>>WE HAVE OUR 3 AFTERNOON
SPEAKERS WHO ANNETTE WILL
INTRODUCE IN A MOMENT AFTER
BRIEF PRESENTATION ON THE
MUCOSAL IMMUNOLOGY STUDIES TEAM.
AND A COUPLE OF ANNOUNCEMENTS I
NEED TO MAKE.
LET'S SEE, ANY INTERESTED MEMBER
OF THE PUBLIC MAY FILE WRITTEN
COMMENTS WITH THE EXECUTIVE
COMMITTEE, SECRETARY OF
COMMITTEE WITHIN 15 DAYS OF THE
MEETING.
THESE COMMENTS WILL BE INCLUDED
IN THE MINUTES OF THE--TO THE
EXTENT PRACTICE RESEARCHICCABLE
AND MAILING AND INFORMATION WAS
PUBLISHED IN THE FEDERAL
REGISTER NOTICE ANNOUNCING
TODAY'S MEETING OF OUR DIVISION
OF ALLERGY AND IMMUNOLOGY AND
TRANSPLANTATION SUBCOMMITTEE OF
COUNCIL.
ANYONE WHO IS SPEAKING MUST BE
ON CAMERA, SO PLEASE MAKE SURE
YOU ACTIVATE YOUR VIDEO IF YOU
INTEND TO SPEAK AND I NEED TO
REMIND OUR STAFF AND COUNCIL
MEMBERS, WE PREFER YOU DO NOT
USE THE CHAT FEATURE OTHERWISE A
FACA RECORD WILL BE CREATED AND
MAKES A LOT OF WORK FOR OTHER
STAFF.
AND I THINK THAT TAKES US UP TO
JUST 1 LAST COMMENT WHICH IS
DOCTORS RANDOLPH AND RAY AND
MR. IDBO ARE LEAVING OUR COUNCIL
AFTER SEVERAL YEARS OF VERY
VALUABLE SERVICE TO THE
INSTITUTE AND AS TONY FAUCI
MENTIONED THIS MORNING, WE'RE
VERY GRATEFUL FOR THAT AND WE
WILL MISS YOU.
SO THANK YOU ALL FOR YOUR
PARTICIPATION OVER THESE LAST
FEW YEARS.
>> IT WAS MY PRIVILEGE TO SERVE.
>> THANKS,.
>> YEP.
>> OKAY.
ANNETTE, WHY DON'T YOU GO AHEAD,
I THINK YOU HAVE SOME SLIDES TO
PROJECT, BACKGROUND ON TODAY'S
SESSION AND WHILE YOU'RE
BRINGING THOSE UP, I WILL JUST
MENTION THAT WE HAVE SEVERAL
CONCEPT CLEARANCES TO GO OVER
LATER IN THE AFTERNOON AND WE
WILL GO THROUGH THOSE AS WE
USUALLY DO.
>> OKAY, IF YOU'RE READY FOR ME,
I WILL START, GOOD AFTERNOON,
EVERYONE, I'M ANNETTE ROTHERMEL,
WITH THE AUTOIMMUNITY MUCOSAL
IMMUNOLOGY BRANCH.
I AM EXCITED TO INTRODUCE THE
SPEAKERS AND THE STUDIES TEAM.
THE MUCOSAL IMMUNOLOGY STUDY
TEAM WHICH IS NICK TAMED MIST
WAS DEVELOPED TO PROMOTE BASIC
RESEARCH LEAD HAPPENING TO
FUNDAMENTAL DISCOVERIES ABOUT
MUCOSAL IMMUNOLOGY.
SO DISCOVERYING NEW CELLS, NEW
PATHWAYS, NEW REGULATORY
MECHANISMS.
THE GOAL WAS TO CREATE A
COLLABORATIVE GROUP OF
SCIENTISTS WITH DIVERSE
EXPERTISE AND WORKING ACROSS A
NUMBER OF MUCOSAL SERVICES WITH
THE IDEA OF SHARING INFORMATION,
CROSS FERTILIZING PROJECTS AND
DEVELOPING KEY COLLABORATIONS.
THE PRSM ITSELF INCLUDES AN
INFRASTRUCTURE AND OPPORTUNITIES
FUND OR IOF AND THIS IS TO ALLOW
TIMELY SUPPORT OF PILOT PROJECTS
ON EMERGING AREAS OF SCIENCE AND
TO SUPPORT EARLY CAREER
INVESTIGATORS WORKING IN MUCOSAL
IMMUNOLOGY.
THE PROGRAM WAS--SORRY.
THE PROGRAM WAS INITIATED IN
2009 WITH SUPPORT FOR
EXPLORATORY AWARDS N2001 THIS
WAS EXPANDED TO SUPPORT SINGLE
COOPERATIVE AWARDS, SO U01
AWARDS AND THIS TIME IT WAS
SUPPORTED BY THE INFRASTRUCTURE
AND OPPORTUNITIES FUND.
THE PROGRAM WAS RENEWED TWICE,
ONCE IN 2006 AND AGAIN LAST
YEAR.
THERE HAS BEEN INCREASING
INTEREST IN FOCUSING VACCINATION
TO GENERATE IMMUNE RESPONSES AT
MUCOSAL SURFACES AND YOU HEARD
ABOUT THAL MORNING IN
DR. FAUCI'S REMARKS AND ALSO IN
DR. HOLLAND'S REMARKS AND THIS
IS OF COURSE UNDERSTANDINGLET
TARGETING IMMUNE RESPONSE OF
PATHOGEN ENTRY IS THE BEST WAY
TO LIMIT INFECTION AND LIMIT
TRANSMISSION.
THE SUCCESSFUL APPROACHES WILL
NEED TO CONSIDER THE
ARCHITECTURE OF THE SURFACE AND
THEIR UNIQUE CELLULAR
COMPOSITIONS AND THESE ARE AREAS
OF INTENSE MUCOSAL IMMUNOLOGY
RESEARCH INCLUDING WITHIN MIST.
FOR EXAMPLE, THE VERY IMPORTANT
TO FULLY UNDERSTAND ANTIGEN
ACQUISITION AT THE MUCOSAL
SURFACE AND UNDERSTAND ANTIGEN
PRESENTING ACTIVITIES AND THE
RESPONSES OF THE UNDERLYING
IMMUNE RESPONSE TO THOSE
ACTIVITIES.
IT'S CRITICAL TO UNDERSTAND THE
ROLE OF INNATE LYMPHOID CELLS
WHICH DOMINATE AT THE BARRIER
SURFACES AND OF COURSE IT'S
IMPORTANT TO UNDERSTAND THE
INNATE ROLES OF THE EPITHELIAL
CELLS THEMSELVES AND THE MUCUS.
WE ALSO KNOW THAT THE MUCOSAL
IMMUNE SYSTEM COMMUNICATES WITH
OTHER SYSTEMS, WE HEARD ABOUT
THAL MORNING AND WE WILL HEAR
MORE TODAY AND WE KNOW THAT THIS
CROSS TALK INFLUENCES IMMUNE
RESPONSES.
SO THIS LEADS US TO THE FACAS
ACCOUNT THAT THERE ARE NO
OPPORTUNITIES FOR COLLABORATIONS
AMONG MUCOSAL IMMUNOLOGISTS AND
VACCOLOGYISTS SEEKING TO ENHANCE
IMMUNITY AT THE SURFACES WITH
JUST A FEW LISTED HERE AND
OBVIOUS OPPORTUNITY IS TO
LEVERAGE THE EXPERTISE OF
MUCOSAL IMMUNOLOGISTS AND MYTHS
AND OTHER DATE SUPPORTED
PROGRAMS SUCH AS THE AIR WAY
BIOLOGY RESEARCHERS IN SAMPLING
AND ANALYZING MUCOSALY IMMUNE
RESPONSES.
THERE'S ALSO AN OPPORTUNITY TO
USE STATE-OF-THE-ART SAMPLE
ANALYSIS, AND SAMPLE SPARING
ASSAYS TO STUDY MUCOSAL
IMMUNOLOGY.
AND ALSO TO TAKE ADVANTAGE OF
THE INTEREST IN ADJUSTICE ACCESS
EXPRENT OTHER FORMULATIONS TO
PROMOTE MUCOSAL IMMUNOLOGY.
AND THERE'S AN OPPORTUNITY TO
STUDY MULTIPLE MUCOSAL SURFACES
BECAUSE THERE THERE ARE VERY
IMPORTANT DIFFERENCES OF THE
ARCHITECTURE OF THE CELLULAR
COMPOSITION AND THE DISTINCT
PATHOGENS AT THESE SURFACES.
WITH THIS, I WOULD LIKE TO
WELCOME OUR SPEAKERS TODAY.
THERE REALLY ISN'T SUFFICIENT
TIME TO DESCRIBE THEIR MANY
ACCOMPLISHMENTS, SO, I WILL BE
BRIEF.
DR. DAVID ARTIS IS THE MICHAEL
COORS PROFESSOR OF IMMUNOLOGY
AND DR. GWENDALYN RANDOLPH AT
CORNELL UNIVERSE AND DR. ARTIS,
FOCUS ON REGULATE ANDA ADAPTIVE
IMMUNE RESPONSES AT BARRIER
SURFACES IN EXPHELGT DISEASE AND
INCLUDE A SIGNIFICANT EFFORT TO
TRANSLATE THESE FINDINGS THAT
ARE FOUND IN PRECLINICAL ANIMAL
MODELS INTO PATIENT BASED
STUDIES OF IMMUNE MEDIATED
DISEASES.
DR. GWEN RANDOLPH IS THE
PROFESSOR OF PATHOLOGY AND
IMMUNOLOGY AT WASHINGTON
UNIVERSITY.
DR. RANDOLPH'S FOCUS HAS BEEN TO
DEFINE THE TRAFFICKING OF
CELLULAR AND MOLECULAR CARGO OUT
OF TISSUES TO THE DISTAL
LYMPHNODE OR DOWN STREAM ORGANS
AND TO UNDERSTAND THE
RELATIONSHIP OF THIS TRAFFICKING
TO CHRONIC INFLAMMATORY
DISEASES.
DR. DEBROSKI HERBERT IS WITH THE
UNIVERSITY OF PENNSYLVANIA
SCHOOL OF VETERINARY MEDICINE
AND PROFESSOR OF IMMUNOLOGY AT
UNIVERSITY OF PENNSYLVANIA.
THROUGH THE STUDY OF PARASITIC
ELEMENTS AND PROTOSWROAA,
DR. HERBERT HAS MADE PROGRESS IN
STUDIES MACROPHAGES AND
RESPIRATORY GI TRACT.
SO WE'RE PLEASED TO HAVE THE
DISTINGUISHED GROUP OF
SCIENTISTS TALK ABOUT WHAT
THEY'RE DOING IN MIST AND WE
WELCOME THEM, DR. ARTIS,
DR. RANDOLPH AND DR. HERBERT.
WITH THIS I WILL CLOSE AND TURN
IT OVER TO DR. ARTIS FOR HIS
FIRST PRESENTATION.
THANK YOU.
>> CAN YOU HEAR ME OKAY?
>> YES.
>> THANK YOU ANNETTE SO I'LL
JUST SHARE THIS SCREEN, LET'S
HOPE THIS WORKS.
CAN YOU SEE IT OKAY?
AND IF WE MAKE IT IS THAT IN
PRESENTATION MODE.
>> YES, THANK YOU.
>> EXCELLENT.
OKAY, THANK YOU DAN, THANK YOU
ANNETTE FOR HOSTING THIS SESSION
AND INVITING US TO TELL YOU A
LITTLE BIT ABOUT WHAT'S
HAPPENING IN THE MUCOSAL
IMMUNOLOGY STUDIES TEAM.
I'LL GO FAIRLY QUICKLY SO WE
STAY ON SCHEDULE.
I'VE HAD THE GOOD FORTUNE OF
HAVING NIAID FUNDING SINCE I
STARTED MY CAREER IN 202004 WAS
AN INDEPENDENT INVESTIGATOR AND
I THINK I ACTUALLY GOT 1 OF THE
THE ORIGINAL MIST R21S BACK IN
2009.
I HAD FOCUS ON THE GOTTEN ABOUT
THE R21 PART BUT I THINK I GOT 1
OF THOSE AS WELL AND I'VE BEEN
EXTREMELY GRATEFUL AND VERY
FORTUNATE TO HAVE WORKED WITH A
BUNCH OF COLLABORATORS OVER THE
LAST 12 OR SO, 13 YEARS.
SO TODAY, I THOUGHT I WOULD GIVE
YOU AN UPDATE ON SOME OF THE
WORK THAT MY GROUP IS DOING AT
THE MOMENT.
PARTLY FUNDED BY MIST AND THE
REGULATION OF IMMUNITY AND
INFLAMMATION OF THE BARRIER
SURFACES.
TODAY I WILL FOCUS PRIMARILY ON
TYPE 2 INFLAMMATION, SO THE
RESPONSE OF COURSE WE SEESHT
WITH ALLERGIC RESPONSES,
IMMUNITY TO HELMET INFECTION,
TISSUE REPAIR AND IN SOME
CIRCUMSTANCES, CANCER.
SO ANNETTE GAVE A VERY NICE
INTRODUCTION AND I USED THIS
CARTOON TO HIGHLIGHT ALL THE KEY
CELLULAR PLAYERS THAT WE THINK
ABOUT OF BARRIER SURFACES LIKE
SKIN, LUNG, GUT AND GI AND
EUROGENERATEDDAL AREA, BUT TOUGH
CELLS, ENDOCRINE CELLS, CELLS IN
THE EPITHELIAL LAYER, OF COURSE
PROFESSIONAL APCs LIKE
DENDRITIC CELLS AND OTHERS, THE
GRANULAR SIGHTS THAT WE
ASSOCIATE WITH TYPE 2
INFLAMMATION, EOSIN O FILLS, AND
BASOPHILS AND T-HELPER SUBSETS.
TODAY I CAN'T TELL YOU ABOUT
EVERYTHING OF COURSE BUT I CAN
FOCUS ON 2 RECENT ADVANCES THAT
HAVE OCCURRED PRIMARILY IN THE
LIFETIME OF MIST, BELIEVE IT OR
NOT SO THE DISCOVERY AND
ELABORATION FUNCTION OF INNATE
LYMPHOID CELLS PARTICULARLY A
BIRRIER SURFACES AND MORE
RECENTLY OUR UNDERSTANDING OF
THE NEWER IMMUNE IRPT ACTIONS
THAT ARE OCCURRING AT THESE
BARRIER SURFACES AND HOW THEY
SHAPE IMMUNITY AND INFLAMMATION
IN TISSUE REPAIR.
SO TRYING TO GIVE YOU A QUICK
OVERVIEW AND THEN I WILL TRY AND
SHOW YOU SOME REALLY, REALLY NEW
UNPUBLISHED DATA SO THIS IS THE
WORLD PREMIER ONLY FOR DAITIs
TODAY.
SO, AND THE REST OF THE WORLD
HAS LOVED IT.
SO INNATE LYMPHOID CELLS IS A
QUICK REMINDER, THEY'RE A
HETEROO GENIUS FAMILY, THEY'RE
FROM A 92 DEPEBDENT PROGENITOR.
THERE'S HETEROGENERATED AITY
WITHIN THE FAMILY, BROADLY THE
NOMENCLATURE THAT'S BEEN USED IS
GROUP 1, 2, 3.
AND INNATE CELLS MARKED BY
DIFFERENT EXPRESSION OF
DIFFERENT TRANSCRIPTION FACTORS,
EXCUSE ME, AND DIFFERENT
SIGNATURE SIGHT SO KINE
RECEPTORS, GROUP 1 INNATE
LYMPHOID CELLS CLUSTER NK CELLS
AND T-BET CELLS THAT PRODUCE
INTERFERON-GAMMA, GROUP 2
EXPRESS HIGH LEVELS AND
SUSTAINED LEVELS OF GATA 3 AND
TH2 ASSOCIATED CYTOKINES IN
GROWTH FACTORS AND GROUP 3,
ASSOCIATED IN INNATE LYMPHOID
CELLS THAT EXPRESS RORGAMMA T
AND R17A AND SOME OTHER PROIN
FLAMMATORY CYTOKINES.
I SHOULD SAY MY CO-PI ON OUR
MIST GRANT IS PROFESSOR GREG
WITH CORNELL AND HE WAS UNABLE
TO BE HERE TODAY AND PRESENTOT
PROJECT BUT WHAT I WANT TO FOCUS
ON IS THE GROUP 2 LYMPHOID CELLS
MARKED AS I SAID BY RECEPTORS
FOR IL25, IL33 AND TSLP.
COURSE THEY ALL EXPRESS
RECEPTORS FOR IL2 AND 7.
THE ILC2 POPULATION OF ALL THE
ILCs IS THE MOST ABUNT ANT IN
THE BODIES, AS FAR AS WE CAN
TELL IT'S THE MOST UBIQUITOUS IN
DISTRIBUTION HIGHLY ENRICHED IN
THE SKIN ALONG THE INTESTINE AND
IN THE WHITE ADIPOSE, BUT FOUND
ON IN ALMOST EVERY TISSUE WE
EVER LOOKED AT, LIVER, PANCREAS,
MUSCLE, ALL OF THE TISSUES, BOTH
IN HUMAN SAMPLES THAT WE HAVEK
HAVE
ACCESS TO AND ALSO IN MODELS.
