

I WANT 0 TO BE CLEAR. I'M NOT SUGGESTING THAT OBO ITSELF WOULD SET STANDARDS IN A VACUUM BUT RATHER I'M SAYING THAT I THINK THAT WE RECOGNIZE THERE'S A NEED HERE AND CAN PERHAPS SERVE AS A CATALYST TO BRING THE APPROPRIATE PARTIES TOGETHER.

DR. BARKLEY.

I HAVE TWO COMMENTS ON THE WEBSITE I THINK IT'S WONDERFUL AND WITH THE RECOGNITION THAT OBO HAS IN THIS FIELD IT'S A LOGICAL PLACE FOR PEOPLE TO SEEK THIS TYPE OF INFORMATION EVEN THOUGH IT'S AVAILABLE AT OTHER LOCATIONS, I THINK THE SENSITIVITY TO THE IMPORTANT ISSUES IS IMPORTANT. AND THE WEBSITE I THINK IS GOING TO DO THAT EXCEEDINGLY WELL AND I THINK EVERYBODY WILL APPRECIATE IT, CDC AND WHO. THE BMBL IS ON A CYCLE REVISION EVERY FIVE YEARS AND IT'S MORE OF A, ITS INTENT TO BE A CODE OF PRACTICE AND A CONCEPT IN TERMS OF RISK ASSESSMENT. IT'S NOT THE VEHICLE FOR UP-TO-DATE INFORMATION, BUT THE MMWR IS. IN FACT, AND THAT IS -- IF YOU GO TO THE CDC SITE WHEN THERE ARE ISSUES OF CONCERN ABOUT INFLUENZA AND OTHERS THAT ARE REALLY IMPORTANT A MMW ARTICLE THAT IS BROUGHT TO GO BY EXPERTS IN THE FIELD WILL COME OUT. WHO DOES THE SAME THING, SO DOES HEALTH CANADA AND THE FACT THAT THE WEBSITE IS CAPTURING ALL OF THIS IS REALLY EXCEEDINGLY IMPORTANT AND I THINK IT'S VALUE ADDED. IT'S ALSO TRUE THAT I THINK MOST OF THE SCIENTISTS WHO ARE ADDRESSING THE ISSUES OF INFLUENZA AT THE OBA CONFERENCE ARE ALSO ON THE BMBL COMMITTEE TO FORMULATE THE SPECIFIC GUIDANCE WHICH I THINK WILL REFLECT MUCH OF WHAT WE HAD PRESENTED AT THAT MEETING. AS FAR AS THE SECOND POINT IS ON TRAINING. I THINK IT'S EXCEEDINGLY IMPORTANT, I THINK IT'S ABSOLUTELY APPROPRIATE FOR O BA TO EITHER TAKE THE LEADERSHIP OR BE PARTNERS IN THAT LEADERSHIP. WHILE TO MAIN DATE THE NHI PROGRAMS AND BIODEFENSE TO ESTABLISH A TRAINING CAPABILITIES AT THE REGIONAL FACILITIES, WE'RE TALKING ABOUT FOUR YEARS OFF BEFORE ANYTHING CAN BE DONE. AND I WILL SHARE OR BRING TO YOUR ATTENTION AGAIN SOME OF THE HISTORY OF IRAQ. THERE WAS GREAT CONCERN WHEN THE GUIDELINES WERE FIRST ISSUED THAT MANY PEOPLE WHO WANTED TO USE THIS TECHNOLOGY HAD NO CLUE ABOUT WHAT MICROBIOLOGICAL PRACTICES WERE ALL ABOUT BUT EVERYBODY WANTED TO USE THE TECHNOLOGY AND THERE WAS A FEAR THAT THERE WAS OBVIOUSLY RISK AND SO TRAINING WAS A VERY MAJOR MANDATE AND CONCERN AT THAT TIME. AND IRAQ ACTUALLY FORMULATED AN ARRANGEMENT WITH MICROBIOLOGICAL ASSOCIATION, AMS, ASM, AMERICAN SOCIETY OF MICROBIOLOGY AND THEY THROUGH A UNIVERSITY OF CONTRACT WITH UNIVERSITY OF MINNESOTA ESTABLISHED A MAJOR TRAINING RESOURCE THAT ACTUALLY MUCH LIKE OBA DOES TODAY SET UP TRAINING PROGRAMS THROUGHOUT THE COUNTRY TO JUST BEGIN TO INTRODUCE SCIENTISTS WHO HAD AN INTEREST IN PURSUING THIS FIELD AND I THINK THIS WOULD BE A VERY, BE A USEFUL THING TO LOOK AGAIN SO THAT WE REALLY HAVE SOME HISTORY THAT COLLABORATION WITH ASM WAS VERY HELPFUL IN THIS REGARD AND MAYBE IT'S AN AREA THAT WE OUGHT TO BE SERVING AS THE CATALYST AND EXAMINING AGAIN.

OTHER COMMENTS?

I THINK MANY SELF OF THE PEOPLE WHO'VE COMMENTED HAVE FOCUSED ON THE NEED TO DO SOMETHING ABOUT TRAINING AND PREEMPTIVE EDUCATION AND SO I'M WONDERING WE'RE GOING TO PROPOSE THAT OBA AND IRAQ TAKE A LEADERSHIP ROLE IN COORDINATING THE VARIOUS GROUPS THAT MIGHT BE INTERESTED IN WORKING ON THIS. IN ORDER TO DO THAT, AS USUAL, WE WILL NEED A WORKING GROUP TO HELP FORMALLY CONCEPTION LIES THE NEXT STEPS. ARE THERE ANY PUBLIC VOLUNTEERS FOR SUCH A WORKING GROUP?

HEARING NONE, THEN I WILL PESTER YOU ALL UNTIL WE HAVE THREE TO FOUR MEMBERS TO HELP CORRIDOR FATE THIS AND GET IT GOING BECAUSE THE SAFETY SYMPOSIUM THAT WE HELD, IS VERY IMPORTANT. THE WEBSITE DR. -RILEY YOU HAVE DONE AN OUTSTANDING JOB IN PUTTING THAT TOGETHER. THE NEXT STEP IS TO GET THE TRAINING PIECE OFF THE GROUND. AND WE'RE GOING TO NEED SOME HELP TO DO THAT.

IF YOU WERE, IN YOUR TERM OF PUBLIC WAS INCLUSIVE OF RAC MEMBERS I WOULD BE HAPPY.

I MET RAC MEMBERS, I MEANT IN PUBLIC AFTER VOLUNTEERS.

I WILL BE PLEASED TO VOLUNTEER IN PUBLIC TO BE PART OF THE --

THANK YOU, DR. BARKLEY. ARE THERE ANY OTHER VOLUNTEERS TO JOIN DR. BARKLEY?

I GUESS I COULD VOLUNTEER SINCE I RAISE IT HAD.

THANK YOU, YOU WOULD HAVE BEEN THE FIRST PERSON I WOULD HAVE CALLED ON, DR. ROSENBERG. COULD I HAVE ONE MORE PUBLIC VOLUNTEER? THEN I WILL PESTER EVERYONE UNTIL I GET ONE MORE. THANK YOU VERY MUCH. AND DR. O'REILLY, THANK YOU AGAIN, BOTH TO YOU AND THE GROUP THAT'S WORKED WITH YOU.

WE HAVE INVITED SPEAKER FOR THE NEXT FEW MINUTES. DR. CRYSTAL McCAL WHO IS WITH THE MCI IS GOING TO TALK WITH US ABOUT THE IMMUNE SPONSORS TO LYMPHOPENIA AS A PRELUDE TO OUR NEXT PROTOCOL. DR. McCAL.

McCALL.