SO IN 2009-2010 IT WAS IN THE
BRIDGE .3 LABS FIRST REPORTED,
THESE WHAT WE NOW CALL INNATE
LYMPHOID CELLS, THEY MIGHT CALL
THAT AT THE TIME, COLLEAGUES AND
ASSOCIATES IN ENGLANDUTES USING
HELMET MODEL SYSTEMS AS POTENT
PRODUCERS OF IL4, 5, AND 13 IN
DIFFERENT CIRCUMSTANCES IN
DIFFERENT TISSUES AND
SUBSEQUENTLY THERE'S BEEN AN
ENORMOUS EXPLOSION IN INTEREST
OF THESE CELLS, OF COURSE THEY
PLAY AN IMPORTANT ROLE IN
REGULATING FOOD ALLERGY AND
REGULATE SAID INFLAMMATION IN
THE AIR WAYS AND ALLERGY AND
ITCH AND SKIN IN CONTROLLING
ADIPOSE TISSUE, HOMEIO STASES
AND I WILL SHOW YOU A FEW
EXAMPLES OF THOSE BUT JUST TO
SUMMARIZE?
OF THE WORK FROM LABS ALL OVER
THE COUNTRY AND ALL OVER THE
WORLD CONTRIBUTED TO THE
EMERGENCE OF THIS FIELD.
SO 1 OF THE THINGS WE DID VERY
EARLY ON, I'M EMBARRASSED TO SAY
WE NEVER PUBLISHED THIS BUT IT
WASN'T 1 PAPER BUT OUR REVIEWER
TOLD US TO TAKE IT OUT SO WE DO
WAWE'RE TOLD BUT HERE WE DID
EARLY RNA SEQ, WHERE WE SOUGHT
ILCs FROM DIFFERENT TISSUES.
IF YOU LOOK AT THE COLORED BAR
ALONG THE TOP, THE DETAILS DON'T
MATTER BUT THE COLOR COATING
GREENOT LEFT-HAND SIDE ARE
ILC2s, SORTED FROM WHITE
ADIPOSE, RED COLORATION IS THOSE
SORTED FROM THE LUNG, THE GOLD
THOSE SORTED FROM THE COLON, AND
THE LIGHT BLUE COLOR SORTED FROM
THE SMALL INTESTINE.
AND AGAIN THE GENE PATTERNS THAT
MATTER, BUT WHAT'S KEY HERE IS
THAT YOU CAN SEE THESE TISSUE
SPECIFIC SETS OF GENE
EXPRESSION.
SO THESE CELLS ARE DERIVED FROM
A COMMON BONE MARROW DERIVED
LYMPHOID PROGENITOR, THEY SEE
THESE DIFFERENT BARRIER SURFACES
IN OTHER TISSUES DURING
EMBRYONIC DEVELOPMENT, THEY'RE
FAIRLY LONG LIVED AND THEY CARRY
CHARACTERISTICS OF GENE
EXPRESSIONS SPECIFIC TO TISSUE
IN WHICH THEY ARE SEEDED IN
TISSUE AND FOR A LONG PERIOD.
SO THEY SHOULD SOME
CHARACTERISTICS WITH MYELOID AND
OF COURSE WITH LYMPHOID LINEAGES
AS WELL.
SO JUST A FEW EXAMPLES, LAURA
[INDISCERNIBLE] WHO I USED TO
WORK WITH, SHE WAS A RECIPIENT
OF 1 OF THE MISS JUNIOR SCHOLAR,
AWARDS FOR TRANSITION TO
INDEPENDENT INVESTIGATOR, AND IS
NOW FUNDED SHE WAS 1 OF THE
FIRST TO SHOW THE ROLE OF
ILC2s IN THE CONTEXT OF
INFLUENZA INFECTION, NOT HERE IN
IMMUNITY TO THE VIRUS BUT
RAGHTENER TISSUE REPAIR AND
PROTECTION AND SHE SHOWED THAT
NAISLY IN A PAPER THAT IS VERY,
VERY HIGHEE CITED AND 1 OF THE
MOST ILC2 PAPERS CITED AND SHOW
ALL THE EXPRESS LEVELS OF THE
USUAL GENES BUT PARTICULARLY FOR
REGGULEIN AND DECORIN, GENES
THAT WE DIDN'T CLASSICALLY
ASSOCIATE WITH TYPE 2
INFLAMMATION AND SHOWING THE
HISTOLOGY.
IF YOU INFECT MICE WITH
INFLUENZA, OF COURSE YOU GET AIR
WAY, IT'S AS A TROAPISM FOR
EPITHELIAL CELLS, CYTOPATHIC SO
IT KILLS THE EPITHELIUM, SO
THERE'S A LOT OF EPITHELIAL
BARRIER DAMAGE AND A LOT OF
REPAIR IN INFLUENZA, IF YOU TAKE
AWAY ILC2, THAT REPAIRS PROCESS,
THE ESSENTIAL REPAIR PANEL, CAN
YOU SEE THIS IS ALMOST GONE,
THEY DIE OF A NONLETHAL DOSE OF
INFLUENZA AND IF YOU ADD BACK
AMP FORREGUE LYNN, CAN YOU
RESTORE THIS EPITHEL YE REPAIR
RESPONSE.
IN THE ADIPOSE TISSUE, DISTANT
FROM THE BARRIER SURFACES, WE
KNOW THAT ILC2'S PRESENT.
IN FACT THE LARGEST DEPOT OF
ILC2s AND IN HUMAN AND MOUSES
THE WHITE ADIPOSE TISSUE, WE
USED TO THINK IT WAS THE LUNG
BUT MOST OF THEM IN THE STEADY
STATE OR AT LEAST IN THE WHITE
ADIPOSE, WE KNOW IN THE STEADY
STATE THAT THE WHITE ADIPOSE IS
A PREDOMINANTLY TYPE 2
REGULATORY T-CELL TYPE
ENVIRONMENT AND IN THE CONTEXT
OF A BC THERE'S A SWITCH TO MORE
PROINFLAMMATORY CYTOKINE
RESPONSE AND WE KNOW FROM RICH
LOCKSLY, OR OLEFSKY, THEY CAN
MAKE EOH SIN O FILLS IN THE AND
THEN ALSO SHOWING PROTECTIVE
ROLE FOR ADIPOSE RESIDENT
ILC2s THROUGH AN IL13
DEPENDENT PATHWAY PROPOSING THE
BEIGING OF WHITE ADIPOSE WHICH
CONTROLS METABOLISM AND PREVENTS
WEIGHT GAIN ALSO IMPORTANT IN
THERMOGENESIS, AND PLAYING AN
IMPORTANT ROLE BURNING CALORIES
AND PREVENTING OBESITY AND I
WON'T SHOW YOU ALL OF THOSE DATA
JUST IN CARTOON FORM, THE
ILC2s PROMOTE PRODUCTION OF
THE PEPTIDES THAT DRIVE THE
BEIGE AND WHITE DIP O SIGHTS TO
THE WHITE ADIPOSITY AND WEIGHT
GAIN.
BACK TO MUCOSAL BARRIERS HERE IN
THE GUT, WE KNOW THAT ILC2s
ARE PARTICULARLY ENRICHED IN THE
LARGE INTESTINE, AND HERE IN A
MOUSE MODEL AGAIN, WE CAN SEE
THAT IF WE TAKE AWAY THIS TISSUE
PROTECTIVE AND FROM REGUE LYNN,
THESE ANIMALS ARE MUCH MORE
SUSCEPTIBLE TO A MOUSE MODEL OF
INTESTINAL DAMAGE AND
INFLAMMATION DRIVEN BY CHEMICAL
DSS THAT MOST ARE AWARE OF, I'M
SURE IN THE DRINKING WATER AND
HERE IF WE TAKE ON THE KD--SALLY
WHARKS YOU CAN SEE IN THE PANEL
HISTOLOGICALLY GOING TO THE
IMUGOLOGY JUST IN THE INTEREST
OF TIME THESE MICE GET VERY SICK
AND IF WE ADD BACK WILD-TYPE
INSUFFICIENT ILC2s WE CAN
RESTORE THE BARRIER GUT FUNCTION
AND THAT IS LARGELY ABSENT WHEN
WE ADD BACK THE ILC2S FOR THE
REGULATOR.
AND WE ALSO HAVE BEEN ABLE WITH
THE HELP OF MIST FUNDING TO
DEVELOP A TRANSLATIONAL ARM TO
THIS RESEARCH SO WHEN WE MOVE TO
NEW YORK CITY, AND TO CONSENT
PATIENTS THROUGH A COUPLE OF OUR
IRBs, AND TO ACCESS NOT ONLY
PERIPHERAL BLOOD AND SAMPLES FOR
MICROBIAL SEQUENCING AND METRICS
TAB O LOAMICS ANALYSIS BUT ALSO
TAKE LIVE TISSUE BIOPSIES DURING
THEIRENDOSCOPY PROCEDURES AND WE
CAN LIVE TRY O PRESERVE THOSE
CELLS WITH EPITHELIAL CELLS AND
IMMUNE CELLS FOR SUBSEQUENT AND
THIS IS WORK I DO IN CLOSE
COLLABORATION WITH RANDY WALMAN
AND ALSO WITH ELEN SHERYL AND
ROBERT [INDISCERNIBLE].
I HAVE TO APOLOGIZE, I HAVE A
BIT OF A COLD.
SO WE'RE ABLE--I WON'T SHOW YOU
ALL OF THESE DATA, I CAN
IMMUNOLOGICALLY PROFILE A SINGLE
CELL BASIS FROM THE VERY SMALL
INTESTINAL BIOPSIES WE GET FROM
PATIENTS AS WELL, WHICH IS A
EFFORT TO TRACK PATIENTS NOT
ONLY CROSS SECTIONALLY BUT OVER
TIME AS THEIR DISEASE EVOLVES
AND THEY GET DIFFERENT
THERAPEUTIC INTERVENTIONS AND SO
FORTH.
SO BACK TO ILC2s, THEY'RE
REGULATED AND MARKED BY T1 ST2
OR ST2 IN HUMANS, THE RECEPTOR
FOR IL33, THE FAMILY OF
CYTOKINES AND WORK FROM
[INDISCERNIBLE] IN MY LAB SHOWED
A FEW YEARS AGO THAT THE SOURCES
OF IL33, HAVE REMAINED A LITTLE
BIT CONTENTIOUS, WE'VE USED THE
REPORTER MOUSE TO SHOW THAT THE
DOMINANT SOURCES IN GUT AT LEAST
APPEAR TO BE NONHEMATOPOIETIC
CELLS AND THESE STROMAL LIKE
CELLS THAT ARE MARKED BY THESE
DIFFERENT MARKERS SO THIS GAME
IMPORTANT BECAUSE I THINK IN
DIFFERENT TISSUES, THE SOURCES
OF IL33 ARE QUITE DIFFERENT IN
THE SKIN AND THE LUNG FOR
EXAMPLE, THE CELL TYPES THAT
WERE MAKING IL33 CHANGE
DRAMATICALLY, SO I THINK WE'RE
LEARNING THAT EVERY BARRIER
SURFACE OF COURSE IS VERY
DIFFERENT AND NUANCED IN TERMS
OF BASAL CELL INFECTION AND
CONTEXT OF INFLAMMATION, HE
SHOWED VERY NICE MICROSCOPY, I
WILL JUMP OVER THIS IN THE
INTEREST OF TIME BUT HE SHOWED
VERY NICELY THAT ALMOST EVERY
VISCERAL ORGAN THAT WE LOOK AT
IS ENVELOPES IN THIS BARRIER,
LIKE AN INTERNAL BARRIER, ALMOST
LIKE THE EPITHELIAL BARRIERS AT
MUCOSAL SITES AND THOSE
BARRIERS, THOSE MESOTHELIAL
CELLS CAN EXPRESS IL13 AND THEY
ARE MAKING THE PROTEIN BUT
THEY'RE NOT SECRETING IT UNTIL 1
DAMAGES OR INFLAMES THAT
PARTICULAR TISSUE, SO IT PEERS,
THIS PARTICULAR CYTOKINE AND
POISE TO RECRUIT AND ACTIVATE
ILC2s, VERY, VERY RAPIDLY
PRIOR TO THE EMERGING ADAPTIVE
IMMUNE RESPONSE AND MIGHT BE 1
OF THE KEY COMPONENTS OF
INFLAMMATORY AND TISSUE
PROTECTIVE RESPONSES LISTED BY
ILC2s.
SO MECHANISTICALLY, WE'VE BEEN
INTERESTED IN HOW IL33 PROMOTES
THESE ILC2 RESPONSES AND TISSUES
HERE AGAIN, THIS IS WORK DONE BY
ANN FLAMAR, WHICH SHE SHOWED
VERY NICELY, IN VIVO OR EXVIVO
IN IL33 AND LOOKED TO GENE
DIFFERENTIAL EXPRESSION.
ALL THE USUAL GENES ON THE
LEFT-HAND SIDE, AND UPREGULATED
AS YOU WOULD EXPECT, A PRO TYPE
2 ALLERGIC TYPE RESPONSE.
ACTUALLY THE MOST HIGHLY
UPREGULATED GENE FOLLOWING
ACTIVATION WITH IL33 IS THE GTPH
1 WHICH ENCODES THE ENZYME
TRANSCRIPT O FAN HYDROX LACE 1,
WHICH IS 1 OF THE KEY ENZYMES IN
SEROTONIN PRODUCTION WHICH IS A
HINT TO THE NEUROOF IMMUNE
ACCESS THAT I WILL FOCUS ON IN
THE LAST 10 MINUTES OR SO.
WHAT WAS MOST REMARKABLE WAS
WHEN WE GOT THIS RESULT
OURSELVES WE WENT BACK AND
LOOKEDDA THE BETOZITTED RNA SEQ
DATA SETS AND OTHER CELL TYPES
THAT HAVE BEEN REPORTED THAT ARE
STIMULATED WITH IL33 AND THE
PREDOMINANT TRANSCRIPT IN ALL OF
THOSE DEPOSITED DATA SETS WAS
TPH 1, IT WAS LARGELY IGNORE
INDEED THE LITERATURE FOR A LONG
TIME AND I THINK THAT'S
INTERESTING AS WITH RETROSPECT
AS WE LOOK AT THAT AND I WON'T
SHOW YOU THE DAILY BASIS THEA
BUT HERE WE WERE ABLE TO
GENERATE DIFFERENT LINEAGE KNOCK
OUTS FOR TPH 1 AND SHOW A
CRITICAL FUNCTION OF THE PATH
WAAND THE EFFECTIVE ILC2s IN
IN VIVO.
BUT I WILL JUMP OVER THAT FOR
NOW.
ONE TECHNOLOGY TRANSFER I WANT
TO ADD HERE IS THAT A LOT OF THE
WORK WE'VE BEEN DOING IN THE
EXTRAMURAL PROGRAM, WE'VE HAD
GREAT PARTNERS IN THE INTRAMURAL
PROGRAM.
I KNOW THAT'S OFF TOPIC FOR
TODAY BUT I KNOW IT'S PART OF
THE BIGGER CONVERSATION EARLIER
WITH THE LATE [INDISCERNIBLE]
AND RON GERMANE, THEY SHOWED
VERY NICELY DIFFERENT SUBSETS OF
ILC2s WHICH THEY TERMED
NATURAL ILC2s OR INFLAMMATORY
ILC2s AND USING THEIR DATA
SETS THEY WERE ABLE TO IDENTIFY
THE IL13 AND PLAY AN IMPORTANT
ROLE OF RC2s THAT BILL POLE
INTERMED INFLAMMATORY ILC2s
SUBSETS.
IESM VERY HONORED THAT IN A WEEK
OR SO, THE INTERNATIONAL
CYTOKINE SOCIETY WILL BE 1 OF
THE RECIPIENTS OF THE BILL POLE
AWARD FOR CYTOKINE RESEARCH SO
IT'S A GREAT HONOR TO GET THAT
AND TO REMEMBER HIS CONTRIBUTION
TO THE FIELD.
SO IN TERMS OF JUST--WE
SUMMARIZE SO FAR THE REGULATION
AND EFFECTOR FUNCTIONS OF
ILC2s, THIS IS A CARTOON WE
MADE, I'M SURE THERE'S BETTER 1S
THAN THIS BUT THE UPPER PANEL OF
THE EXTRINSIC FACTORS,
CHEMOKINES AND PROSTAGLANDINS WE
KNOW TO BE ACTIVATOR OF THE ILC2
RESPONSE AND DIFFERENT TISSUES
AND THE LOWER PANEL, EFFECTOR
FUNCTIONS, IL5, EOH SIN O
PHILIA, IL13 DRIIVE GOBLET
RESPONSES AND MANY, MANY OTHERS,
BEIGING
BEIGING THAT I MENTIONED AND 2
YEARS AGO WE WROTE THIS ARTICLE
AND IT'S WAY OUT OF DATE ALREADY
BUT I THINK ITY ABOUT BEGINS TO
ELABORATE THE DIVERSITY
FUNCTIONS OF THESE CELLS IN
DIFFERENT TISSUE
MICROENVIRONMENTS.
SO JUST IN THE LAST 5 MINUTES OR
SO, WE'VE BEEN VERY INTERESTED.