OKAY . WELL, THANK YOU FOR INVITING AND I HOPE IN 20 MINUTES I CAN GIVE A RELATIVELY SIMPLE PICTURE OF A PRETTY COMPLEX PROCESS. I'M NOT SURE HOW MANY OF THE FOLKS IN THE ROOM ARE I AM NO, MA'AM OBLIGATIONS, PLEASE FEEL FREE AND ASK ME QUESTIONS IF I MAKE TOO MANY ASSUMPTIONS ABOUT YOUR BACKGROUND BUT BASICALLY FOR THE LAST 10 YEARS OR SO HAVE WE'VE BEEN STUDYING HOW HUMAN BEINGS RESPOND TO T CELL DEPLETION HOW THEY TRY TO MAKE NEW T-CELLS WHEN THEY'VE DONE DEPLETED BY DISEASE OR THERAPY AND I THINK THAT IN THE LAST SAY FIVE TO SIX YEARS THERE'S BEEN A REAL EXPLOSION ON THIS IN THE BASIC SCIENCE THAT HAS RENDERED US A LOT, A LOT BETTER IN TERMS OF UNDERSTANDING WHAT GOES ON. WE STILL HAVE A WAYS TO GO BEFORE WE CAN ADDRESS THIS THERAPEUTICLY BUT IN THE MEANTIME, PEOPLE ARE TRYING TO EXPLOIT THIS THERAPEUTICALLY IN THE CONTEXT OF CANCER THERAPY. AND LIKE MOST THINGS I WANT TO SHARE WHY THERE MIGHT BE DRAWBACKS AS WELL. JUST A BRIEF REVIEW OF THE IMMUNE SYSTEM EASY WAY TO DIVIDE IS TO TALK ABOUT THE RELATIVELY SIMPLE ASPECTS OF THE NATO IMMUNITY. THOSE CELLS THAT DO NOT MANIFEST IMMUNE LOGIC MEMORY OR SPECIFICITY. THOSE POPULATING, OF COURSE, WE'RE ALDER ARRIVED BY PROCEED 10 ENGINEER CELLS, REGENERATING THEM OVER THE COURSE OF WEEKS AND PROBABLY THOSE THAT ARE REGENERATE RHODE ISLAND REALLY FUNCTIONLY NORMAL AND YOU CAN LOOK THE BEST EXAMPLE IS POSSESS BONE MARROW TRANSPLANT THESE POPULATIONS ARE PRETTY WELL REESTABLISHED. AND EVEN CELLS THAT ARE DERIVE THE OTHER LYMPHOID PROCEED JENNIFER CELLS, THE DAYS THAT WE SEE IN THE ADAPTIVE IMMUNE SYSTEMS ARE NOT DUE TO DEFECTS BUT RATHER THOSE DLAELS REQUIRE SPECIFIC MICROENVIRONMENTS FOR THEIR REGENERATION THAT BEING THE EQUIVALENT IN HUMANS FOR B-CELLS AND, OF COURSE, THE THYMUS FOR IT. CELLS TEND TO TAKE A MORE PROTRACTED COURSE IN RECOVERING. AND ESPECIALLY FOR IT. CELLS IT GETS ALL MORE COMPLICATED BECAUSE YOU HAVE CLEAR AGE RELATED CHANGES WINE THE THIGH MOW ENVIRONMENT AND MATURITY CELLS CAN CONTRIBUTE TO THEIR OWN RECONSTITUTION SO THIS IS REALLY WHERE MOST OF THE ACTION IS IN TERMS OF ONGOING STUDIES OF IMMUNE RECONSTITUTION. WHAT WE HAVE LEARNED THAT I THINK WE FEEL FAIRLY CONFIDENT NOW IN CONCLUDING THAT IS WE CAN PRETTY WELL DISTINGUISH MIME MICK PROGENY FROM THOSE PROGENY THAT ARE DERIVED BY THE PERIPHERAL EXPANSION OF IT. CELLS AND I'LL GO THROUGH A TYPICAL PATIENT WHO WE TREATED FOR LYMPHOMA WHO SHOWED WHAT YOU WOULD EXPECT TO THE HOST WAS GOING TO RECOVER THEIR T-CELLS VIA I'M MICK REGENERATION. SO THIS IS A PATIENT WHO PRESENTED WITH ABOUT 8 TD FOUR CELLS, A LITTLE LOW FOR AGE BUT WITHIN THE NORMAL RANGE FOR MOST HUMANS. CELLS NOO. BASEMENT. THIS ISN'T JUST TRAFFICKING WHICH YOU CAN GET WAY LADY WITH IF I AM SITES BECAUSE 2% LIVE IN THE BLOOD BUT WITH CHEMOTHERAPY THIS IS A TOTAL BODE LEGS AND WHAT YOU SEE, THIS IS RECOVER. OVER THE COURSE OF ABOUT THREE TO SIX MONTHS THIS PATIENT REGENERATES RELATIVELY NORMAL CD 4 LEVELS IN THEIR SPEAKER PERSISTENT OVER TIME. AT THIS TIME YOU SEE CHANGES IN WHAT CD FOUR'S ARE CIRCULATING. ESPECIALLY IN YOUNG FOLKS YOU SEE A NUMBER OF WHAT WE'LL CALL NAIVE CELLS EXPRESSING CELLS. AND SOME C 45 RO CELLS AND WHEN YOU GIVE INTENSE CHEMOTHERAPY OR ANYTHING THAT DEPLETES THE T CKPARPT YOU LOSE THE CELLS BECAUSE THE THERAPY ITSELF BUT BECAUSE MOST CELLS ARE DRAWN INTO CIRCLE WHEN THE THYMUS CONTRIBUTES IT GENERALLY CONTRIBUTES THE NEW NAIVE CELLS, AND YOU SEE COULD HE INCIDENT WITH RECOVERY IN THIS YOUNG RELATIVELY HEALTHY PATIENT UPON TREATMENT OF LYMPHOMA THEN YOU SEE RECOVERY OF THESE NAIVE POPULATIONS AND THIS IS ACCOMPANIED BY EVIDENCE OF WHAT WE CALL I'M IK REBOUND, THERE IS THAT VERY NICE JUICY PLUMP THYMUS THAT'S RESPONSIBLE FOR SELLING OUT THESE NAIVE CELLS. SO THIS IS ABOUT AS GOOD AS IT GETS. NOW MOST OF THE TIME YOU HAVE PATIENTS THAT ARE EITHER SICKER BECAUSE THEIR DISEASE HAS RENDERED THEM SICKER OR THEY'RE OLDER OR MAYBE THE THERAPY WAS MORE TOXIC THAT THEY WERE THAT THEY RECEIVED AND THIS IS, FOR EXAMPLE, 21-YEAR-OLD PATIENT WHO RECEIVED VERY SIMILAR CHEMOTHERAPY, YOU CAN SEE AT ABOUT, I WANT TO TIMER, LET ME JUST TAKE A MINUTE HERE SO I DON'T HAVE TO BATTLE THAT. THIS PATIENT -- ALWAYS DEFAULTS TO THAT. OKAY. SO THIS PATIENT SIMILAR CD PRESENTATION, SIMILAR DISTRIBUTION OF NAIVE AND MEMORY CELLS, SIMILAR DEPLETION BUT WHAT YOU SEE HERE IS PROLONGED DEHE PLEADINGS AND THIS IS ASSOCIATED WITH OPPORTUNISTIC INFECTION. THIS ISN'T JUST SOME LABORATORY FINDING. AND YOU SEE THESE LACK OF ANY OF THE NAIVE CELLS RETURNING AND THEN FINALLY AT 15 MONTHS WE SAW THESE NAIVE CELLS RECOVER AND AGAIN THEY WERE SUSTAINED AND IF YOU LOOK AT THE I'M I CAN SHADOW IN THIS PATIENT IT STAYED SMALL THROUGHOUT. WE COULD HAVE MISSED IT YOU DON'T DO CT SCANS ALL THE TIME BUT YOU FOLLOW THESE PATIENTS OUT FOR A YEAR OR TWO AND YOU SIMPLY SEE THESE SMALL THYMUSES AT BEST. SO WE GENERALLY CAN USE THYMUS OUTPUT AND NAIVE MARKERS AND TREKS WHICH ARE PIECES OF D NA THAT ARE EXCISED OR RECEPTOR AND REACCEPT STORE REPERTOIRE DIVERSITY AND USING ALL THOSE PARAMETERS, FRAM HACKUM. REALLY HAS CONTACT RISED LARGE NUMBERS OF ADULTS THAT HAVE BEEN NOW TREATED WITH INTENSIVE CHEMOTHERAPY FOR CANCER AND IS GIVING US THIS KIND OF SCHEMATIC THAT GIVES THE PICTURE OF PATTERN OF HER CONSTITUTION AFTER T CELL DEPLETE AN ADULT. CD 4'S. YOU START WITH A SMALL THYMUS, THE CHEMOTHERAPY DEPLETES IT FURTHER, IF YOU SEE LONG ENOUGH SOME EVIDENCE FOR REBOUND, IN SOME OF THE PATIENTS AND IT SORT OF DEPENDS ON WHOLT PATIENT IS AND WHAT THEIR AGE IS. WE KNOW UP TO THE AGE OF 40 YOU CAN SEE THIEMIK REBOUND. WHEN YOU DO SEE THE THIMIK IT'S ACCOMPANIED IN THE CELLS THAT YOU CAN MEASURE AND IT'S ASSOCIATED WITH A RISE IN RA CELLS AND THEN, OF COURSE, ULTIMATELY THE THING THAT IT'S DOING FOR YOUR REPERTOIRE IS TO DIVERSIFY SO THIS IS ABOUT AS GOOD AS IT GETS FOR ADULTS. JUST TO MAKE THE POINT FOR 8 IT'S A BIT OF A DIFFERENT STORY BECAUSE YOU HAVE A LOT MORE ACTION IN THE EIGHT THAT IS NOT THIMIK DEPENDENT, YOU SEE A DRAMATIC EXPANSION BUT THESE ARE LEADER DERIVED AND THEY CAN GIVE YOU THE IMPRESSION THAT THE PATIENT HAS IMMUNE RECONSTITUTED BUT IT TENDS TO BE TRANCE YET. I SORT OF SKIMMED OVER THIS PART THERE BUT THERE'S ALSO THAT SORT OF BLIP THAT YOU SEE IN CD 4'S AND THIS RAISES THE POINT THAT IT'S JUST NOT THE I'M I CAN PATHWAY THAT CAN CONTRIBUTE TO REDISTRIBUTION, YOU COULD HAVE EXTRA WHERE IMMATURE CELLS FROM THE BONE MARROW DEVELOP OUTSIDE THE THYMUS AND GIVE RISE TO NEW CELLS BUT FOR CD 4 CELLS IN HUMAN BEINGS IT'S ARGUE WHETHER IT EXISTS AND IF IT DOES EXIST IT'S QUANTITY TIVEL NEGLIGIBLE RATHER WHAT YOU HAVE GOING ON AT THE SAME TIME IS A SUBSTANTIAL TRANSCRIBING OF THE PERIPHERAL POLE BECAUSE T-CELLS ARE VERY GOOD AT EXPANDING THEMSELVES THEY AS THEY COME OUT FROM THE THYMUS OR ANY RESIDUAL CELLS LEFT IN THEIR HOST AT THE END OF THE DEPLETED INSULT CAN CONTRIBUTE TO REGENERATION AND HEMOSTATIC OR JUST PERIPHERAL T CELL EXPANSION. WAS THIS? BECAUSE THIS IS REALLY WHAT THE CANCER IMMUNO THERAPIST ARE TRYING TO EXPLOIT. IT INVOLVES VERY ACTIVATED CELLS. JUST TO GIVE YOU AN INDICATION, THIS IS AGAIN THOSE CD 45 RA CELLS THAT MOST US ARE WALKING AROUND WITH. AS WE GET OLDER WE TEND TO LOSE A PERCENTAGE OF THESE BUT WE MAINTAIN SOME NAIVE COMPONENT. THIS IS WHAT HAPPENED WHEN YOU'RE DEPLETED THEY BECOME ACTIVATED AND BECOME INVESTIGATING. AND YOU CAN SEE IT'S EVEN UP REGULATED THED THE R O. UNDER NORMAL CIRCUMSTANCES HLDER ON THE T-CELLS IS ONLY PRESENT ON A SMALL NUMBER OF YOUR TCELLS AND IN GOOD HUMANS IT'S A GOOD ACTIVATION MARK HE. THIS IS WHAT HAPPENS WHEN WE GIVE CHEMOTHERAPY. THE DEPLETED HOST ALSO ALMOST ALL OF THEIR T-CELLS EXPRESSING HLDER. FURTHERMORE AS I MENTIONED, TO YOU IN PASSING WHEN THESE CELLS ARE RECOVERING VIDEO HEMOSTATIC IT TENDS TO BE UNSTABLE BURST OF RECOVERY AND THEN THEY TEND TO FALL OFF AND THIS IS IN LARGE PART BECAUSE THERE'S A HIGH RATE OF PROGRAM CELL DEATH IN THESE HIGHLY ACTIVATED LIMB SITES AND INDUCED IN OUR HANDS WE SEE THIS IS DIRECTLY TO THE EXPRESSION AND THAT ISN'T TOO SURPRISING IN MOST CIRCUMSTANCES WE KNOW THAT THESE CELLS ARE GENERALLY KEPT UNDER CONTROL BY PROGRAM CELL DEATH A. SO HOME STATIC PERIPHERAL ACTIVATED CELLS. THEY CAN CLEARLY UNDERGO EXPANSION THAT IS REMARKABLE. BUT THEY ALSO TEND TO HAVE THE OFFSET IN TERMS OF THEIR EFFICIENCIES EFFICIENCY BY A HIGH RATE OF CELL DEATH. TO SUMMARIZE OUR GENERAL UNDERSTANDING OF IMMUNE RECONSTITUTION WE THINK OF IT OCCURRING IN A HOST THAT HAS THINK SUICIDES MIK SUFFICIENCY IN THE COURSE OF THE FIRST YEAR YOU HAVE RECOVERY OF FUNCTION EVIDENCED BY DIVERSIFICATION OF THE REPERTOIRE, NORMAL DIVERSIFICATION OF IT. CELLS AND TREKS IN RA CELLS. MORE, IN THAT CASE THERE IS SOME CYCLING IN THE PERIPHERAL EXPANSION KPARPT. BUT IT'S A MINOR CONTRIBUTION. MORE COMMONLY THOUGH WHAT YOU SEE IN HOSTS THAT HAVE A DISEASE THAT'S RENDERED THEM T CELL DEFICIENT, YOU MIGHT SEE SOME CONTRIBUTION OF I'M MOW POE E CYST AND THAT THE LARGE PORTION OF THE ACTIVITY IS OCCURRING IN THIS PERIPHERAL EXPANSION COMPARTMENT WHICH ISN'T GOING TO BE ABLE TO RESTORE REPERTOIRE DIVERSITY AND WHILE CAN GIVE