WE KNOW THAT THESE CELLS DO SO
MUCH IN DIFFERENT TISSUE
SETTINGS BUT THEY CAN'T BE
ENTIRELY REGULATED BY CYTOKINES
BECAUSE THESE CYTOKINES HAVE
SIMILAR THINGS TO OTHER CELL
TYPES OF THE SAME TIME, SO FIRST
OFF CLOSER JOIN THE LAB A FEW
YEARS AGO AND HE USED THE
MICROSCOPY TO VISUALIZE FOR
ILC2'S WEAR IN DIFFERENT
SITUATIONS, I WILL SHOW YOU THE
MOUSE FIRST OF ALL.
THIS IS ON THE LEFT-HAND SIDE,
SOME CLASSIC OF COURSE AN AERIAL
VIEW LOOKING DOWN AND PROARPIA
OF THE LC MOUSE AND MARKED IN
RED AND WE CAN SEE A DEGREE OF
PROXIMITY AND SELECTIVE
PROXIMITY OF THESE COLONERGIC
NEWONS THAT ARE MARKED BY THE
NEUROPEPTIDE AND NEUROMED AND
YOU.
AND YOU CAN SEE THAT PERHAPS
NICEOT RIGHT HAND SIDE WHEN YOU
CAN USE CLARITY AND YOU
CONSTRUCTIONS OF THE TISSUES, I
THINK GWEN WILL SHOW MUCH NICER
IMAGES THAN I WILL SHOW YOU
TODAY BUT YOU CAN ALMOST SEE
HERE THE UPPER PANEL IF I PAUSE
IT IS THE LUMEN OF THE INTESTINE
AND THE UPPER PANEL IS THE
LAMINA PROPRIA, AND THE
NEUROPOSITIVE NEURONS FOR THE
FLEXUS AND SO FORTH.
YOU CAN SEE THESE ELABORATE AND
SOPHISTICATED EXTENSIONS OF
NEURONS ALL THE WAY THROUGH THE
SOUTHERN MUCOSA TOLET TIPS OF
THE VIIIA, RIGHT TO THE MICROBI
OTA, DIETARY ANTIGENS AND
INFECTIOUS AGENTS AND THINGS ARE
SO I THINK WE'RE JUST BEGINNING
TO UNDERSTAND THIS BIOLOGY.
THIS IS 1 JUST USING LIGHT SHEET
MICROSCOPY WHICH GIVES US NICE
VISUALIZATION, SO LET'S SEE IF
WE CAN STOP THIS GUY, THIS IS
WHERE YOU CAN RECREATE, TAKE THE
ENTIRE INTESTINE.
SO HERE WE'RE LOOKING THROUGH
THE LUMEN OF THE INTESTINE, SO
THE FOOD MATERIALS AND SO FORTH,
THIS IS THE MUSCULARIS ON THE
OUTSIDE AND USING AN IL14
REPORTER IN THE MAX, YOU CAN SEE
AGAIN, THIS ELABORATE NETWORK OF
NEURONS THROUGHOUT THE BARRIER
SURFACE, WHERE IT'S HIGHLY
ENRICHED FOR IMMUNE CELLS IN THE
MICROBI OTA AND SO FORTH, SO
WE'RE ACTIVELY STUDYING THAT
RIGHT NOW.
SO WHAT DOES THIS DO?
WE KNOW IT'S A POTENT ACTIVATOR
OF THESE ILC2s, WE CAN TAKE
THEM OUT OF A MOUSE OR HUMAN.
I WILL SHOW YOU THE MOUSE.
THIS IS USING IL13 REPORTER AND
YFP MOUSE JUST A SURROGATE FOR
ACTIVATION, IF WE GIVE THEM A
BRIEF PULSE WITHIN A FEW HOURS,
YOU CAN SEE A NICE ACCUMULATION
OF IL13 YFP POSITIVE ILC2s AND
WE KNOW THAT'S IN THE MIDDLE AND
WE KNOW IT'S SORT INTRINSIC IF
WE SORT THEM IT LOOKS NICELY.
THIS IS ALL PUBLISHED SO I WILL
GO FAST.
IN VIVO IT'S DRIVING
INFLAMMATION TO OOH LC2s
RESPONSES AND ALSO DRIVES
RESPONSES IN THE GUT SHOWN IN
THE UPPER RIGHT AND CAN DRIVE
IMMUNITY TO A GUT PARASITE
CALLED [INDISCERNIBLE].
THIS IS 1 THAT'S A POTENT
STIMULUS FOR ILC2s IN VIVO AND
A USEFUL MODEL FOR STUDYING
THEIR BIOLOGY.
SO FOR THE NEURONAL PART, WE'RE
BEGINNING TO TAKE APART, WHAT WE
CALL A NEURONAL STIMATTORY AND
INHIBITORS FACTORS THAT ARE
DRIVING TISSUE RESPONSES AND
FOCUSING HERE TODAY ON ILC2s,
AS I SAID BUT THIS COUNTS FOR
OTHER ILC SUBETS AS WELL, SO
THIS WILL BE A LOT MORE TO DO
THAT, THIS IS A SUMMARY OF LOTS
OF OTHER LABS.
SO I WILL END WITH 1 LAST THING
THAT'S BEEN A BIT OF A
CONTROVERSY AS TO WHETHER THERE
ARE REDUNDANT OR NONREDUNDANT
ANT FUNCTIONS BETWEEN INNATE AND
ADAPTIVE LYMPHOCYTES.
SO SOME PEOPLE ARGUED THAT
ILCs ARE THERE AS A SORT OF
EVOLUTIONARY HANG OVER ONCE WE
EVOLVED AN ADAPTIVE IMMUNE
SYSTEM, 1 DIDN'T REALLY REQUIRE
INNATE LYMPHOID CELLS AND
ADAPTIVE LYMPHOCYTES VASTLY
OUTNUMBER ILCs SO PERHAPS
THEY'RE NOT REQUIRED.
IT'S VARIOUS DIFFERENT THINGS
LIKE THAT THAT GO BACK AND FORTH
AND I'M FAIRLY NONPARTIS AN I'M
JUST INTERESTED IN INTO THESE
CELLS WORK
COOPERATIVELY--COOPERATIVELY.
EXCUSE ME A MINUTE.
OR IN AN INTIRELY REDUNDANT WAY.
SO THE WAY WE START THINKING
ABOUT IT IN THE STEADY STATE, OF
COURSE THE LUMEN OF THE GUT IS
ANYTHING BUT STEADY SO CONSTANT
EXPOSURE TO NEW AND KNOWN FOOD
ANTIGENS, THE MICROBI OTA
CONSTANTLY CHANGING, INFECTION,
ALLERGENS, POLLUTANTS AND DRUGS
AND SO FORTH, ALL THESE CELLS
ARE RESIDENT IN THE LAMINA
PROARP RIA AND MUCOSA AND IN THE
EPI-BLAST THELLIAL COMPARTMENT
AND ALONG WITH WHAT WE'RE
UNDERSTANDING ABOUT THE ROLE OF
INNOVATION AT BIRRIER SURFACES
AND OF COURSE THE NEUROLOGISTS
AND NEUROSCIENTISTS WILL TELL
YOU THERE ARE MORE NEURONS AT
BARRIER SURFACES THAN THERE ARE
IN THE BRAIN, IT'S 1 OF THESE
BUT I HEAR ABOUT IT ALL THE TIME
AND WE WERE INTERESTED IF THERE
WERE NONREDUNDANT TWEEZE ILC2s
AND BOTH HIGH PRODUCERS OF IL5
AND IL13 AND RECOMMEND LOTS OF
OTHER SHARED FACTORS.
SO BACK TO THESE 3 PAPERS THAT
WERE PUBLISHED IN 2017 THAT
REPORTED THAT NMU WAS A
STIMULANT OF ILC2s, 1 FROM MY
LAB AND 1 FROM VQ
[INDISCERNIBLE] AND 1 FROM
ENRICKY [INDISCERNIBLE] IN
LISBANE, AND ALL THESE PATES
DIFFERENT WAYS BUT IT SHOWED
THAT ILC2s ARE MARKED BY
WHAT,A PEERS IN THE
HEMATOPOIETIC COMPARTMENT AND
NEEDS TO BE EXCLUSIVE EXPRESSION
OF RECEPTOR 1S IF YOU--THESE ARE
DATA FROM MY OWN LAB AND THE
OTHERS DID SOMETHING SIMILAR, IF
YOU GET THE POSITIVE CELLS ARE
ABOUT 95 TO A HUNDRED% OF THEM
ARE ILC2s, SO THIS WAS
POTENTIALLY A WAY TO TARGET
ILC2s GENETICALLY IN THE
PRESENCE OF A FUNCTIONAL
ADAPTIVE IMMUNE SYSTEM WHICH HAS
BEEN A CHALLENGE FOR QUITE A
WHILE.
HERE'S THE WAY WE DID IT.
WE MADE A MOUSE WHERE WE
TARGETED CREE EXPRESSION TO THE
NMU RECEPTOR TO THE LOCUST AND
THERE'S A GFP TAG IN THERE SO
YOU CAN REPORT AN IMMUNE
RECEPTOR, DELETE THESE CELLS AND
YOU CAN GENE EDIT THEM IF IT
WORKS, SO IT WORKS PRETTY
NICELY, CAN YOU SEE HERE JUST
LOOKING AT IMMUNE RECEPTOR
EXPRESSION BY EGFP.
THEY'RE THE ONLY CELLS WE COULD
FIND ARE ILC2s THAT ARE
POSITIVE SO THE REPORTER SEEMS
TO BE WORKING FOR CREE AND EGFP
AND THAT'S ENUM RATED HERE WHEN
WE LOOK AT EVERY OTHER CELL TYPE
WE THINK OF AND THEN WE CROSS IT
TO A DTR TO ASK IF THIS, THIS
WOULD TELL US IF IT'S A
SUCCESSFUL DELETER AND IT LOOKS
PRETTY GOOD AND IT APPEARS TO
DELETE ACROSS MULTIPLE TISSUES.
WE HAVEN'T UNPUBLISHED THIS
STUFF YET AND THEN WE TOOK AMP O
REGUE LYNN AS A POTENTIAL TARGET
THAT WE KNOW IT'S MADE BY
RC2s, AS WE TOLD YOU EARLIER
ANDY WOO KNOW IT'S MADE BY TREGS
AND TH2 CELLS.
SO WE DID A HEAD-TO-HEAD
DELETION OF REGULATE IN T-CELLS
VERSUS ILC2s AND HERE WE USE
THE DIFFERENT HELMET FOR THIS 1
INHABITS THE LARGE INTESTINE AND
WE GET NICE DELETION OF AMP O
REGUE LYNN AND WE DON'T GET ON
THE CD4, IT'S NOT SHOWN HERE.
BUT HERE WHEN WE LOOK AT
[INDISCERNIBLE] BUSHEDDENS AND
THEREY'S NO DIFFERENCE WITH IF
WE DELETE IT IN THE ILC2s AND
THERE'S SHOWN A HISTOLOGICALLY
AS WELL.
SO I WENT OVER THAT KIND OF FAST
IN THE INTEREST OF TIME BUT I
WILL END BACK WITH THIS CARTOON
AS WE START TO PIECE TOGETHER IN
MY OWN CAREER HOW WE'VE LEARNED
SO MUCH ABOUT THE ROLE OF THE
EPITHELIUM AND SHAPING IMMUNE
FUNCTION THERE.
WE'RE BEGINNING TO REALLY
UNDERSTAND A BIRRIER SURFACES,
HOW NEURONS ARE ALSO SHAPING THE
IMMUNE TONE AND IMMUNOLOGIC
RESPONSE IN THE CONTEXT OF
WHETHER IT'S FOOD OR MICROBI OTA
INFECTION OR ALLERGENS AND SO
FORTH.
AND THE HOPE IS THAT THE WORK
THAT YOU WILL HEAR A BIT FROM
GWEN FROM DEBROSKI IS A SAMPLER
ON IN THE PROGRAM, WHERE THIS
GOES NOT ONLY TO OUR OWN
UNDERSTANDING OF MUCOSAL
IMMUNOLOGY BUT TO PERIPHERAL
TISSUES IN THE CONTEXT OF
INFECTION, VACCINATION, CHRONIC
INFLAMMATION, REPAIR, CANCER AND
MORE RECENTLY PRECISION
NUTRITION AS WE REALLY START TO
THINK ABOUT HOW THIS COULD BE
USED IN CONCERT WITH OTHER
INTERVENTION STRATEGIES.
SO I WILL STOP THERE, LET YOU
READ THE ACKNOWLEDGMENTS BUT
ENORMOUS THANKS TO BOTH AID AND
DDK THAT SUPPORT MY LAB AND MIST
OF COURSE, OUR OTHER FUNDERS ARE
LISTED AND ALL OF OUR
COLLABORATORS.
I DON'T KNOW IF THERE'S TIME FOR
QUESTIONS, I WOULD BE HAPPY TO
TAKE A FEW IF ANNETTE ALLOWS,
THAT'S IT AND APOLOGIES FOR MY
CONGESTION.
>> YES, I THINK THERE'S TIME FOR
A COUPLE QUESTIONS.
I WILL START OFF BY JUST ASKING,
DAVID FOR THOSE REALLY ELABORATE
NEURONAL NETWORKS ARE THEY
DEPENDENT ON THE PRESENCE OF
BACTERIA OR MICROBES IN THE HOST
DEVELOPMENT OR ARE THEY SERVE AN
INNATE--OR IS IT KNOWN, IS IT
EVEN KNOWN?
>> SO THAT'S A GOOD QUESTION, I
WAS MOVING THE SCREEN AROUND.
YOU WERE ASKING IF THE
INNOVATION OF GUT OR OTHER
BARRIER TISSUES ARE MIKE ON BI
OTA ARE DEPENDENT?
GREAT QUESTION.
WE HAVEN'T REDERIVED ALL THE
USEFUL REPORTER INTOS A
GERM-FREE SETTING YET BUT IT
WOULD BE VERY NICE.
WE'VE DONE IT FOR A COUPLE AND
WE'RE DOING IT RIGHT NOW, THESE
INENERIVATION FOR PAIN RECEPTORS
AND COLONERGIC NEURONS APPEARS
TO BE INTACT, I THINK BUT THAT'S
A WHOLE SET OF STUDIES THAT
ABSOLUTELY HAS TO BE DONE.
IT'S A GREAT QUESTION.
>> IF I COULD ASK A QUESTION,
ANNETTE?
>> YES, PLEASE DO.
>> HI, DAVID, WONDERFUL
PRESENTATION AND OF COURSE YOUR
WORK, MY QUESTION IS ABOUT HOW
THE NEUROPEPTIDE THAT'S IN
NEURO[INDISCERNIBLE] AND THE
RECEPTOR COME TOGETHER.
THEY ARE BOTH CONSTITTATIVELY
EXPRESSED IS IT SOLELY TO THE
INSULT AND THAT CAUSES SECRETION
AS A NEUROTRANSMITTER AND THAT
ENGAGES THE RECEPTOR, OR IS
THERE MORE TO IT.
>> HELLO BY THE WAY, HAVEN'T
SEEN YOU IN AGES.
WISH WE WERE IN PERSON, SO TO ME
1 OF THE FUNDAMENTALS OF ALL
THIS IS A BIT OF A BLACK BOX SO
HOW IS THE INNERVATION OF THESE
BARRIER SURFACES IN PARTICULAR
SENSING ENVIRONMENTAL MICROBI
OTA INFECTION, WHATEVER STIMULUS
WE TALK ABOUT, DIET, HOW ARE
THEY SENSING AND HOW ARE THEY
ACTIVATED, IS IT DIRECT,
EPITHELIAL, BUT WHAT WE DO KNOW
IS THAT NOT ONLY ILCs BUT
GRANULAR SIGHTS AND A SUBSET OF
ADAPTIVE LYMPHSIGHTEDS ARE WHAT
APPEARS BY THE IMAGING SO FAR
ARE CONSTITTATIVELY, I DON'T
LIKE TO USE THE TERM CO LOCALIZE
BECAUSE IT MEANS DIFFERENT
THINGS TO DIFFERENT PEOPLE, GWEN
WILL KILL ME IF I GET IT WRONG
AND ALSO--ALSO, YOU KNOW IF YOU
SAY CO LOCALIZE TO A
NEUROSCIENTIST, THEY THINK
IT'S--YOU'RE TALKING ABOUT
SYNAPSE WHICH WE'RE NOT.
I THINK, WHAT I CAN SAY IS
THEY'RE IN--CONSTITTATIVELY IN
CLOSE PROXIMITY APPEARS IN THE
TISSUES SO FAR FROM THE IMAGING
SO IT MAY FOR WHATEVER REASON
THERE'S SOMETHING CONTROLLING
THAT AND REGULATING THAT.
IT'S NOT COMPLETELY STOCHASTIC
BUT THEN, THOSE HEMATOPOIETIC
LINEAGES ARE POISED FOR THE
IMMEDIATE RELEASE OF PREFORMED
NEUROPEPTIDES LIKE NEUROMEDIN
AND CGRP AND ALL THOSE OTHERS
THAT ARE BEING STUDIED, VIP, SO
SO I THINK A LOT TO DO WITH
ANATOMY AS WELL.
BUT I THINK THERE'S OBVIOUSLY
SOMETHING CONTROLLING THAT
PROCESS.
NOW THERE MAY BE SOME SORT OF
SYNAPSE FORMATION, I DON'T KNOW
BUT I DON'T THINK ANYONE KNOWS
THAT YET.
>> ESPECIALLY BECAUSE THE
POSITIVE ACTORS ARE ALSO COUNTER
BALANCED, YOU RAISED THE POINT
TO USE THAT, CGRP AND OTHERS VIP
ARE VERY POSITIVE INHIBITORS
JUST THE WAY
NEURO[INDISCERNIBLE] IS A
POSITIVE ACTIVATOR, AND SOME OF
THE STUFF WE DID WITH JOHN, THAT
WE PUBLISHED LIKE AIER OR 2 AGO,
LIKE UNEXPECTEDLY, CGRP WAS A
POTENT INHIBITOR AND THAT WAS A
REGULATOR OF THAT ADAPTIVE
RESPONSE SO I THINK THERE'S A
LOT MORE DO THERE FOR SURE.
>> THANK YOU.
>> THANK YOU AND I THINK IN THE
INTEREST OF TIME WE NEED TO MOVE
ON.
>> OKAY.
>> THANK YOU DAVID.
>> THANKS A98 AND THANKS
EVERYONE.
>> OKAY, GREAT, LET ME SHARE
AGAIN, IT'S GREAT TO BE HERE AND
IT'S BEEN A PLEASURE TO BE A
MEMBER OF COUNCIL AND
OPPORTUNITY TO PRESENT AND END
THIS ON MY LAST TIME AND REALLY
FANTASTIC.
LET ME SEE THE SLIDES IN THE
APPROPRIATE MODE ONCE I GET THEM
TO THE RIGHT PLACE.
>> YEAH.
>> HERE WE GO.
SO I'M A NEW MEMBER OF MIST I
APPLIED AND CAME ON, YOU KNOW IN
MOST RECENT ROUND.
SO I WANTED TO SPEND A LITTLE
TIME SHOWING YOU WHAT WE STRTED
AND TRY TO REALLY HOW THE MIST
IS WORKING TO BRING
INVESTIGATORS TOGETHER SO BY THE
END, I WILL SHOW YOU A
COLLABORATION THEY STARTED WITH
ANOTHER MIST PI JUST IN THIS 50
YEAR OF FUNDING.
SO MY INTEREST IS IN THINKING
ABOUT TRAFFICKING AS ANNETTE
MENTIONED AND I WANT TO START
THERE BY SAYING THAT I ACTUALLY
THINK THAT THE ANATOMY OF OUR
BODY EVOLVED BENDING TOWARD
IMMUNOLOGY AND THAT THE
ANATOMICAL ARRANGEMENT OF
LYMPHNODE, SPLEEN AND LIVER
CREATE A FORTRESS THAT IS
CRITICAL FOR LIMITING ADVERSE
DISSEMINATION OF MOLECULES AND
SIGNALS THAT MIGHT FOR EXAMPLE
DRIVE SEPSIS, OTHERWISE.
SO WHEN REALLY LOOK AT WHERE
EVERYTHING'S POSITIONED WE LIKE
TO THINK ABOUT LYMPHNODES NOT
JUST AS PLACES THAT INITIATE
ADAPTIVE IMMUNITY BUT ALSO
STRUCTURES THAT FILTER TO
PROTECT THAT CENTRAL BLOOD
STREAM, YOU KNOW FROM DOWN
STREAM EVENTS LIEB SEPSIS.
BUT IN THAT LIGHT, THE INTESTINE
IS A PARTICULARLY POTENTIALLY
PRONE TO DISSEMINATION OF
INFLAMMATORY SIGNALS FROM THE
MICROBIOME AND THE LIVER IS
SITTING THERE, REALLY, YOU KNOW
RECEIVING BLOOD, NOT FROM
LYMPHATICS BUT FROM THE VENUS
CIRCULATION ACTING, I WOULD
ARGUE AS A FILTER.
AND SO, OUR POSITION IN MIST IS
TO--1 OF THE STRUCTURES OF MIST
OF COURSE IS TO THINK ABOUT
BASIC SCIENCE BUT WE WANT TO
THINK ABOUT IT FROM THE CONTEXT
OF UNDERSTANDING HOW REMIGHT
BETTER UNDERSTAND DISEASES OF
CHRONIC INFLAMMATION BY AND
IMPROVING BASIC SCIENCE AND
UNDERSTANDING.
SO THIS VENUS OUTFLOW TO THE
LIVER HAS REALLY CAPTIVATED OUR
ATTENTION ON MULTIPLE FRONTS AND
YOU CAN SEE HERE A MORE DETAILED
CARTOON OF THE SMALL INTESTINE
AND THE COLON AND VENUS SUPPLY
COMING AS THE MAJOR BLOOD SUPPLY
OF THE LIVER.
SO, YOU KNOW IN THE BE CONTEXT
OF THINKING ABOUT CHRONIC
INFLAMMATORY DISEASES, WE KNOW
THAT ANTITNF THERAPEUTICS ARE
HUGELY BENEFICIAL FOR NOT ALL
BUT MANY PATIENTS WHO HAVE
INFLAMMATORY BOWEL DISEASE SO
IT'S RATHER IRONIC AND WE
THOUGHT POTENTIALLY WORTH
EXPLORING BASIC SCIENCE AROUND
WHY ANTITUMOR OR ANTITNF
THERAPIES CAN ACTUALLY IN SOME
CASES INDUCE LIVER INJURY IN
PATIENT WHO IS ARE TAKING THEM
AND RECEIVING BENEFIT AT THE GUT
LEVEL FROM THIS SAME DRUG.
SO IT SEEMS A BIT COUNTER
INTUITIVE AND IT'S THAT KIND OF
COUNTER INATURATIVE SCENARIO WHY
WE THINK WE HAVE PLOAR TO LEARN
ABOUT BASIC SCIENCE.
SO IN THIS CONTEXT AND THE IN
THE CONTEXT OF OUR MIST GRANT
THAT WE'RE IN THE MIDST OF
LAWNCHLING 1 OF THE THINGS THAT
WE DID WAS USE MOUSE MODELS OF
INFLAMMATORY BOWEL DISEASE THAT
ARE DRIVEN BY TNF, 1 OF THOSE
ARE THE TNF ALTASDA ARE MOUSE
THAT'S BEEN IN THE LITERATURE OF
THE MOUSE MODEL FOR A COUPLE OF
DECADES, AND ALSO SMALL BOWEL
RESECTION, SO RADICAL SMALL
BOWEL RESECTION IN MICE IS
MIMICKED TO--IS MEANT TO MIMIC
THAT TYPE OF RESECTION THAT
OCCURS SOMETIME IN KIDS AFTER
NECK ROUGH ATOMITIZING ENTERIC
COLITIS AND IN THAT CONTEXT WE
KNOW THAT 1 OF THE MOST DOWN
STREAM PROBLEMS OF KIDS HAVE
MASSIVE SMALL BOWEL RESECTION IS
ACTUALLY LIVER FAILURE SO WHAT
INTERESTED US IS THAT ANTITNF
THERAPEUTICS, SO THESE ARE MOUSE
MONOCLONAL ANTIBODIES TARGETING
TNF, ACTUALLY INCREASED THE
PRESENCE OF BACTERIA THAT WE
COULD RECOVER, FROM THE LIVER
EITHER IN THE ILIATIC MODEL OR
IN THE SMALL BOWEL RESECTION
MODEL AND CONSEQUENTLY WE ALSO
SEE ELEVATED CYTOKINE RNA, SO
THIS WAS JUST, YOU KNOW BACTERIA
AS IT STOOD IN THE MOMENT THAT
WE SACRIFICED THE ANIMAL SO WE
ALSO TRIED AN ORAL LAUGHERAGE
THAT WE COULD TRACK USING
RESTRICTION ELEMENTS AND INDEED
AFTER GIVING A LAVAGE OF
CLEBSIELLA, WE WOULD FIND THAT
ANTITNX THERAPY WOULD INCREASE
THIS LIVER TRANSLOCATION OF
KLEBSIELLA, SO WE GOT INTERESTED
IN WHAT'S GOING ON UPTREME AND
HOW COULD THEY RESPOND
DIFFERENTLY FROM THE LIVER AND 1
THING WE NOTICED THAT VENUS
OUTFLOW I'VE BEEN DISCUSSING BY
THE LIVER GOING BY THE PORTAL
VAIN.
NORMALLY, THIS REALLY SURPRISED
US BUT LEUKOCYTE COUNTS IN THE
PORTAL VEIN APREVIATED HERE AS
PV, ARE ACTUALLY 2 OR 3 OR 4
FOLD ELEVATED COMPARED WITH
OTHER SYSTEMIC VENUS VESSELS AND
THIS INCLUDES, NUTRIFILLS AND
MONOCYTES AND ALSO LYMPHOCYTES,
AND SO HERE YOU CAN SEE THAT
ELEVATED INCREASE AND IT'S
BLUNTED BY ANTITNF SO IT LOOKS
LIKE IT'S INHIBITING
INFLAMMATION BUT WE'RE CURIOUS
IF IT MAY BE HOW COULD IT BE
DRIVING LIVER FAILURE, 1 OF THE
THINGS OR LIVER INFLAMMATION, 1
OF THE THINGS THAT WE WERE
WONDERING IS COULD IT BE THAT
THIS ENHANCED LEUKOCYTE COUNTS,
YOU KNOW IS IT MAYBE ROLLING OF
LEUKOCYTES ON THE ENDOTHELIUM.
AND SO, 1 OF THE THINGS THAT
WE'VE DONE IS WE'VE PUT TNF
RECEPTOR KNOCKOUT MICE, WE PUT
WILD-TYPE MARROW BACK INTO
DIFFERENT RECIPIENTS SO WE'RE
TRYING HERE IN TNF RECEPTOR
KNOCKOUT MICE TO GET
NONHEMATOPOIETIC CELLS LIKE
CELLS DELETED OF TNF RECEPTOR
AND WHAT YOU CAN SEE IS THAT YOU
DO NOT GET A COMPLETE REVERSAL
OF THIS ELEVATED PORTAL VENUS
ACCOUNT BUT WE GOT A PARTIAL
REVERSAL, ESPECIALLY WHEN
THEY'RE BOTH MISSING AND FOR
MONOCYTES IT'S QUITE IMPRESSIVE
REVERSAL OF THAT ELEVATION, SO
THIS IS ALSO A THING THAT WE
SEE, IF WE BLOCK CLASSICAL
ADHESION MOLECULES THAT WOULD BE
INVOLVED IN LEUKOCYTES AND
INTERACTIONS ON HE'S VESICLES,
SO IF WE CLOCK BETA 1 AND 2
INVOLVED LEUKOCYTE TRAFFICKING
WE CAN SEE THAT NUTRIFILLS AND
MONOCYTES COUNTS ARE REDUCED IN
THE MORTAL VEIN AND THIS RESULTS
IN MORE OF THE GAFFAGE BACTERIA
REACHING THE LIVER.
SO OUR MODEL IS WHAT WE'RE IN
THE MIDDLE OF TESTING USING
INTRA VILAL IMAGES IS THAT TNF
THAT'S MADE FROM THE INTESTINE
IS NOT ALWAYS JUST DRIVING
INFLAMMATORY DISEASE BUT IT
ACTUALLY ALSO ACTIVATES THE
MESENTERIC OUTFLOW DEEP VAIN IN
A MANNER THAT FACILITATES A BIT
OF LEUKOCYTE ROLLING WHICH YOU
CAN SEE HERE IN OUR INTERVITAL
IMAGES IN THE LOWER PANEL WE PUT
20 PANELS TOGETHER TO SHOW YOU
THE TRACKINGS THAT LEUKOCYTES
MAKE AND THAT THAT ROLLING
ACTUALLY ALLOWS FOR PHAGOCYTES
BETWEEN THE INTESTINE AND THE
LIVER TO PICK UP PHAGOCYTIC
CARGO AND CONSUME IT BEFORE IT
ARRIVES TO THE LIVER AND IN THAT
WAY, YOU KNOW TNF DOES HAVE A
ROLE PROTECTING THE LIVER SO AIM
1 OF OUR GRANT IS TO DIVE INTO
THAT IN A DEEPER WAY AND REALLY
TEST THIS CONCEPT THAT
PHAGOCYTES THAT DON'T EVEN LEAVE
THE BLOOD STREAM BUT SIMPLY ROLL
ALONG THE BLOOD VESSELS MAY HAVE
A ROLE OF LIMITING DISSEMINATION
OF MICROBES FROM THE GUT TO THE
LIVER AND WE THINK THIS MIGHT
HELP US UNDERSTAND SOME OF THE
48URES OF ANTI[INDISCERNIBLE]
THERAPEUTICS THAT ARE PUZZLING.
SO NORMALLY WE THINKING ABOUT
THE LYMPHATIC OUTFLOW FROM THE
INY TESTINE AND OURY
SOPHISTICATED OUR MOVE TO THINK
ABOUT THE BLOOD VASCULATURE IS
NEW, SO HERE I SHOW YOU THE
MESSENTERIEN TARY, ACTUALLY
DAVID BROUGHT UP THE MESOTHELIAL
CELLS SO MESENTERIC THATCH LINED
BY THE CELLS AND HOUSING ALL THE
LYMPHNODES IN THE GUT AND ARE IN
THE GUT AND WE'VE BEEN
INTERESTED IN THOSE AND IN THE
CONTEXT OF CROHN'S DISEASE, WE
KNOW THESE LYMPHATICS THAT ARE
FOUND IN FAT NOT ONLY EXPAND
THEMSELVES BUT THAT TERTIARY
LYMPHOID ORGANS DEVELOP ALONG
THE LYMPHATIC TRACKS THAT FEED
DOWN TO DRAINING LYMPHNODES AND
IN MOUSE MODELS WHAT WE HAVE
BEEN ABLE TO SEE IS THAT YOU
HAVE THE TNF DELTA ARE MOUSE
DEVELOPS THOSE STAIN TYPES WITH
TLOs ALONG WITH LYMPHATIC AND
WE END UP CONVERTS WHAT IN A
WILD-TYPE SCENARIO WOULD BE
MOVEMENT OF TRACER THAT HERE WE
INJECT THE PATCH DOWN TO THE
DRAINING LYMPHNODE THIS, IS A
VERY NORMAL PROCESS THAT TAKES
JUST A FEW MINUTES.
IF THESE TLOs DEVELOP FROM THE
CONTEXT OF CROHN'S LIKE ILEITIS,
THE TRACER COOPERATE PASS
THROUGH THE TLO, NEVER MAKE ITS
TO THE LYMPHNODE AND ACTUALLY
THE CARGO INSIDE THAT ENDS UP
LEAKS OUT AND WE EVEN HAVE BACK
FLOW AND WE THINK THAT SOME OF
THESE FEATURES MAY DRIVE SOME OF
THE PATHOLOGY BUT ON THE OTHER
HAND THEY PREVENT DISTEMNATION.
SO BACK TO THAT DISSEMINATION
CONCEPT.
SO I WANT TO SWITCH GEARS JUST A
LITTLE HERE AND SAY THAT AS WE
WERE THINKING ABOUT OUTFLOW FROM
THE GUT IN THE CONTEXT OF
CROHN'S DISEASE, I PAPER THAT
REALLY STRUCK US AS REALLY
INTERESTING WAS THAT OF A STUDY
CONDUCTED BY LEE VINCENT FROM
CINCINNATI WHERE HE WAS STUDYING
THE PEDIATRIC IBD SO CALLED RISK
COHORT.
AND YOU CAN SEE FROM THIS
PUBLICATION FROM 2014 A NUMBER
OF GENES THAT ARE ELEVATED AS
DISEASE BECOMES MORE SEVERE, SO
CD STANDS FOR CROHN'S DISEASE
AND DI FOR ULCERING FOR SEVERE
CONVERSION BUT WE CAN ALSO SEE
IS SOME OF THE MOST DOWN
REGULATED GENES ARE ASSOCIATED
WITH LIP O METABOLISM.
SO BEFORE JOINING OTHER
YAIRPINGS OF CHRONIC
INFLAMMATION THAT WE HAVE
STUDIED HAVE INVOLVED
CARDIOVASCULAR DISEASE AND
THINKING ABOUT FLIEK O PROTEINS
AND WE WERE INTRIGUE BODY THIS.
THE FIRST THING YOU THINK ABOUT
IS WELL, OKAY, GUT IS
TRANSPORTING FAT THROUGH THE
LYMPHATICS AND A LOT OF THESE
PROTEINS THAT GET DOWN REGULATED
IN CROHN'S DISEASE ARE
ASSOCIATED WITH FAT ABSORPTION
OF NUTRIENTS.
SO HERE'S A PICTURE OF THE
TRIGLYCERIDES AND CHOLESTEROL
THAT YOU BRING INTO THE ENTERO
SIGHT AND APO B AND APOAC1 ALL
CONVERGE ON THIS MICRON TO
ASSEMBLE THE FAT SO THAT THEY
CAN COME AS THIS PARTICLE INTO
THE ABNORMALITIES LIMINAL SPACE
SO THIS IS HOW YOU ABSORB FAT.