SUBSTANTIAL EXPANSIONS IT IS OFFSET HIGH RATE OF A PTOSES. AGAIN THAT'S WHAT WE AS CANCER ONCOLOGISTS AND I AM NO THERAPISTS ARE TRYING TO EXPLOIT BY ALTER. IN MICE IF YOU GIVE AN ADOPTIVE TRANSFER TO REPLETE OR LYMPHOPENIC YOU GET A DIFFERENT RELATES. THIS IS WHAT A POLYCLONAL, THEY TEND TO EXPAND TO TRY TO FILL UP THE HOST. BUT IF YOU TIGHTER THIS DOWN AND GIVE LOWER DOSES MANY INVESTIGATORS AND THIS IS OLD NEWS, THIS IS STUFF FROM THE '80s HAVE SHOWN THAT THIS EXPANSION CAN BE QUITE REMARKABLE. RICHARD MILLER AND IS TO THE MAN DOCUMENTED 10,000 FOLD EXPANSION SO THIS CAN BE A POTENT STIMULUS THAT'S DRIVING THESE CELLS TO EXPAND IN THE LYMPHOPENIC HOST. ANTIGEN INDEPENDENT. WE DID SOME WORK ON THIS SEVERAL YEARS AGO NOW WHERE WE BASICALLY USE IT. CELL TRANSJENICK CELLS AND/OR LYMPHOPENIC. AND THEN WE LOOKED AT THE IMPACT OF SUPPLYING AROUND TY GENERAL OR NOT SUPPLYING ANTIGEN. AND YOU CAN SEE THAT WHEN YOU HAVE A LYMPHOPENIC HOST AND YOU SUPPLY THE ANTIGEN YOU CAN REMARKABLY SKEW THE REPERTOIRE. HE'S HOW ARE STARTING. ONLY 10% STARRING IN THE RED THERE, WHEN YOU GIVE THIS COULD GO NANT ANTIGEN TO A LYMPHOPENIC ANIMAL YOU CAN. SO THAT'S VERY POWERFUL IN THE REPLETE ANIMAL WHO'S PUTTING CELLS OUT THROUGH THE THYMUS, YOU GET SOME EXECUTING, THE CELLS SURVIVE BUT THEY DON'T GENERALLY EXPAND. AND THIS ISN'T SIMPLY A DELUSIONAL EFFECT, THIS IS AN ABSOLUTE INCREASE IN THE DEGREE OF ANTIGEN SPECIFIC EXPANSION THAT YOU GET. IF YOU I AM NEEDS ANIMALS IN LYMPHOPENIC ENVIRONMENT. NOW WE THOUGHT THEN THAT WE UNDERSTOOD THAT LYMPHOPENIC HOST TO COULD GO NANT ANTIGEN AND THAT LARGELY EXPLAINS THE HOME SAT TICK EXPANSION BUT YOU WONDER IN THOSE ANIMALS THAT WEREN'T IMMUNIZED WHAT WERE THE ANTIGENS DRIVING THE PROCESS AND SOME WORK IN THE LAST FIVE YEARS, THIS IS THE NICEST PAPER THAT I ENJOYED READING SHOWED US THAT THIS WASN'T JUST A QUANTITATIVE DIFFERENCE IN THE RESPONSE TO A HIGH OF A IF I WANT ANTIGEN BUT RATHER A QUALITATIVE DIFFERENCE AS WELL. THE OPPONENT EVEN IF WE MISS SOME OF THE DETAILS THE POINT IS VERY CLEAR. THE DIFFERENCE IS THAT THESE FOLKS NOT ONLY HAD T CELL TRANCE JENICK, IT WAS A VERY CLEAN SYSTEM BUT THEY ALSO CONTROLLED THE ANTIGEN INVESTIGATION IN THE HOST SO THE HOST WAS TAP DEFICIENT, THERE WERE NO AND DODGE IN US PEPTIDES BEING PRESENTED AND CROSS ANIMALS TO ANIMALSED THAT EXPRESSION OF VARIOUS ANTIGENERALS. AND THEN THEY MONITORED HOME STATIC PROLIFERATION SO THE FIRST ANIMAL WAS ANIMALLED THAT TRANSJENICK EXPRESSION OF THE VSV VIRAL EPI TOBACCO AND THIS HAD NO AFFIANT FORTUNATE. IN THAT CASE HERE'S YOUR. THERE'S ESSENTIALLY NO PROLIFERATION OF THESE CELLS IN THE LYMPHOPENIC HOST SO YOU NEED SOME ANTIGEN I CAN INTERACTION IN ORDER TO GET. THE OTHER SPECTRUM WAS ALBUMIN AND THAT IS YOU KNOW, LEADS TO DRAMATIC EXPANSION IN THE LYMPHOPENIC HOST. THE REAL INSIGHT WAS WHEN THEY USED AN AND TAG IN HIS PEPTIDES, THESE ARE PEPTIDES THAT SHOULD NOT BE AGE TO INDUCE PROLIFERATION, IT'S A LOW AFFIANT INTERACTION SO NORMALLY THE HOST IGNORES THEM IN THE PERIPHERY BUT THE LYMPHOPENIC HOST DOES NOT IGNORE THEM. THEY ACTUALLY PROLIFERATE IN PROCESS TO THE AND TAG ANY OF THE IN THE HOST OF SO IT PROVIDES EVIDENCE THAT NOT ONLY IS THERE AN INCREASE BUT NEW ANTIGENS WHICH INDUCE PROLIFERATION DURING EXPANSION AND CHARLIE GROUP WENT ON TO SHOW THAT SELF AND TY GENERALS ARE CAPABLE OF DOING THIS AS WELL. WHAT WE KNOW NOW NORMALLY I'M MICK DIFFERENT DIFFERENTIATION TAKES A BACK SEAT AND HOME STATIC PERIPHERAL EXPANSION INVOLVES BOTH NAIVE AND MEMORY CELLS AND SOMETIMES IT'S MISUNDERSTOOD. NAIVE CELLS CERTAINLY CAN CONTRIBUTE THAT IT PRESENTS AN EXAGGERATED PROLIFERATION TO GOOD ANTIGENS BUT TO WHAT WOULD BE WEAK, LOW AFFIANT OR SELF AND TY GENERALS. THERE'S ALE SEVEN STORY, IT'S A MEMBER OF THE GAMMA SITE CON FAMILY IT'S MOST FAMOUS FOR THE IS ROLE IN EARLY TCELL DEVELOPMENT IN HUMANS AND EARLY T AND B'S IN MICE SO BECAUSE ANIMALS THAT LACKED L SEVEN LACKED T-CELLS WE WEREN'T ABLE TO STUDY THEM FOR QUITE SOME TIME AS PEOPLE STARTED TO LOOK AT THIS HOME STATIC PROLIFERATION WHAT THEY FOUND THAT ISLE 7 WAS THE FACTOR LARGELY RESPONSIBLE FOR WHAT WAS BEING OBSERVED. THIS IS A VARIETY OF MODELS THAT WERE USED EITHER POLYCOLONIAL T CELL POP TLAIGS TRANCE IRRADIATED AND LOOKING AT THIS HOME STATIC EXPANSION THESE ARE THE CFC PLOTS AND THE POINT IS THAT THIS IS WHAT YOU SEE IN A NORMAL B-6 AND DEFICIENT IN I WILL ALE 15 THEY UNDERGO THE -- ANIMAL THAT'S DEFICIENT IN ALE SEVEN THAT DOES NOT UNDERGO HOME STATIC PROLIFERATION SO IT PLAYS A CENTRAL ROLE IN THIS PROFESSIONALS. OKAY. ALE