SOPHISTICATED WE THOUGHT MAYBE
THE MEANING OF THESE DATA ARE
THAT YOU CAN'T TRANSPORT FATS
NORMALLY IN CROHN'S DISEASE BUT
WE ACTUALLY CARRIED OUT A STUDY
IN HUMAN CROHN'S PATIENTS USING
STABLE TRACERS WHERE WE COULD
ATTRACT THE APPEARANCE OF THE
TRIGLYCERIDES INTO THE PLASMA
AFTER IT GOES THROUGH LYMPHATICS
AND GOES THROUGH THE EMILY NODES
AND HITS PLASMA AND WE FOUND
THIS IS NORMAL IN CROHN'S
DISEASE AND THAT MAKES SENSE
BECAUSE ABSORPTION OF MICRONS
HAPPENS REALLY PROXIMAL IN THE
GUT TO THE ILIUM BUT IT WAS AN
IMPORTANT THING THAT TO RULE OUT
AND IT CAUSED US TO THINK THAT
THESE GENES MIGHT BE MORE ABOUT
OTHER GLYCOPROTEINS SO WE DO
KNOW THAT CROHN'S PATIENTS HAVE
A DECREASE IN HDL CHOLESTEROL, A
DIFFERENT TYPE OF PROTEIN, A
TYPE OF PROTEIN HAVE YOU
MEASURED BY YOUR DOCTOR WHEN YOU
MEASURE YOUR CARDIOVASCULAR
HEALTH.
AND INTERESTINGLY THIS IS KNOWN
TO BE DECREASED IN CROHN'S
PATIENTS.
SO HDL AGAIN IS NORMALLY--HOLD
ON HERE, I DIDN'T MEAN TO DO
THAT.
I'M SORRY.
I NEED TO MOVE THIS OVER AND I
DON'T KNOW WHAT I DID HERE HERE,
HERE WE GO, IS NORMALLY MADE BY
THE LIVER AND ENTERS THE BLOOD
STREAM AND WHAT WE KNOW THE
TISSUE INTERACTS WITH THE TISSUE
CELLS TO OTHERWISE BE TOXIC AND
IT PICKS UP IT THROUGH ABCAC1
TRANSPORTER THAT DONATES
CLEFTERAL 2 HDL PARTICLES.
AND IN MOST TISSUES AND WE
WORKED ON THIS MANY OTHER
TISSUES, LIKE SKIN, ARTERY WALL
IN THE PAST, THIS HDL WILL CARRY
THAT CHOLESTEROL OUT AND
DISSEMESTER NAT OUT OF THE ORGAN
VIA THE LYMPHATICS AND
EVENTUALLY WILL BRING THIS BACK
TO THE LIVER FOR PRODUCTION OF
BIOACIDS BUT WHATIA NOT SHOWN ON
THIS CARTOON IS THAT WE'VE KNOWN
SINCE THE 1970S THAT THE
TRANSPORTER AND KEY PROTEIN
APOA-1 THAT FORMS AT NASCENT HDL
IS MADE BY THE SMALL INTESTINE.
AND SO YOU WOULD THINK BASED ON
THE FACT THAT YOU KNOW YOU HAVE
THIS BEAUTIFUL LYMPHATIC IN
EVERY VILLUS THAT THE HDL OF THE
INTESTINE WOULD GO OUT THROUGH
THE LYMPHATIC AND IN FACT IN THE
LITERATURE LIKE THIS REALLY NICE
ARTICLE THAT WAS PUBLISHED
SEVERAL YEARS AGO ASSUMED THAT
ALL DPLIEK O PROTEINS NOT JUST
[INDISCERNIBLE], BUT HDL MADE BY
THE INTESTINE GOES INTO THE
LIMP.
BUT IT COULD BE DIFFERENT IN THE
SMALL INTESTINE SO THINKING
ABOUT AGAIN ABOUT THE
SPECIALIZED FEATURES OF
DIFFERENT REGIONS OF THE GUT, WE
KNOW THIS HAS THE VASCULATURE
THAT OVERLIES THE AREA, SO IT
COULD BE THAT HDL DON'T FOLLOW
THE RULE OF GOING INTO
LYMPHATIC.
SO TO LOOK AT THIS WE ACTUALLY
MADE A MOUSE SEVERAL YEARS AGO
WHERE WE CAN PHOTO TAG HDL
WITHIN TISSUES BECAUSE THE HDL
THAT MADE HAS A PHOTO
ACTIVATABLE GFP DOMAINOT END
TERMINUS SO WE CAN SHINE THE
LIGHT ON DIFFERENT ORGANS AND
FOR EXAMPLE, WITH WHEN WE SHINE
LIGHT ON THE SKIN AND PAST, WE
WOULD TAKE THE FLUID OUT OF THE
SKIN AND SEE THIS FLUORESCENT
HDL BUT IF TIME PASSED WE WOULD
SEE THAT THAT FLUORESCENT HDL
WOULD MOVE OUT INTO THE SKIN OUT
OF THE SKIN AND INTO PLASMA.
YOU CAN SEE THAT TIME COURSE
HERE AND IN THIS CASE, THIS IS
LYMPHATIC DEPENDENT WHICH I'M
NOT SHOWING YOU BUT IN THE GUT,
WE FOUND--WE USE THE SAME TOOL.
WE LIT UP, WE CUT A LITTLE SLIT
INTO THE LUMEN OF THE INTESTINE
SO WE COULD LIGHT UP THE
INTESTINAL PRODUCED HDL AND WE
FOWBD THAT THE FLUORESCENCE
ENDED UP IN THE PORTAL VEINS AND
NOT THE LYMPHATICS IN THE FIRST
FEW MINUTES AND IT WAS NOT UNTIL
30 MINUTES WENT BY WHEN THE
WHOLE BODY COULD EQUILIBRATE
THAT WE WOULD SEE THAT THE HDL
WAS IN EVERY COMPARTMENT SO WE
CONCLUDED THAT THE INTESTINE
MAKES HDL AND PUTS IT DIRECTLY
INTO THE VENUS VASCULATURE TO
THE LIVER, NOT AT THE LYMPHATIC
AND IT ACTUALLY ONLY GOES INTO
THE LYMPHATIC WHEN IT LATER
ARRIVES FROM THE INTESTINE FROM
A LOCATION, SAY AS IT COMES IN
FROM THE MUSCLE SIDE.
NOW, WE ALSO WOULD FIND THAT THE
MAIN PRODUCTION OF HDL WAS AT
THE ILIUM, SO IT SEEMS AS THOUGH
HDL IS GOING TO THE PORTAL VEIN,
NOT THE LYMPHATICS AND MAYBE
IT'S REALLY BEING GENERATED IN A
PLACE WHERE YOU START TO SEE A
RICHER MICROBIOME LIKE THE ILIUM
SO IS THERE A ROLE IN HOST
DEFENSE FOR THIS HDL AND
PARTICULARLY PERHAPS HOST
DEFENSE OF THE LIVER SINCE IT
ENDS UP IN THIS PORTAL VENUS
VASCULATURE.
AND SO WHAT WE ENDED UP FINDING
BY SPECIFIC DELETION OF HDL FROM
THE INTESTINE, ET CETERA IN
ADDITION TO THE MODEL OF PHOTO
ACTIVATION THAT I JUST SHOWED
YOU, IS THAT HDL THAT'S MADE BY
THE SMALL INTESTINE IS ENTERING
THE PORTAL VAIN AND IT'S
ASSOCIATING WITH SPECIFIC CARGO
AND 1 OF THOSE IS LPS BINDING
PROBETWEEN OR LBP AND INSTEAD OF
WHEN IT ARRIVES TO THE LIVER,
INSTEAD OF THE LBP PRESENTING
LPS TO TLR4 TO DRIVE
INFLAMMATION THAT YOU MIGHT
EXPECT, IN FACT, IT'S HIDING THE
LPS, SO SOMEHOW ON THIS PARTICLE
AND WE'RE VERY INTERESTED IN THE
STRUCTURE OF THIS, THE LPS GETS
HIDDEN BY HDL AND THIS ACTUALLY
PREVEBTS FLAMMATION AND WE CAN
SO THIS DRAMATICALLY PROTECTS
THE LIVER IN THE SMALL SECTION
MODEL BUT IT LEAVES THIS BIG
QUESTION, WHICH IS OKAY, THE
INTESTINE IS MAKING AND THE
ILIUM IS MAKING HDL TO
NEUTRALIZE LPS, AND PROTECT DOWN
STREAM TISSUES, YOU MIGHT THINK
PLACES LIKE THE COLON WHICH HAVE
LOTS OF LPS WOULD MAKE EACH MORE
HDL, BUT IF YOU LOOK AT SINGLE
CELL SEQUENCING DAT THAT'S NOT
WHAT YOU SEE, THE COMPONENTS
LIKE APO1, ARE SEEN WELL IN THE
ILIUM BUT NOT THE COLON.
SO WE WERE ALSO CURIOUS ABOUT
THIS CONUNDRUM AND INCORPORATED
SOME PLANS TO DO BASIC RESEARCH
TO BETTER UNDERSTAND WHY COLON O
SIGHTS DON'T MAKE IT AND JUST TO
REVIEW, YOU KNOW WE TALKED ABOUT
THE FACT THAT EVERY VILLUS IN
THE SMALL INTESTINE HAS THIS
LYMPHATIC SO IT'S INTIMATE, NEAR
THE SURFACE AND THEN THERE'S
ALSO A POETIC TEBTIAL FOR
ABSORPTION IN THE SMALL
INTESTINE SO THE COLON OF COURSE
IS DIFFERENT AND THE STRUCTURE
OF THE COLON, YOU KNOW DOESN'T
NECESSARILY HAVE A LYMPHATIC IN
EVERY, YOU KNOW SCRIPT SPACE OR
DOES IT.
AND THIS IS WHAT WE ALSO BEGAN
TO REALIZE IS THAT WE DON'T
REALLY UNDERSTAND THE 3
DIMENSIONAL ORGANIZATION OF THE
COLON WITH RESPECT TO OUTFLOW
VESSELS LIKE LYMPHATICS.
SO THIS CARTOON HERE ON THE LEFT
DOES NOT DEPICT ANOTHER MAJOR
FEATURE OF THE COLON WHICH ARE
THESE KIND OF, THESE FOLDS,
WHICH ARE KNOWN IMPORTANT
FEATURES OF THE COLON, SO WE'VE
UNDERTAKEN A CLEARED APPEAR TO
LOOK AT 3 DIMENSIONAL STRUCTURES
OF THE LYMPHATICS, THEY'RE IN
GREEN, THE BLOOD VESSELS ARE IN
RED SO WHEY WANT YOU TO NOTICE,
I'M GOING FASTER THAN I WAS
THINKING IT WOULD, IS THAT IN
FACT THE RED GOES VERY CLOSE TO
THE SURFACE BUT MOST OF THE
LYMPHATICS ARE DOWN BELOW THE
KREBS, THEIR ONLY EXPRESSION TO
THIS IS THERE ARE A FEW LITTLE
TRANDS, SO THIS IS CLOSER TO THE
MUSCLES DOWN HERE, AS SOON AS WE
GET BACK TO THE EPITHELIAL,
THESE FEW STRANDS, THERE ARE A
FEW SPACES IN THOSE FOLDS, WHERE
THE LYMPHATICS WILL COME CLOSER
TO THE SURFACE.
SO, WE'RE CURIOUS ABOUT THOSE
AND THERE'S LOTS MORE TO LEARN
BUT OVERALL, WE CAN DEFINITELY
SAY THAT THE COLON IS DESIGNED
TO PUT AT A DISTANCE, YOU KNOW
THE VESSELS THAT WILL BE
INVOLVED IN ABSORPTION.
SO WE'RE TRYING TO FIGURE OUT IF
THAT, PLUS THE FACT THAT THE
COLON IS NOT ABSORBED AND THE
EXTRA MUCUS MIGHT REALLY CHANGE
HOW LPS AND OTHER CARGO ARE
TRANSPORTED FROM DIFFERENT
REGIONS OF THE GUT BUT I JUST
WANT TO END HERE BY SHOWING YOU
AN EVOLVING VIEW AND POINTING TO
THIS COLLABORATION THAT WE JUST
START BIDE INTERACTING WITH
GROUPS IN THE MIST ANDOOSE
REALLY AN EVOLVING VIEW AROUND
THE QUESTION OF WHAT ELSE IS
UNIQUE ABOUT THE ILIUM THAT
MIGHT BE LINKED TO HDL
BIOGENESIS SPECIFICALLY THERE,
AND YOU KNOW DISTINCTLY IN THE
COLON.
SO WE WENT BACK TO SOME OF OUR
DATA, IN THE GUT, YOU KNOW, THE
DATA WE LOOKED AT IN HDL WAS
REALLY MOSTLY IN THE LIVER AND
IN THE SMALL BALB RESECTION, WE
REALIZED WHEN THE INTESTINE
CANNOT MAKE HDL, THE GUT WAS
DOWN REGULATING INTERESTING
GENES IN CELLS AND ENTERO
ENDOCRINE CELLS, ET CETERA, ET
CETERA THAT ARE LISTED HERE SO
WE DO THINK THAT HDL AT THE
ILIUM PLAYS A ROLE AT LEAST IN
THE CONTEXT OF INFLAMMATION AND
I WOULD SAY SMALL BOWEL
RESECTION, INJURY TO THE
INTESTINE.
IN REGULATING OUTCOMES THERE.
I WANT TO POINT OUT THAT, YOU
KNOW THE BIOACID TRANSPORTERS
WERE NOT CHANGED.
HOWEVER, WHEN WE SET OUR SIGHTS
ON DOING 3 DIMENSIONAL
RECONSTRUCTION BY IMAGING OF
SOME OF THESE MEDIATORS AND
DIFFERENT TYPES OF EPITHELIAL
CELLS, [INDISCERNIBLE] WHO WAS
DOING THIS IN THE LAB SAID WE
CAN'T DO IT BECAUSE THE TISSUES
DISSOLVE.
ONLY THE KNOCK OUT, THE HDL
DEFICIENCY IN THE IMIUM TUMLY
DISSOLVED.
SO WHEN WE DISCOVERED THAT THE
TISSUE WAS DISSOLVING WE
IMMEDIATELY THOUGHT, OH, WOW,
THOSE ACIDS MIGHT BE REALLY
DIFFERENT.
SO ANOTHER COLLEAGUE IN MIST IS
[INDISCERNIBLE] WHO JUST MOVED
TO DARTMOUTH AND HE'S BEEN
WORKING ON ILEITIS AND HERE'S 1
OF HIS CORTOONS THAT REVIEWS FOR
YOU, WHEN THE LIVER MAKES
BIOACIDS THEY GET MOVED THROUGH
THE BILE DUCT AND IN THE ILIUM,
THEY'RE ACTIVELY REABSORBED AND
ONLY A SMALL PROPORTION ENDS UP
IN THE COLON AND OF COURSE
THEY'RE UNDERGOING ALL KIEFNEDS
OF MODIFICATIONS, HYDROXALATION
AND OTHERS IN THE MIC ROW BIOME
BUT HE HAS POINTED OUT THAT
BIOACID TOXICITY IS A REAL
POETIC TEBTIAL PROBLEM AT THE
ILIUM, THEY DISSOLVE, TISSUES
FOR EXAMPLE AND THEY CREATE A
NUMBER OF [INDISCERNIBLE]
STRESS.
SO ANOTHER FIGURE FROM HIS
REVIEW SHOWS T-CELLS HERE,
EXPRESSING THIS TRANSPORTER MDR
1 WHICH ACTUALLY PROGRAMS
T-CELLS TO RESIST BIOACID
TOXICITY AND IT TOO IS IN THE
ABC FAMILY, IN THE ABC FAMILY
MEMBER, BUT IT'S NOT ABCAC1, THE
CHOLESTEROL TRANSPORTER BUT
HERE'S A PICTURE OF HIS PAPER
WHERE HE REVEALED THAT NDR 1 OR
ABC 1 EXPRESSION BY T-CELLS
ACTUALLY IS CRITICAL FOR
REDUCINGOXIDATIVE STRESS, TNF
INDUCTION IN THE CONTEXT OF
ILLUMINATE YIETIS.
IT'S POTENTIALLY A REALLY
IMPORTANT FEATURE OF CROHNS
DISEASE SO WE HAVE NOW GONE INTO
THE MOUSE THAT CANNOT EXPRESS
INTESTINAL HDL BECAUSE IT LOOKS
ADCA 1 AND BLOCKS ACROSS THE
CREE AND WE'VE PROFILED DEEPLY
PROFILED BIOACID AND I JUST WANT
TO SHOW YOU A LITTLE SNIPIT OF
THIS DATA HERE.
AT THE ILIUM, NOT AT THE LIVER,
BUT AT THE ILIAL TISSUE, YOU CAN
SEE THAT PRIMARY BIOACIDS ARE
REALLY STUCK THERE IN THE
TISSUE, COMPARED WITH THE LITTER
MATE.
AND INDEED, IF WE LOOK AT A
BUNCH OF DIFFERENT COMPARTMENTS
FROM THE ILERAL CONTENTS TO THE
FECAL CONTENTS AND OTHER PLACES
LIKE PORTAL PLASMA AND SYSTEMIC
PLASMA IT APPEARS QUITE CLEARLY
THAT IF THE EPITHELIAL CELLS ARE
ABC1 NEGATIVE THAT THE TISSUE
EPITHELIAL CELLS JUST REALLY
HOLD ON TO THESE PRIMARY
BIOACIDS AND THAT'S CLEARLY WHAT
CAUSED OUR TISSUE TO DISSOLVE
AND WE THINK THIS WILL BE REALLY
IMPORTANT IN THINKING ABOUT THIS
CONNECTION OF DPLIEK O PROTEIN
MEDIATORS TO CROHN'S DISEASE SO
KIND OF BACK TO THIS.
SO THE BIG QUESTION FOR US AT
THE MOMENT IS IF ILIAL HDL IS
LINKED TO BIOACID HANDLING.