SEVEN IS REQUIRED BUT IT CAN EXPLAIN THE INCREASED HOME STATIC PROLIFERATION WHICH WE OBSERVED IN LIMB PENIC ANIMALS IN HUMANS THAT WERE SUBJECTED OR SUSTAINED T CELL DEPLETION FROM A VARIETY OF INSULTS AND THIS IS A COULD HE HORT ACROSS HIV INFECTION AND WHAT YOU SEE IS THAT UNDER, WHEN YOUR CD FOUR COUNSEL REPRESENTS THE NORMAL LEVEL E LEVEL OF AISLE SEVEN THAT WE ALL HAVE. YOU CAN MEASURE IT IN THE SERUM. AS YOUR C GOES DOWN IN HIV INFECTION AND DROPS BELOW 200 YOU SEE A RISE IN THE AISLE SEVEN LEVEL. VERY STRONG INVERSE CORRELATION WITH CD 4'S. WE DID NOT SEE CORRELATION WITH B'S OR STRONGER CORRELATION WITH CD 8'S. IF I HAD A POPULATION THAT HAD ISOLATED CD DEFICIENCY BUT I DON'T HAVE THAT POPULATION. CORRELATED WITH WAS THE CD FOUR COUNSEL AND IN OTHER STUDIES AS WELL. TESTIMONY PARLY I WANT DUFD YOU TO IN THE INITIAL SLIDES WHO SUSTAINED T CELL DEPLETION AS A RESULT OF CHEMOTHERAPY WHEN THEY HAVE PRETTY GOOD CD 4 COUNTS ABOUT IN THE 800 RANGE, AISLE SEVEN LEVELS WE DEPLETE THEM WITH CHEMOTHERAPY IN ABOUT A COURSE OF A YEAR AND THEIR AISLE SEVEN LEVELS RISE. SO THERE IS AN INVERSE RELATIONSHIP BETWEEN AISLE SEVEN AND CD 4 COUNTS, OUR WORKING MODEL, AND WE'RE WORKING ATTEMPTING TO WORK THIS OUT IN MICE. IT'S A LITTLE DIFFICULT IN MICE BECAUSE WE DON'T HAVE THE ASSAYS THIS DOES NOT THE REFLECT INCREASE PRODUCTION OF AISLE SEVEN BUT RATHER DECREASED UTILIZATION AISLE SEVEN AS HOME STATIC SITE COULD HE KIND. UNDER NORMAL CIRCUMSTANCES, T-CELLS ARE PLENTIFUL, NEARLY ALL T-CELLS EXPRESS THE AISLE SEVEN RECEPTOR. THE AISLE SEVEN AND IT'S BEING UTILIZED. IT'S SORT OF A FIRST ORDER REGULATION. ON THE OTHER HAND WAR, WE SEE IS THAT IN T CELL DEPLETED HOSTS YOU HAVE LESS CELLS THAT ARE EXPRESSING THE AISLE SEVEN RECEPTOR. IT APPEARS TO BUILD UP IN THE TISSUES AND WE SEE DECREASED MESSAGE IN AISLE SEVEN IN LYMPHOPENIC MICE SO WE THINK THIS IS AN ACCUMULATING OF AISLE SEVEN SO TO KIND OF THINK ABOUT A MODEL FOR THIS EFFECT, UNDER NORMAL CIRCUMSTANCES WHEN YOU HAVE A POT THAT'S FULL, THE HOST GENERALLY ONLY USES THE CELLS TO RESPOND TO AN ANTIGEN THAT ARE OF THE HIGHEST AFFIANT. YOU'RE GENERALLY WORKING WITH A VERY SMALL SLIVER OF CELLS OF THAT ARE HIGH AFFIANT UNDER THE SITUATION OF LOW AISLE SEVEN BUT AS THE HOST LOSES T CELL NUMBER, AISLE SEVEN ACCUMULATES AND YOU SORT OF LOWER YOUR THRESHOLD FOR TORCH CELL ACTIVATION AND YOU SAY I'LL ACCEPT A LOWER T CELL AND THAT MIGHT HELP THE HOST TO DEAL WITH LYMPHOPENIA, NOW, SO IF YOU THINK ABOUT THIS, AND YOU SAY, WOW, WE'VE GOT ALL THESE SELF AND TY GENERALS THAT CAN BE CALLED INTO THE PROLIFERATIVE POOL, CONSISTENT THIS PREDISPOSE HOST TO AUTO IMMUNITY AND THIS INTERFACIAL WITH AUTO IMMUNITY AND LYMPHOPENIA IT DEPENDS ON HOW HARD YOU LOOK YOU WILL FIND IT. CERTAINLY THERE ARE PLENTY OF MOUSE MODELS OF AUTO IMMUNITY THAT INVOLVE LYMPHOPENIA AND IT'S NOT BEEN VERY WELL STUDY THERE BUT AUTO IMMUNE GASTROTIGHTS, OR MICE GIVEN ADULT PINE AND TREATED WITH SEIKO. THE T REG STORY IF YOU DEPLETE YOU CAN GET COULD HE LIGHTS BUT THAT ONLY OCCURS IN MICE. AND RECENT WORKS PAPER BY DUMBER AND JCI, USED LYMPHOPENIC MICE TO SHOW THAT THE HOME STATIC, THESE WERE MOUSE MODELS, IN THE HUMAN SETTING THERE ARE IMMUNE POPULATION SYNDROME, THE REPLETE IN THE LITERATURE. BUT IT'S UNCLEAR HOW MUCH OF A PUBLIC HEALTH ROB THIS IS BUT, INDEED, IF YOU LOOK AT PATIENTS THAT HAVE DRAMATIC RECOVERY WITH HIGHLY ACTIVE RETROVIRAL THERAPY AND HIV INFECTIOUS, YOU OFTEN WILL SEE, WHAT WE CALL IMMUNE RECOVERY NEW RATES TO AND THIS TENDS TO CMC INFECTIOUS, NO LONGER HAVE ACTIVE VIRAL REPLICATION BUT FOR WHATEVER REASON TOLERANCE AT THAT ORGAN HAS BROKEN DOWN. PROGRESSIVELY MULL IF I FOCAL NUKE CLOSE ENCEPHALOPATHY. THEY DON'T, LUPUS OR RHEUMATOID ARTHRITIS. RATHER THEY TEND TO DEVELOP AUTO IMMUNITY LIMITED TO ONE ORGAN AND THEN I ALSO WANT TO POINT OUT THE GROUP BY ROSENBERG'S GROUP WHERE THEY USED LYMPHOPENIC PATIENTS AND ADMINISTERED LARGE NUMBERS OF ANTITUMOR CELLS, THEY SAW POTENT ANTITUMOR RESPONSES IN THE CONTEXT OF LYMPHOPENIC AND AUTOIMMUNE IN YOUR RIGHTS IN THAT STUDY AS WELL SO THERE APPEARS TO BE AN INTERFACE BETWEEN LYMPHOPENIA AND AUTO IMMUNITY, BUT IT DOESN'T HAPPEN IN EVERYBODY AND IT IT MAY REQUIRE OTHER FACTORS SUCH INFLAMMATION IN ANOTHER SITE. LET ME JUST LAST COUPLE SLIDES. JUST TO SAY, WELL, YOU HAD THESE LYMPHOPENIC MICE, HOW EASY IS IT TO GET THEM TO DO WHAT YOU DO. CAN YOU REJECT A TUMOR BETTER IF YOU MAKE THE MOUSE LYMPHOPENIC, THERE ARE ADVANTAGES AND DISADVANTAGES. WE HAVE USED THE HY MODEL IT'S A MINOR HISTOCOMBAT.