IF LOOKS LIKE IT FROM THE ADA 1
STANDPOINT, WE'RE IN THE MIDST
OF THIS, THERE'S NOTHING IN THE
LITERATURE ON THIS, WE HAVE AN
APOAC1 FLOCKS MOUSE, WHERE WE
CAN SEPARATE IS THIS HDL OR IS
THIS TRANSPORTER DOING SOMETHING
INDEPENDENT.
ALL OF IT IS INTERESTING AND
WOULD BE SURPRISING.
SO JUST TO END, YOU KNOW OUR
SECOND AIM, AS WE LAUNCHED THIS
INTERACTION WITH THE MIST GROUP
IS TO THINK ABOUT DISTEMNATION
OF MOLECULAR MEDIATORS WHERE OUR
FIRST THING WAS MORE ABOUT
LEUKOCYTE TRAFFICKING FROM THE
GUT.
SO, HAPPY TO END THERE.
I THINK I USED UP PRETTY MUCH
THE WHOLE 30 MINUTES OF MY TIME.
PERHAPS THERE'S TIME FOR A FEW
QUESTIONS.
SO, I JUST WANT TO HIGHLIGHT KEY
PEOPLE IN THIS WORK BECAUSE
THERE'S SEVERAL KEY PEOPLE TO
POINT OUT.
[INDISCERNIBLE] IS THE PERSON
WHO WORK ARED ON HDL FROM THE
GUT INITIALLY HE'S IN SOUTH
KOREA RUNNING HIS OWN LAB RAARE
TOY.
THE KEY IMAGING INDIVIDUALS IN
THE GROUP ARE BARON AND RAFAEL
AND HE ALSO WORKS ON TNF DELTAA,
AND THE CONTEXT OF TLOs AND
LYMPHATIC TRANSPORT AND
[INDISCERNIBLE] HAS BEEN WORKING
ON THE BIOASIGNIFYS RESEARCH
THAT I SHOWED.
SO THANKS A LOT.
>> THANK YOU VERY MUCH GWEN.
I THINK WE HAVE TIME FOR A
QUESTION OR 2.
EITHER SPEAK UP OR RAISE YOUR
HAND, I'LL LOOK FOR YOU AND CALL
ON YOU.
>> THANK YOU.
THAT WAS BEAUTIFUL, I SAW THE
UNUSUAL LYMPHATICS THAT ARE
DRAINING INTO THE CECUM AND
COLON, DO YOU KNOW ANYTHING
FURTHER ABOUT THEM AND WHAT
DISTINGUISHES THEM GIVEN THEY'RE
SOMEWHAT RARE?
>> YOU ARE TALKING ABOUT THOSE
LITTLE SPINS?
>> SO WE'RE TRYING TO, THERE'S A
WHOLE STORY BEHIND THAT THAT I
DIDN'T INCLUDE, SO WE'VE BEEN
PUTTING TRACERS INTO THE COLON,
AND THE BEHAVIOR AND TOTAL
DIFFERENT THAN THE SOLID, SO
SOME OF THEM ARE LUMINAL
TRACERS.
SO WE ARE TRYING TO FIGURE OUT
IF WE CAN GET THEM LABELED IN A
SPECIFIC WAY SO THIS WAY WE CAN
EXACERBATE THE TISSUE AND WE CAN
ASK WHEN WHAT YOU JUST ASKED SO
AT THE MOMENT WE DON'T KNOW IF
THOSE TAGS HAVE SPECIAL FEATURES
OR WHAT THEY'RE ABOUT, BUT WE
CAN SAY THAT ALWAYS HAPPENS IN
THOSE SPECIALIZED FOLDS OF THE
COLON.
AND WE--IT'S VERY CLEAR THAT OUR
OUTFLOW TRACERS WILL ACCUMULATE
IN THAT LITTLE SPACE IN THOSE
FOLDS SO WE THINK THIS IS A
CRITICAL MEDIATOR OF OUTFLOW AND
WHAT WE'RE FINDING THAT'S SO
DIFFERENT IN THE SMALL INTESTINE
IS THAT AS THAT MATERIAL
ACCUMULATES, SOME OF IT DRAINING
OUT IN A PERIVENUS ROOT WHICH IS
VERY SIMILAR TO THE MENENG ESE,
AND 0 DIFFERENT THAN THE SMALL
INTESTINE.
BUT IT'S ALL DIFFERENT IF WE TIE
OUT THE LYMPHATICS IT ALL PUSHES
BACK.
SO I DON'T KNOW WHY, THESE
LITTLE THINGS STICK OUT.
ONE IDEA I HAVE ABOUT THE FOLD
IS THAT, YOU KNOW
[INDISCERNIBLE] HAS ARGUED THAT
THESE ARE PLACES WHERE
PARTICULAR MICROBIOME MIGHT BE
ENRICHED SO THAT MIGHT BE AREAS
WHERE LYMPHATIC OUTPUT WAS
REALLY, REALLY IMPORTANT BUT YOU
KNOW AT THE MOMENT, I'M TOTALLY
OPEN TO IDEAS.
WE ARE TRYING TO, YOU KNOW
DETERMINE DISTINGUISHING
FEATURES AND CAN WE JUST GET RID
OF THOSE.
I WILL JUST TAKE 1 QUICK COMMENT
AS A TEASER, EVERGHT THING I WAS
GOING TO PRESENT TODAY BUT
DIDN'T, WAS A PAPER WE HAD
ACCEPTED ON FRIDAY, WHICH IS ALL
ABOUT BIOELASTIC COALIC ACID
CONTROLLING IMMUNE FUNCTION IN
THE GUT AND AS PERIPHERAL
TISSUES IN THE GUT SO I THINK
YOU AND MARK HAVE SOMETHING TO
TALK ABOUT THE END OF THE
MEETING FOR SURE.
>> YEAH, WE HAVE LOTS TO TALK
ABOUT, TOO.
>> I KNOW, I KNOW.
I'M LOOKING FORWARD TO IT.
>> SO JUST TO SAY WE'VE ONLY HAD
1 MEETING SO FAR AND IT'S BEEN
ON SCROOM.
SO, LOOKING FORWARD TO MORE.
REAL LIEOF THE MIST INTERACTION.
>> THANK YOU, BEAUTIFUL TALK.
>> GWEN I HAVE A QUESTION IF
ANNETTE IS THERE TIME FOR
ANOTHER QUESTION.
>> WE'RE RIGHT AT 2:10 SO IT'S
UP TO YOU.
>> YES, PLEASE, PLEASE!
>> PLEASE, PLEASE!
>> WELL IT'S A REALLY LOVELY
PRESENTATION, THE KIND OF WORK
YOU CAN DO IN THE MOUSE BUT
WOULD BE EXTRAORDINARILY HARD TO
DO IN HUMANS BUT THEN YOU
ALLUDED TO THE PUZZLING
QUESTIONS ABOUT ANTITNF THERAPY
AND LIVER BIOLOGY THAT YOU WANT
TO PURSUE, AND I WAS HOPING YOU
COULD ELABORATE A LITTLE BIT ON
WHAT THOSE APPROACHES MIGHT BE
AND WHERE YOU MIGHT BE STYMIED
BY THIS WORKING IN HUMANS?
>> YEAH, SO, A BIG COMPONENT OF
OUR GRANT THAT WE'RE, YOU KNOW
WE'RE REALLY LAUNCHING NOW, WE
LET A BUNCH OF BATCHES CATCH UP
OF TISSUE BUT WE'RE TRYING TO
PROFILE ACROSS THE GUT DIFFERENT
VENUS COMPARTMENTS, AND WE CAN'T
REALLY DO THIS IN THE MOUSE SO
WELL BECAUSE THE MOUSE IS SO
TINY AND OF COURSE WE WOULD LIKE
FOR IT TO BE RELEVANT IN YOU HAD
PLAN SO WE'RE SAMPLING PIGLETS
AND WE HAVE A CONTRACT WITH AN
INVESTIGATOR NAMED KD--SALLY
WHERE WE CAN GO IN, IN THE
BIGLET MODEL IN THE LIVER INJURY
THERE'S A NUMBER OF REALLY NICE
MODELS ABOUT YOU HOO AS A SMALL
BOWEL RESECTION MODEL WHICH IS
NOT PART OF OUR GRANT AND OUR
GRANT WE'RE TRYING TO DO THE
BASIC SCIENCE PROFILING OF
DIFFERENT REGIONS BUT WHAT WE'RE
THINKING IS THAT IN FACT,
CHANGING LEUKOCYTES ABILITY TO
SAMPLE AND ROLL ALONG THE
VESSELS IS YOU KNOW AT HEART OF
SOME OF THE PROBLEMS IT CAN
DEVELOP IN THE LIVER, AREA WHERE
WE'RE STYMIED, IS THAT SURGICAL
MANIPULATION EFFECTS ACTUALLY
LIKE MONOCYTES AND NUTRIFILLS
MASSIVELY GO BACK TO THE BONE
MARROW AND SEE WE LOSE SOME OF
THE SENSITIVITY OF THE DATA IN
SOME OF OUR IMAGING PROTOCOLS,
SO THAT ALSO MEANS THAT IN A
HUMAN SCENARIO WHERE SURGERY IS
HAPPENING WE DON'T GET THE SAME
RESULT AS IF THERE ISN'T A
SURGERY.
SO THERE ARE SOME OBSTACLES TO
TRANSLATING IT TO HUMANS, WE'RE
HOPING THAT THE PIGLET MODEL
WILL BE SOMETHING THAT CAN BE
REALLY, REALLY HELPFUL AND THE
BEAUTY--THE BEAUTY OF THE
PICTURE IS THAT IT HAS A NORMAL
PROFILE.
THE MOUSE IS VERY SKEWED TO HDL
IN A NONCARDIOVASCULAR DISEASE
SETTING BUT THE BIGLET REALLY
HAS--THE PIGLET HAS THE OPTION
FOR PARENTAL NUTRITION AND YOU
KNOW VARIOUS OTHERS--SO THIS IS
WHERE WE LANDING.
IT SHOULD BE MORE TRANSLATIONAL
IN THAT WAY.
>> GREAT.
THANK YOU.
>> THANK YOU GWEN, AND NOW
DR. DEBROSKI, YOU CAN SHARE YOUR
SLIDES.
>> CAN YOU SEE THAT?
>> YES, IT LOOKS GOOD.
>> SO THANK YOU ANNETTE AND
NIAID STAFF FOR INVITING ME
TODAY AND BEING PART OF THIS
TRIO OF INVESTIGATORS IN THE
MIST THAT ARE GOING TO KIND OF
DESCRIBE TO YOU OUR EFFORTS.
I JUST--TO TELL YOU ABOUT
MYSELF, I LIKE TO START OFF WITH
A SLIDE AS SUCH.
THIS IS A GREAT TEACHING SLIDE
FOR THE VET OPPORTUNITIES AT
PENNVET, I SPENT MY ENTIRE
CAREER THINK BEING THIS CLASS OF
ORGANISMS, YOU KNOW HOOK WARMS
AND THEY'RE ALWAYS GREAT FOR
FEAR PACT FACTOR OR WOW FACTOR
IN THEIR BIOLOGY WITH EITHER
THEIR CUTTING PLATES OR TEETH
DEPENDING ON THE HOOK WORM
SPECIES.
BUT THE REASON WHY I THINK THAT
MUCOSAL IMMUNOLOGY HAS BEEN AT
THE CENTER OF MY ENTIRE CAREER
IN BIOMEDICAL RESEARCH IS MOSTLY
CAPTURED BY THIS IMAGE ON THE
FAR LEFT.
YOU CAN SEE HERE SOME ADULT
PARASITE REALLY LATCHED ON TO
THE GASTROINTESTINAL MUCOSA AND
THESE ORGANISMS CAN SURVIVE UP
TO A DECADE IN THEIR HOST BEFORE
THEY'RE OFTEN REPLACED BY NEW
PARASITES THAT ARE ESTABLISHED
THIS NICHE.
THERE'S A VARIETY OF ISSUES
AROUND THAT FORM DISEASE THAT
UNFORTUNATELY STILL EXIST IN THE
U.S. AS WELL AS PLACES ACROSS
THE GLOBE AND IN THE DEVELOPING
WORLD AND 1 MOST NOTABLY IS THAT
THERE ARE NO VACCINES,
REINFECTION RATES ARE HIGH
AND--BUT WHAT WE LOOK AT IN THE
LAB IS HOW THESE ORGANISMS BY
FOLLOWING THEIR UNIQUE BIOLOGY
HOW MUCH WE CAN LEARN ABOUT THE
BASIC TENNANTs OF THE MUCOSAL
SYSTEM.
BECAUSE THESE PARASITES FOR A
CERTAIN DECADE IF THEY'RE IN THE
HOST NEED TO,A VOID THE IMMUNE
SYSTEM AND THEY DO THAT BY A
VARIETY OF DIFFERENT MECHANISMS,
MANY OF WHICH WHOLE LOT THE
INVESTIGATORS HAVE INVESTIGATED
AND TODAY WE ARE DEFER -
-DEFINITELY USING MORE
INFORMATION ABOUT THE HOOK WORM
AND IMMUNE SYSTEMS AND I WILL
TELL YOU A BRIEF STORY BY
STUDYING THEIR BIOLOGY.
BUT BRINGING THIS BACK, I THINK
THE LAST PRESENTER, I WANTED TO
BRING THIS BACK TO SOME OF THE
COMMENTS THAT DR. FAUCI MADE
WITH THE OVERARCHING GOAL OF
NIAID AND PARTICULARLY OF MIST
IS TO REALLY COME UP WITH WAYS
TO SAVE LIVES, RIGHT?
WE'RE IN THE PANDEMIC AND
THERE'S A WHOLE HOST OF VIRUSES
BUT ALSO MANY OTHER PATHOGENS
WHICH WE JUST REALLY DO HAVE AN
UNMET NEED FOR VACCINE COVERAGE
AND SO I KIND OF GRABBED THIS
RECENT REVIEW AND JUST GOING
OVER, HERE'S--YOU KNOW SARS
COV-2 DUCKED INTO THESE OTHER
BACTERIAL PATHOGENS LIKE STREP,
THERE'S RSV, AND CERTAINLY IN
THE GI TRACT THERE ARE A WHOLE
HOST OF PATHOGENIC BACTERIA THAT
WE NEED VACCINES FOR AS WELL AS
IN THE GENITAL/URINARY TRACT.
WE HEARD ABOUT HIV, THE TOOL BOX
THAT WE HAVE BUT CERTAINLY WE
STILL NEED BONA FIDE VACCINES
THERE AND HEPATITIS HEPATITIS O
THERE'S A HUGE NEED FOR THE MIST
PROGRAM I THINK IT REALLY
CAPTURES SOME OF THE MOST
PREEMINENT SCIENTISTS IN THE
FIELD AS YOU JUST HEARD FROM
DAVID AND GWEN IN THE ELEGANT
WORK THAT THEY'RE DOING TO TRY
TO UNDERSTAND MORE ABOUT THESE
MUCOSAL SERVICES SO KEY CAN
DEVELOP VACCINES TO PREVENT THE
NEXT FOR SURE HAPPENING
BIOLOGICAL THREAT.
SO WHAT'S THE PROBLEM?
, RIGHT?
THERE ARE A NUMBER OF ISSUES
WHEN 1 NEEDS TO--1 DESIRES TO
VACCINATE AT THE MUCOSAL SURFACE
SO THIS SLIDE IS DESIGNED TO
CAPTURE SOME OF THOSE CHALLENGES
TO TO VACCINATION.
YOU KNOW, YOU MAY THINK OF THIS
AS THE GI TRACT JUST AS WELL AS
THE RESTIER REVIEWATTORY TRACT
BUT ANY GIIVE ACSEEN WOULD NEED
TO WITHSTAND THE CLINICAL
GENETICS DODGE NOWS MUCUS LAYER
OR ALL THE PROTEASE ACTIVITY
THAT IS OFTEN PRESENT.
CERTAINLY THERE ARE SPECIALIZED
DEPOTS FOR ANTIGEN ACQUISITION
AND TO GET ANTIGENS TO THE RIELT
PLACE AND TO THE RIGHT CELLS, IS
STILL A VERY MUCH A CHALLENGE.
I'M GOING TO TELL YOU A BIT
ABOUT DENDRITIC CELLS, DENDRITIC
CELLS TODAY THAT WE'VE UNCOVERED
BUT, MOVING ALONG, YOU KNOW,
THEN YOU NEED TO GET THE ANTIGEN
PASSED THIS MUCOSAL SURFACE OR
PAST EPITHELIUM, WHETHER IT'S
TIGHT JUNCTIONS AND YOU KNOW
THERE'S BEEN A LARGE BODY OF
WORK INDICATING HOW DENDRITIC
CELLS COME IN MANY DIFFERENT
FLAVORS AND DISTINCT SUBSETS,
MANY OF THEM ARE TOLL-LIKE
RECEPTORRER GENIC IN THE GI
TRACT SO EVEN VACCINATION COULD
LEAD TO HITTING THE ROLE DC
SUBSET, NOT TO THE TYPE OF
RESPONSE THAT WOULD LEAD TO HOST
PROTECTIVE IMMUNITY.
AND SO TARGETING HAS BEEN A
LONG-TERM INTEREST OF MINE AND
IT STILL STANDS TO BE A BIRRIER
SURFACESSIER BUT REALLY WHAT I
WANT TO GET TO TODAY IS
WHEN--AND SO NICELY INTRODUCED
BY GWEN, WE WANT TO GET THE
RIGHT LYMPHOID TISSUE PRIMED
WITH OUR VACCINE OF INTEREST,
RIGHT?