ANTIGEN AND STRINGENT ANTIGEN AND WE'VE WITH USED SKIN RETRO JEX TO GET AUGMENTED IMMUNE RESPONSES IN LYMPHOPENIC HOSTS WE NOTED THAT THAT'S WHAT THESE HOSTS TENDED TO USE THE NOMINAL ANTIGEN RATHER THAN THE HIGH ORDER RESPONSES TO ALOE ANTIGEN, SO HOW MANY T-CELLS DO YOU NEED IN ORDER TO GET HE AN IMMUNE RESPONSE TO A VIN GENT, TO PROVIDE SPACE FOR YOURSELF, AT SOME POINT YOU'RE GOING TO LOSE YOUR REPERTOIRE AS WELL AND THE ANSWER WAS INTERESTING, VERY CONSISTENT. WE SAW THIS BOTH FOR REJECTING SKIN GRAFT AND REJECT HE TUMOR. YOU BASICALLY NEED 10% OF THE REST FOR, WE TRANSFERRED NO CELLS, 3 1/2, 3% OF THE REPERTOIRE, 10% OF THE REPERTOIRE IN CONCERT WITH I AM IN MY SAYINGS TO HIGH PRESSURE Y, HERE IS YOUR NORMAL ANIMAL, THEY ALL REJECT THE SKIN GRAPH VERY WELL. IT ACTS LIKE A NORMAL AND MA'AM BUT THERE'S A VERY STRICT STEEP FALL OFF AS YOU DROP BELOW A ONE LOG REDUCTION. SO REPERTOIRE MATTERS. BUT YOU'LL HAVE TO PROBABLY GET BELOW 10% FOR IT TO MATTER. THE OTHER THING THAT WE HAVE FOUND WHICH IS NOT ENTIRELY WORKED OUT IN AND THIS REPRESENTS WORK IN PROGRESS TO OUR SURPRISE WE ALSO SEE THAT LIMB POE PENIC HOSTS ARE MORE PRONE TO TOLERANCE IF YOU DON'T, IMMUNIZED WITH MALE DENDRITIC CELLS AND WE LOOK AT THE ABLE. MALE SPLEEN IS ABLE TO SENSE SENSITIZE TO SKIN GRAPH REJECTION BUT WHEN YOU TAKE A LYMPHOPENIC ANIMAL, T-CELLS TO REPEAT SKREK THAT 10% OF THE REPERTOIRE BUT THEY SAY IN THAT LYMPHOPENIA, DENY DRET TICK CELLS BUT IF YOU GIVE MALE B-CELLS, SPEEN BUT THE B-CELLS ARE THE CULPRIT, IN FACT, THESE ANIMALS ARE TOLL RISED. AND WE HAVE BEEN ABLE TO SHOW THAT WHAT IS HAPPENING HERE IS THAT THESE HOST DEVELOPS A TOLL JENICK CD 8 CELLS. WITH OTHER REGS THERE WAS A NICE PAPER CAME OUT IN IMMUNITY IN AUGUST BY REDEMSKI'S GROUP THE CD-20 FIVE'S AND THEY WERE LOOKING AT THE REPERTOIRE OF THESE CELLS AND THEY SHOWED THAT BOTH CD FOUR REGS AND NEGATIVE CELLS BOTH HAVE DIVERSE REPRESENT TORS BUT THE REPRESENT TORS ARE VERY DIFFERENT AND THEY BASICALLY WENT TONIGHT SHOW THAT THE T REG REPERTOIRE IS HIGHLY SKEWED TOWARD SELF AND TY GENERALS SO IF YOU TAKE AWAY THE SUPPRESSOR FEATURE OF THOSE CELLS BUT KEEP THE REPERTOIRE THEY DEVELOP RAMPANT COULD HE LIGHTS, IF YOU TAKE THE REPERTOIRE OF THE T REG CELLS AND PUT THEM INTO 25 NEGATIVE CELLS THAT THEY ARE SKEWED TOWARDS DEVELOPING AT IT. REGS, WHY DO I BRING THAT UP IS IT BECAUSE THE CD FOUR REG REP FOR IS SELF-REACTIVE. THEY'RE GENERALLY FAVORED DURING HOME STATIC PERIPHERAL EXPANSION AND OUR PRELIMINARY WORKING SUGGESTS THAT AS YOU MAKE A HOST LYMPHOPENIC AT THE SAME TIME YOU ARE PREFERENCELY SEEING SURVIVAL OF A REGULATORY CELLS AND IT'S NOT TOO SURPRISING TO TREEPTS RAMPANT AUTO I AM MUNICIPAL TY THE IDEA TO AUGMENT AUTOIMMUNE RESPONSE IS LIKE MOST THINGS, IT'S GOT A YANG AND THE YIN, IN THE MAGNITUDE TO HIGH OF A TIP ANTIGEN AND PROBABLY BE BETTER ABLE TO INDUCE ANTIGENS AND TUMOR ANTIGENERALS ARE THOUGH OF A FIN, INDUCED LARGELY BY THE ACCUMULATION OF THE KYLE SEVEN IN RESONS TO CD FOUR DEPLETION. AND DEPENDING ON THE METHOD OF DEPLETION, YOU MIGHT BE DEPLETING REG CELLS WHEN YOU DEPLETE THE HOST OR YOU MIGHT NOT BE. I THINK THAT'S ENTIRELY UNCLEAR, THE LAW SAYS IT A PSYCHO FOSS MY DEPLETES REGULAR, THERE'S A YIN, FIRST OF ALL, BETWEEN THIGH MOW PROCEED E CYST, IN ADULTS OR OLDER ADULTS, CD 4 LYMPHOPENIA THAT'S DUFD IS GOING TO BE RELONGED AND DEPENDING ON THE DEGREE YOU'RE GOING TO HAVE CLINICAL ECONOMY INDICATIONS, IF 200 CD 4 IS THE CUT OFF IT'S, IS IT ALSO THE CUT OFF FOR OR DO PATIENTS WITH DON CANNON CERTIFY DO BETTER WIN HIV IT HASN'T BEEN WELL WORK OUT. ONCE YOU GET BELOW YOU ARE AT SOME RISK FORTUNE IN HIS PARTICULARLY INDICATIONS. YOU HAVE TO ALSO CONSIDER THAT YOU ARE DIMINISHING THE REPERTOIRE DIVERSITY IF YOU HAD LESS T-CELLS TO WORK WITH AND SO IN OUR CASE IF WE TRY TO DO THIS WE'D BE ADOPT TIVEL TRANSFERRING THAT ARE HARVESTED WHEN IT'S HOST HAS A DIVERSE REPERTOIRE, BUT THAT'S CERTAINLY LABOR-INTENSIVE AND I DON'T KNOW HOW EXPORT BELIEVE THAT IS. THERE'S HIGH RATE OF HELP PTOSES AND REGULATORY CELLS MAY BE INDUCED IT A THIS IS A STORY THAT'S STILL EVOLVING. SO AT THIS POINT WE'RE IN A PRETTY CRUDE STAGE WE KNOW THAT A LYMPHOPENIC HOST HAS ENHANCED REACTIVELY BUT BY TAKING OUT THE LYMPHOCYTES, IT'S SORT OF THE SAY THE OF THE ART NOW BUT WHAT WE HAD'S LIKE SO REVOLVE I AM NO SUPPRESSION, THE -- GOOD ROBUST ANTITUMOR RESPONSE, WE HAVE REASONED THAT ADMINISTERING PHARMACOLOGIC DOSES OF AISLE SEVEN TO REPLICATE HOME STATIC SUPPER WHICH IT DOES MIGHT ACCOMPLISH THAT AND MAYBE THERE ARE OTHER SITE KIND THAT CAN SELECTIVE DELEGS OF IT. REGS THAN SORT OF KNOCKING OUT EVERYTHING THAT'S THERE, BUT WE'RE NOT THERE YET SO I THINK THAT'S WHAT WE SHOOT FOR. I WANT TO THANK PEOPLE IN MY GROUP. AND WE HAVE WORKED CLOSELY THROUGH THE YEARS WITH RON GREV AND FRAM HECKCOMM AND TOM FLESHER AS WE'VE MONITORED OUR PATIENTS WITH LYMPHOPENIA THROUGH THE YEARS. THANKS.

DR. McCALL. THANK YOU VERY MUCH FOR A RAPID AND THOROUGH REVIEW FOR US. ARE THEIR QUESTIONS FROM RAC MEMBERS?

YES, DR. .

IN THE OVER 40 CROWD, DO YOU SEE A DECREASE IN AISLE SEVEN PRODUCED DURING THESE ISSUES?

NO, IT WOULD BE, YOU KNOW, WE ALL KIND OF HOPED WHEN WE MADE THIS OBSERVATION THAT PATIENTS WHO DON'T IMMUNE RECONSTITUTE MAYBE WON BECAUSE THEY DON'T HAVE ENOUGH AISLE SEVEN AND IT'S JUST NOT TRUE. HIV'S WHERE IT'S BEEN MOST WELL STUDIED AND MOST OF THE PATIENTS WHO ARE THE POOR IMMUNE RECONSTITUTERS IN H IV HAVE PLENTY OF AISLE SEVEN AROUND. I DON'T KNOW ABOUT THE HE WOULD HE WERE. WE HAVEN'T DONE STUDIES INTO THE VERY OLD AND.

T REG DEPLETION, SOME OF THE APPROACHES TO T REGS ARE TO TARGET THE IS CD-20 FIVE BUT THAT TAKES OUT A BUNCH OF OTHER CELLS TOO. CAN YOU COMMENT ON THAT SORT OF APPROACH GENERICALLY.

SO, YOU KNOW, WE'RE ALL SORT OF SCRATCHING OUR HEADS FIGURING OUT THE BEST WAY TO DO THIS. I THINK, YOU KNOW, ON AN ACTIVATED CELL EXPRESSION OF THE TWO RECEPTOR IS FAIRLY TRANSIENT AND IF YOU HAVE A HEALTHY REPERTOIRE, AND WHERE IS AS THE T REGS SEEMS TO EXPRESS, IF YOU COME INTO A HOST AND DEPLETE AT A GIVEN POINT IN TIME YOU'RE GOING TO LOSE SOME ACTIVATED CELLS BUT NOT MANY. YOU CERTAINLY WOULDN'T HAVE GIVEN YOUR VACCINE BEFORE THAT TIME AT A GIVEN POINT IN TIME YOU CAN GET GOOD DEPLETION AND THE HOME STATUS OF THESE CELLS THEN MOST OF US WOULD ACCEPT THE COST LOSING WHATEVER WERE PRESENT AT THAT TIME. YOU CERTAIN WANT TO LET THAT CLEAR OUT BEFORE YOU COME WITH YOUR VACCINE THOUGH BUT I DON'T THINK WE'VE IF I CAN OUT THE BEST WAY TO DEPLETE THESE THINGS YET.