SO NOT ONLY DO WE NEED THE RIGHT
ANTIGEN BUT WE WILL GET TO THE
RIGHT LYMPHOCYTES AND THE RIGHT
PLACE AND THE RIGHT TIME TO
AVOITD THE WRONG IMMUNE
PHENOTYPE.
AND WHAT I WANT TO ARGUE TODAY
IS THAT CYTOKINES MAY BE PART
AND PARCEL TO ANSWER HOW TO
DIRECT SOME OF THIS.
RIGHT?
SO, IT'S REALLY CATCHING ON THAT
INCLUDING CYTOKINES, AS
ADJUVANTS TO HELP TO DIRECT THE
TYPES OF IMMUNE RESPONSES NEEDED
FOR PROTECTIVE IMMUNITY MIGHT
REALLY HOLD SOME OF THE PROMISE
THAT WE NEED IN MOVING FORWARD
BECAUSE A LOT OF INSTANCES, WE
HAVE THE RIGHT ANTIJEVENS BUT
WE'RE NOT LISTENING IN THE RIGHT
IMMUNE RESPONSES, AND PERHAPS
BOTH CYTOKINES, WE COULD DO
THIS, YOU KNOW, MY COLLEAGUES
HERE AND OTHER MEMBERS OF THE
MIFULT, BORIS AND CHRIS WE ARE
PART OF THE PENN INSTITUTE FOR
INFECT YOWZ DECEASES AND SWRO
NOTTIC DISEASES.
SOPHISTICATED AND WE'RE USING
IMEULOGIOLOGY TO FORCE A MODEL
AND IL7 IS THE LAB THAT IS
NEEDED TO HELP AUGMENT MRNA
ACNATION IN THE ANIMAL MODEL.
SO KIND OF WATCH THAT SPACE AND
WE ARE DOING A LOT OF THINGS
HERE AT PEIN, N.
BUT LAWEDDER DALE I WANT TO GET
TO IS THE CYTOKINE THAT IS NEAR
AND DEAR TO MY HEART AND 1 THAT
DAVID INTRODUCED AND THAT IS
METAAT THAT TIMIC IL1 SUPER
FAMILY AND IL1S CYTOKINE VS LONG
BEEN RECOGNIZED THAT THEY COULD
AUGMENT VACCINE INDUCED IMMUNE
RESPONSES AND THAT'S PERHAPS
BECAUSE THE NATURAL BIOLOGY OF
THE IL1 FAMILY CYTOKINE CANS
THAT OF BEING RELEASED AT SIGHTS
OF TISSUE INJURY AND DEATH.
WE NOW KNOW THERE ARE A VARIETY
OF DIFFERENT FLAVORS OF DEATH
AND POPITOSEIS, ON AND LET ALONE
PROCESSING AND APOPTOSIS BUT
THESE PROCESSES OFTEN LEAD TO
ELABORATION IL1 FAMILY
CYTOKINES.
IL1 BETA, IL18 AND I'M GOING TO
TALK TO YOU TODAY A LOT ABOUT
IL13.
SO, THIS IS MODEL CAPTURES THE
IDEA THAT PERHAPS IN LOOKING AT
HOW CYTOKINES AND ENDOGENOUS
REGULATORS OF THE ADAPTIVE
IMMUNITY, INNATE AND ADAPTIVE
IMMUNITY THAT BY LEARNING MORE
ABOUT THEIR SOURCES AND THE
DIFFERENT CONTEXT IN WHICH THEY
AUGMENT OR MODULATE THESE
RESPONSES, WE CAN DEVELOP BETTER
VACCINES, THAT'S REALLY THE MAIN
STATEMENT.
SO TAKE SOMETHING THE BODY
NORMALLY MAKES THAT HAS A SIGN
OF INJURY OR DAMAGE AND WAKES UP
THE IMMUNE SYSTEM AND
INCORPORATE THAT INTO VACCINES
THAT ARE GOING TO BE ROBUST AND
HOPEFULLY LONG LIVE VACCINE
RESPONSES AND IT'S NOT A NEW
IDEA REALLY, THERE'S IDEAS THAT
ARE AROUND FOR A LITTLE WHILE.
HERE'S AN EXCERPT FROM--THIS IS
AS FAR AS IN 2010 SO ABOUT, YOU
KNOW 12 YEARS AGO, BUT INCLUDING
THE IL1 FAMILY OF CYTOKINES INTO
HA SUBUNIT VACCINES AGAINST FLU,
IS LISTED VERY PROFOUND ANTIBODY
RESPONSE IN SALIVA AND THERE'S A
WASH FLUID WHICH IS REALLY WHERE
WE WANT THOSE ANTIBODY TITERS,
RIGHT?
THAT'S WHAT'S ROUGH ATOM TECTING
PEOPLE RIGHT NOW.
SO LOOK AT THIS, IL1 ALPHA, IL1
BETA, IL18 AND HERE'S MY
FAVORITE IL33 AND SO I WAS
TRYING TO HIGHLIGHT FOR YOU
THAT, YOU KNOW THERE IS AN
APPRECIATION FOR USING ALARMINS
AND UNDERSTANDING THE BIOLOGY OF
ALARMINS IS KEY TO THIS PROCESS.
O IL33, IL33 AS ALREADY
MENTIONED IS A MEMBER OF THE
SUPERFAMILY, IT SIGNALS THROUGH
HETERODYNAMMIC RECEPTOR AND
ACCESSORY PROTEIN AND ST2, AND
THESE ARE LARGELY ATTRACTED TO
THE IL33 RESPONSE OF THE CELLS
AND ONCE ENGAGED IT CIRCLES
THROUGH THE RECEPTOR SIGNALS AND
INVOLVING NF-KAPPAB SIGNALING.
IL33 HAS LONG BEEN APPRECIATED
TO BE CONSTITTATIVELY EXPRESSED
CYTOKINE AT BARRIER SURFACES,
INVESTIGATORS LIKE GERARD AND
COLLEAGUES WHO ORIGEALLY
IDENTIFIED THIS MOLECULE IN
PLACES LIKE THE SKIN, AND THE
INTESTINE AND THE, HERE, IT'S
KIND OF A CROSS SECTION THROUGH
THE VILLI AND THE AIR WAY
EPITHELIUM, HAVE REALLY KIND OF
STIMULATED INTENSE INTEREST AND
HOW THE CYTOKINE WANTS ITS
RELEASE FROM DAMAGED CELLS CAN
LEAD TO ROBUST IMMUNE RESPONSES
BUT THOSE IMMUNE RESPONSES THAT
IL33 ILLICITS HAVE BECOME MORE
AND MORE COMPLEX THE MORE
THEY'VE BEEN STUDIED AND IT
FIRST STARTED OUT AS IL33 TYPE 2
RESPONSES AND NOW, I DARE SAY
THERE'S NOT 1 TYPE OF CONONICLE
RESPONSE THAT WE UNDERSTAND IN
T-CELL ADAPTIVE IMMUNITY THAT
IL33 DOESN'T HAVE SOME KIND OF A
ROLE.
AND ALSO IN CHRONIC DISEASE, WE
HEARD ABOUT SOME OF THE NIAID
PRIORITIES IN FOOD ALLERGY,
THESE ARE EXCERPTS FROM--THESE
ARE IMAGES FROM ESOPHAGEAL
BIOPSIES OF PATIENTS WITH EOE OR
EOCENOPHILIC ESOF GIETIS.
YOU CAN SEE THE BASAL CELLS HERE
AND THE ESOPHAGUS ARE FULL OF
IL33 AND IT'S ENVISIONED THAT
UPON AN INJURYIOUS EVENT THE
IL33 AND ELABORATED AND HELPS
DRIVE THE PATHOPHYSIOLOGY OF
THIS DISEASE.
CAN YOU SEE HERE THE NUMBER OF
IL33 POSITIVE BASAL CELLS AND
ACTIVE EOE PATIENTS
SIGNIFICANTLY HIRE THAN THAT
THAN THOSE INACTIVE PATIENTS WHO
ARE INITIATIVE.
SO, YOU KNOW WHAT WE'VE BEEN
INTERESTED IN 33, FOR QUITE A
FEW YEARS, AND YOU KNOW WHAT
REALLY PERTURBED ME HOW IMAGES
SUCH AS THIS, PARTICULARLY
BECOMING DOGMA AND I THINK SOME
OF THE WORK THAT I'M GOING TO
SHOW YOU TODAY HELPS TO
CHALLENGE THAT OR AT LEAST
EXPAND THE VIEW AS WAS POINTED
OUT.
IT HAS LONG BEEN THOUGHT THAT
IL33 WAS SOLELY A DAMAGE
RELEASED PRODUCT OF, YOU KNOW
INJURED CELLS, WE RELEASE THIS
AND GOING--ONCE IL33 MADE IT OUT
TO THE EXTRA CELLULAR SPACE, IT
WAS ENGAGE RECEPTOR EXPRESS ON A
VARIETY OF DIFFERENT CELL TYPES.
AND HIGHLIGHTED FOR YOU HOW
ILC2s, USE IL33 AS A MAJOR
STIMULUS BUT ALSO IT WAS
ORIGINALLY IDENTIFIED AS A MASS
CELL AND ACTIVATING CYTOKINE.
AND RECENTLY POWERING AND OTHERS
HAVE DEMONSTRATED 33, HAS THE
ANTIINFLAMMATORY ROLE IN BEING A
GREAT ACTIVATOR TREG EXPANSION
IN THE GUT AND ACTUALLY
ENFORCING THE IMMUNOSUPPRESSIVE
CHARACTER OF CERTAIN T-CELLS,
TREG SUBSETS, SO YOU KNOW WHAT
PERTURBED ME ABOUT THIS ENTIRE
MODEL WAS THAT A CELL INJURY
EVENT COULD MEDIATE SUCH
DESPERATE OUTCOMES.
IT JUST SEEMED LIKE THERE WAS
SOMETHING MISSING THAT WE NEEDED
TO UNDERSTAND ABOUT THE BIOLOGY
OF THE CYTOKINE.
AND WE HAD A BIT OF A INSIGHT IN
THIS WORK, WHERE MY GROUP WAS IN
CINCINNATI WHERE FOR VARIOUS
REASONS WE DECIDED TO SORT CELLS
THAT WERE THE EPITHELIAL CELLS
OR IN THE MYELOID COMPARTMENT,
AND YOU KNOW I'M NOT TALKING
ABOUT TRIPLE FACTORS TODAY, IT
WAS ANOTHER KIND OF DAMAGE
INDUCED MOLECULE OF THE AREA
SURFACES BUT WE WE FOUND WAS
THAT IL33 AT LEAST AT THE
TRANSCRIPT LEVEL COULD BE
EXPRESSED IN BOTH EPITHELIALS
COMPARTMENT AS WELL AS A MYELOID
COMPARTMENT, 11 C AND CONONICLE
FEATURE AT LEAST IN THE LUNG FOR
THE MACROPHAGES AND AS WELL AS
DENDRITIC CELLS.
NOW, MOST INVESTIGATORS WOULD
HAVE COMPLETELY--LOOKEDDA THE
DIFFERENCE IN SCALE AND IGNORED
THIS, RIGHT?
BECAUSE CLEARLY EPITHELIAL
CELLS, THE ORDER OF MAGNITUDE
GREATER SOURCE OF IL33 THAN
ANYTHING IN THE MYELOID
COMPARTMENT COULD EXPRESS AND I
THINK THIS IS WHY MANY
INVESTIGATORS EVEN USING IL33
REPORTER MICE HAVE MISSED THIS
BECAUSE THEY'RE LOOKING AT MAJOR
SOURCES AND NOT MINOR SOURCES
BUT I'M HERE TO TELL YOU THAT
JUST BECAUSE YOU'RE A SMALL
PERSON DOESN'T MEAN YOUR NOT AN
IMPORTANT PERSON, SPEAKING
METAFOREVERICALLY BUT ANYWAY, WE
WENT ON TO LOOK AT MUCOSAL
SURFACES IN A VARIETY OF
DIFFERENT PLACES AND I HAVE A
VERY CLOSE COLLEAGUE WHO STUDIES
CHRONIC SIGNUEICITIS FROM NAISAL
POLYPS SO WHAT YOU'RE LOOKING AT
WITH THE PUBLISHED WORK THAT
WE'RE LOOKING AT FROM THE COHEN
LAB AND BRANCHRATORY TO LOOK AT
HUMAN NAISAL POLYPS DISEASE AND
YOU CAN SEE THAT SURPRISE,
SURPRISE IL33 AS EXPECTED WHILE
IT WAS IN THE NUCLEI OF
EPITHELLIAL CELLSIAL CELLS
BORDERING THIS, POLYP, HERE IN
THE LAMINA PROARP RIA AREA WE
CAN SEER CLEAR EVIDENCE THAT
THERE WERE--WHAT LOOK LIKE
ANTIGEN PRESENTING CELLS BY
VIRTUE OF EXPRESSING HLA-DR AND
THEN ALSO OOH LIERKS 33.
THERE WERE INSTANCES WHERE THERE
WERE MYELOID INIAGE CELLS THAT
WERE NOT ANTIGEN PRESENTING
CELLS BY NOT HAVING HLA-DR BUT
STILL HAD IL33 AND I HOPE CAN
YOU ALREADY APPRECIATE THAT THIS
IL33 WAS IN THE CYTOPLASM OF
MANY OF THESE CELL TYPES, NOT IN
THE NUCLEI WITH THE EPITHELIAL
CELLS.
SIMILARLY IN MICE, WE FOUND
ALMOST THE EXACT FINDING NOW
NOTE THAT IS CHRONIC
INFLAMMATORY STATE AND THIS HERE
IS A QUIESCENT STATE WHERE MICE
THAT ARE IN SPF CONDITION SO
THEY CERTAINLY HAVE A MIRROR
IMAGE ROUGH ATOM BIOME, DIDN'T
DRIVE THAT FEATURE BUT IL33
AGAIN WAS IN THE YOU THIS CLE I
OF EPITHELIAL CELLS BUT WE COULD
FIND THESE RARE APCs THAT ARE
CONSTITTATIVELY FOUND IN THE GI
TRACT AND EXPRESS IL33 IN THE
CYTOPLASM.
SO YOU KNOW, PART OF NOT OUR
MIST WORK BUT NIAID FUNDED WORK
IS TO DEFINE WHETHER THERE'S A
PARTICULAR LANDSCAPE IN THE
MODEL VERSUS THOSE THAT DO NOT.
BUT I WON'T BE TALKING ABOUT
THAT TODAY.
BUT I WILL BE TALKING ABOUT
HOWEVER, IS AGAIN, MY LOVE FOR A
PARASETTIC HELMETS AND HOW
IMPORTANT THEY ARE FOR BOTH
HUMAN AND ANIMAL HEGHT AND WE
FIGURED THAT TO PARSE OUT THIS
POETIC TEBTIAL DIFFERENT
BIOLOGICAL ROLE FOR IL33, IN THE
EPITHELIAL COMPARTMENT VERSUS
THE MYELOID COMPARTMENT IS
WORKED OUT USING THE MOUSE
INFECTION MODEL.
SO THE RESILIENCE IS THE WORK
HORSE OF THE PARASITE LIKE
MYSELF AND TO BECOME QUITE A
POPULAR MODEL EVEN FOR
INDIVIDUAL WHO IS DON'T LOVE
WORMS AS MUCH AS I DO, AND
INFECTIOUS STAGE LARVA AND
MIGRATE THROUGH THE LUNG IN THE
FIRST 3 DAYS OF INFECTION,
THEY'RE COUGHED UP AND SWALLOWED
TO ENTER THE GI TRACT AND HERE'S
WHERE PIPE 2 IMMUNE
DYSFUNCTIONUNITY ELIMINATES
THOSE PARASITES FROM THE GI
LUMEN OF IMMUNO COMPETENT
ANIMALS.
SO WHAT WE DECIDED TO DO WAS TO
SELECTIVELY DELETE AL33 AND
EITHER THE EPITHELIAL
COMPARTMENT OR THE MYELOID
COMPARTMENT, OKAY IN AND ASK
DOES IT MATTER?
AND WHOA, IT REALLY MATTERS, SO
LOSS OF 33 IN THE INTESTINAL
EPITHELIAL COMPARTMENT AS WOULD
BE EXPECTED AND WHAT HAPPENS IN
A MOUSE THAT LACKS IL33 AND ALSO
ALL CELLS IT GREATLY IMPAIRS
HOST IMMUNITY.
RIGHT?
SO HERE'S NUMBER OF WORMS THAT
ARE IN THE BOWEL, IN THE
INTESTINAL LUMEN, NUMBER OF EGGS
COMES OUT IN THE STOOL BUT
SURPRISINGLY LACK OF 33 IN THE
MYELOID COMPARTMENT GAVE A VERY
ROBUST OPERATING OPPOSITE RESP.
AND WE KNOW THAT WHEN THE
MYELOID CELLS LACK 33, WAS
MANIFEST VERY EARLY IN
INFECTION, ACTUALLY WE NOW THINK
IT'S TOTALLY A BASAL DEFECT THAT
THE BASAL CONDITIONS BEFORE WARM
INFECTION IS INITIATED, AND IN
THE SMALL INTESTINE 92 THE
INFLAMMATORY ENVIRONMENT AND SO
WHEN WE LOOKED AT IN MORE KIND
OF NUTS AND BOLTS IMMUNOLOGICAL
APPROACHES FOR THE IMPORTANCE OF
MYELOID 33, SORTING OUT
DENDRITIC CELLS EITHER LACKED OR
POSSESSED THE CYTOKINE AND POST
AND STIMULATING NAIVE T-CELLS WE
FOUND THAT SURPRISE, SURPRISE,
LACK OF MYELOID 33 HAD NO IMPACT
ON KIND OF CONVENTIONAL TH2
CELLS.
VERY MODERATE EFFECT ON TH1
CELLS OR TH17 CELLS BUT WHAT
HAPPENED WAS THAT IT REALLY
IMPAIRED THE FULL EXPANSION OF
THE T-REGS APART SO THIS STARTED
TO SMELL LIKE THE FEELING OF
[INDISCERNIBLE] WORK THAT HAD
BEEN PUBLISHED A FEW YEARS PRIOR
AND IT MADE US THINK THAT
PERHAPS 33 WAS A VERY IMPORTANT
ROLE IN DRIVE FOR MYELOID CELLS
IN VIVO WAS IMPORTANT FOR
EXPANTEDDING TREGS IN THE GUT.
SO TURNS OUT THAT DAN CAMP WILL
BELL AND OTHERS THAT--DAN
CAMPBELL AND OTHERS THAT WORKED
ON THIS THEY ARE SUITED TO
EFFECTIVELY EXPRESS THE
POPULATIONS THAT EXPRESS THEIR
TRANSCRIPTION FACTORS.
SO THERE'S THELPER 2 CELLS
EXPRESS GATTA 3 AND THERE'S TREG
THAT EXPRESS GATTA 3 AND THEY
CROSS REGULATE 1 ANOTHER AND ON
DOWN THE LINE AND TFRs AND TFH
AND DBET EXPRESSING AND TREGS
AND WORKING IN THE TREGS AND
THERE'S A LOT, LOT OF INTEREST
IN THIS PARTICULAR EXPOSURE BUT
FOR US FOR WORMS WE THOUGHT
ABOUT THE GATTA 3 EXPRESSING
TREG SUBSET AND LOW AND BEHIND
WHEN WE GENERATED ANIMALS THAT
SPRVEGLY LACK GATE KEEPER THEA 3
IN THE TREG COMPARTMENT THOSE
ANIMALS JUST LIKE THE ANIMALS
THAT LACKED MYELOID 33, HAD
ENHANCED IMMUNITY.
SO WE STARTED TO THINK THAT
THERE WAS A CIRCUIT THAT WE HAD
UNCOVERED WHERE, MYELOID 33--SO,
YOU KNOW, AGAIN THERE'S THE
ADULT WORM EXPS EGGS AND WE LOSE
THESE ST2 EXPRESSIONOT SAME TREG
SUBSET.
SOPHISTICATEDY WE STARTED TO
THINK THAT PERHAPS THE MYELOID
DERIVED 33 WAS TALKING TO THE
GATTA 3 EXPRESSING SUBSET.
AND WHEN YOU THINK ABOUT CELLS
TALKING TO 1 ANOTHER, ISN'T THAT
REALLY THE BASIC TENANTS OF WHAT
WE WANT DURING VACCINATION,
RIGHT?
WE WANT A SELL THAT AS HASN'T
GEN, IN ORDER TO PRIME AND
PROGRAM ADAPTIVE LYMPHOCYTES SO
WE CAN HAVE LONG-TERM BOF-CELL
AND T-CELL IMMUNITY SO WE THINK
THAT WHEN THESE CELLS COME
TOGETHER, PERHAPS THERE WAS SOME
UNKNOWN--AS YET UNKNOWN
MECHANISM WHEREBY THIS EABT
ANTIGEN PRESENTING CELL, THE
LARGER CELL, DELIVERS 33
EXQUISITELY DELIBERATELY TO A
T-CELL.
AND WE TOOK A TOTALLY AGNOSTIC
APPROACH AND PERFORM RNA
SEQUENCING, TO LOOK AT DENDRITIC
CELLS THAT WERE CD103 POSITIVE
AND MUCOSAL DCs AND MESENTERIC
LYMPHNODE, AND ASKED, DID IT
MATTER, IF THEY LACKED IL33 OR
PROCESSED IL33.
I AND TELL YOU THIS WAS A RARE
EXCITING MOMENT WHERE WHEN THE
DATA CAME OUT, THERE WAS THIS
TEAM THAT WAS A PART FROM ALL
OTHERS THAT WAS MODERATELY DOWN
REGULATED AND WASN'T QUITE 2
FOLD DOWN REGULATED BUT IT WAS
IL33 DEPENDENT, INTRINSICALLY IN
THE COMPARTMENT AND YOU CAN SEE
AGAIN, YOU KNOW THE HERBERT LAB
DOES, WE GO AFTER THE SMALL
PERSON, THE LESS LIKELY
CANDIDATE.
SO THIS IS THE LOWEST CHANGE OUT
OF THE ENTIRE GENE SET BUT THIS
GENE WAS ENCODED, CALLED MPEG 1
FOR MACROPHAGE EXPRESS GENE 1
AND CODED A PROTEIN FOR PERFORIN
2, AND THOSE WHO ARE FAMILIAR
WITH THE EXPLOSION OF INTEREST
IN POOR FORMING PROTEINS AND THE
[INDISCERNIBLE] FAMILY AS
DELIVERING IL1 BETA FROM LIVE
SALES AND THE VACCINE ADJUSTICE
ACCESS VEPTS YOU'VE SEEN CAN BE
AUGMENTED THROUGH THE IL1 BETA
[INDISCERNIBLE] PATHWAY AND SO
THAT TYPE OF LITERATURE REALLY
GOT US EXCITED ABOUT IL33 AND
PERFORIN 2.
AND PERFORIN 2 IS EXPRESSED ON A
VARIETY OF DIFFERENT INNATE LIKE
CELLS, IT'S EVOLUTIONARY
CONSERVED IS VERY SIMILAR TO
PERFORIN 1 BUT WHAT MAKES
PERFORIN 2 UNIQUE IS THAT IT HAS
THE TRANSMEMBRANE TETHER AND
THAT ALLOWS PERFORIN 2 TO BE
CONSTITTATIVELY EXPRESSED INTO
ENDOSTUDIES OF MULTIPLE
ENDOCRINES IN APCs, MOSTLY THE
WORK HAS FOCUSED ON TISSUE
MACROPHAGES, IT WAS LITERALLY
NOTHING KNOWN ABOUT DENDRITIC
CELLS BEFORE WOR PERFORIN 2
EXPRESSION BEFORE WE STARTED
WORKING ON THIS.
MECHANISTICALLY IT HAD BEEN
RECOGNIZED BY [INDISCERNIBLE]
AND OTHERS IN FLORIDA AT
UNIVERSITY OF MIAMI THAT
MICROBIAL EXPOSURE TO APCs
LIKE TISSUE MACROFAJS, CAUSES A
RAPID RELO XAIGZ AND A EFFUSION
OF CONTAINING ENDOSEEMS WITH
LYSOSOMES SO THE PH AGO-LIES
STUDIES OF MULTIPLE ENDOCRINAL
THAT OCCURS ONCE THE BACTERIUM
WAS PART OF THE EFFECTOR
RESPONSE SO NOW WHEN THAT OCCURS
WHEN THAT FUSION OCCURS WHEN YOU
HAVE A BACTERIUM INSIDE AND
ENDOSTUDIES OF MULTIPLE
ENDOCRINE THAT HAS
[INDISCERNIBLE] ON THE OUTER
MEMBRANE, THAT PERFORIN 2 IS
ABLE TO THEN RELOCATE AND
DEPOSIT ON THE BACTERIAL CELL
SURFACE AND LIES WITH BACTERIA.
BUT FOR US WE WERE NOT JUST
INTERESTED IN AN ENDOSTUDIES OF
MULTIPLE ENDOCRINE TEEP OF
EXPRESSION PATTERN BUT VERY
INTERESTED IN THE FACT THAT WE
HAD BEEN RECOGNIZE THAD PERFORIN
2 HAD TO BE ON THE PLASMA
MEMBRANE.
SO BACK WE WENT TO OUR OWN
TISSUE SAMPLES AND PARTICULARLY
THE NAISAL POP POLYPS AND YOU
CAN SEE HERE THE MICROSCOPY
APPROACH ALLOWED US TO CAPTURE
QUITE EXCITING 3 EXPRESSION OF
PERFORIN 2 WITH THE BUSY END
POINTING OUT INTO THE EXTRA
CELLULAR SPACE AND SEEMED TO BE
KIND OF EMBEDDED, I DON'T WANT
TO SAY IN THE MEMBRANE, MAYBE
SINCE GWEN IS IN THE AUDIENCE, I
WILL BE CAUTIOUS AS LI WANT TO
SIMPLY SAY THAT IT LOOKS LIKE
THE PERFORIN END OF THIS
MOLECULE IS POINTED OUTWARD AS
WE WOULD ENVISION IT TO WORK TO
DELIVER TO DLEA TO SOME OTHER
CELL TYPE AND THIS IS A C11 C
POSITIVE CELL IN A HUMAN NAISAL
POLYP.
SO THIS CERTAINLY AS A RELEVANCE
TO THE HUMAN UPPER WEAR A
EPITHELIUM AND THERE ARE--IT'S
THESE DCs THAT ARE FULL OF
PERFORIN 2, YOU CAN SEE HERE
THAT IT REALLY TAKES ON THIS
KIND OF CHANNEL LIKE
CONFIGURURATION IN CELLS AND
THEY'RE JUST CHOKED FULL OF IT,
BOTH IN ENDOSEEMS AS WELL AS
SOME PART OF THEIR LIFE CYCLE
MAKING IT TO THE CELL SURFACE.
>> ALL RIGHT, SO WHEN WE STARTED
TO LOOK AT THIS MORE INTENTLY,
WE SEE THAT PERFORIN 2 LOCALIZED
THIS INTERFACE AND WE LOCALIZE
THESE TOGETHER IT WAS IL33
DEPENDENT, IF THE DC'S LACK 33,
WE NO LONGER GOT THAT CO
LOCALIDESSATION AND THAT KIND
OF--YEAH, THAT POTERN AND MOST
IMPORTANTLY, WHEN WE USE A
COUPLE OF DIFFERENT APPROACHES
TO DELETE PERFORIN 2, HERE YOU
SEE THE MPEG 1, WE FOUND THAT
IL33 WAS NO LONGER ABLE TO MAKE
IT OUT INTO THE SUPERINATENT
WHERE WE LYSE THE CELL THERE WAS
NO DIFFERENCE IN CELLS FROM THE
DENDRITIC CELLS.
WE NOW KNOW THROUGH UNPUBLISHED
DATA THAT IT'S NOT JUST IL33, WE
KNOW THAT LACKING PERFORIN 2
IMPAIRS A VARIETY OF CYTOKINES,
WE THINK WE UNCOVERED SOMETHING
THAT'S IMPORTANT FOR CYTOKINE
DELIVERY FOR ANTIGEN CELLS AND
THAT'S WHAT OUR MIST IS ALL
ABOUT AND TO PUT THE NAIL ON THE
COFFIN, WE USE A COCULTURE
APPROACH WHERE WE CO CULT
CULTURE DENDRITIC CELLS AND
TREGS AND ASK IF WE BLOCK THE
PERFORIN TO DELIVER CYTOKINE
WOULD IT IMPAIR THE
DIFFERENTIATION OR EXPANSION OF
TREGS AND THE BOTTOM LINE IS,
CONTROL ANTIBODY HAS NO IMPACT
ON THE COMMITMENT OR
PROLIFERATIVE EXPANSION BY SFF
PHASE COMMITMENT OF T-REGS IF
YOU BLOCK THEM, THE CELLS COULD
COMMITMENT TO THE TREG BUT
THEY'RE NOT EXPANDING, RIGHT?
AND YOU CAN SEE HERE I SHOWED
YOU THE DAT HA THERE ARE MORE
SIGHTY KINES THAT ARE COMING
THROUGH, TO LIKELY THAN JUST
IL33 WHICH IS MOST LIKELY THE
EXPLANATION FOR WHY WE DIDN'T
GET AS MUCH SUPPRESSION OF THAT
PHENOMENAL IN THE IL33 KNOCK
OUT.
SO LET ME JUST WRAP THIS UP, I
THINK DENDRITIC CELLS AND IL33
AS WELL AS WE KNOW IT CAN MAKE A
LOT OF GCs MAKE A WHOLE HOST
OF CYTOKINES, PERFORIN 2 SEEMS
TO BE A CONDUIT AT LEAST THAT'S
WHAT WE'RE STUDYING RIGHT NOW AS
A POI TOGETHER SIS, WHETHER
THERE IT'S A CONDUIT FOR IL33
AND THIS MECHANISM CAN EFFECT
TREG ECPANGZ.
SO EPITHELIAL CELLS DIE AND THEY
THOUGHT TO EXPAND ILC2s FOR
ELABORATING INFLAMMATION AND
MUCOSAL SURFACES BUT OUR NEW
DATA SUGGESTS THAT THERE'S A
DIFFERENT CIRCUIT WHERE THEY CAN
FOLKALLY DELIVER 33 TO TREGS AT
MUCOSAL SURFACES THROUGH THE
POOR FORMING ACTIONS OF PERFORIN
2 AND SO WHAT THIS WOULD
INDICATE THEN IS THE IL33 HAS A
INFLAMMA ARE TOY ROLE THROUGH
THIS DEATH PATHWAY WHERE IT HAS
AN IMMUNOSUPPRESSIVE ROLE
THROUGH A DIFFERENT SOURCE AND
KIND OF INTERESTING THIS
DIFFERENCE, I WOULD ENVISION TO
BE HARMLESS FOR RATIONAL VACCINE
DESIGN, THE GOALS OF OUR GRANT
ARE WE WANT TO THICK THIS APART
AND PUT IT BACK TPGHT AGAIN TO
UNDERSTAND THE DIVERSITY OF
CYTOKINES RELEASED FOR IT AND
HOW THEY'RE TRAFFICKED TO THE
SURFACE AND WHAT CONTEXT VIRAL
INFECTION OR WORM INFECTION IS
PER FORIN 2 IMPORTANT.
I WOULD LIKE TO REALLY THANK THE
MEMBERS OF MY LAB RAARE TOY AND
I REALLY AND THE COLLABORATORS
AND THE CENTER, COHEN AND OTHERS
AND WITHOUT THE SUPPORT FROM
THERE, THIS WORK WOULD NOT BE
POSSIBLE, THANK YOU VERY MUCH.
>> THANK YOU DR. DEBROSKI.
WE'RE OVER ABOUT 3 MINUTE
SPECIALIZATION OF SPECIFIC
ENDOTHELIAL ANN IS IT OKAY IF WE
TACK A QUESTION.
>> YES, ABSOLUTELY.
>> THANK YOU.
>> ANYONE WITH A QUESTION CAN
JUST SPEAK UP OR IF YOU RAISE
YOUR HAND, I'LL CALL ON YOU.
WELL, I GUESS THAT WAS SUPER
CLEAR, THANK YOU DEBROSKI AND
THANK YOU EVERYONE FOR THESE
OUTSTANDING TALKS.
VERY MUCH APPRECIATED.
AND I THINK THEN WE WILL TURN IT
BACK TO DAN AND THE CONCEPT
CLEARANCES.
STHRKS YEAH, SO AS USUAL WE HAVE
SEVERAL CONCEPT CLEARANCES FOR
COUNCIL CONSIDERATION.
AND AND I THINK WHAT WE WILL DO
IS AS WE USUALLY DO GO THROUGH
THESE 1 BY 1 BUT IF YOU HAVE
QUESTIONS, COMMENTS, THAT RISE
TO A LEVEL THAT WARRANTS
INDIVIDUAL APPROVALS, WE CAN DO
THAT.
IF NOT, WE WILL ASK FOR AN
UNBLOCKED APPROVAL AT THE END OF
THE SESSION AND HOPEFULLY SAVE
TIME.
SO AS WE BEGIN, I THINK THERE'S
A SLIDE SET THAT SHOULD BE
PROJECTED NOW.
YVETTE DO YOU HAVE THAT OR DO
THE IT FOLKS HAVE IT.
>> THE IT. WILL PUT IT ON THERE,
THERE IT IS.
>> WE WILL HAVE, OKAY, THE USUAL
DISCUSSIONS OF CONCEPT
CLEARANCES FOR 3 GENERAL AREAS.
WE HAVE 2 CONCEPT CLEARANCES FOR
THE CONSORTIUM ON FOOD'LLERGY
RESEARCH.
ONE WILL BE FOR THE LEADERSHIP
CENTER AND 1 FOR THE CLINICAL
SITES.
WE HAVE RECOMPETITION OF THE
INSTITUTES ADJUVANT DISCOVERY
PROGRAM AND THEN 2 CONCEPTS IN
THE RADIATION COUNTERMEASURES
PROGRAM THAT OUR DIVISION IS
RESPONSIBLE FOR.
BEFORE WE GET TO THOSE, THOUGH,
I WANTED TO BRING TO YOUR
ATTENTION 3 INITIATIVES THAT
WERE DISCUSSED QUITE SOMETIME
AGO AT COUNSEL AS CONCEPT
CLEARANCES AND WE'RE BRINGING
THEM BACK NOW, NOT FOR
DISCUSSION, BUT JUST TO BE SURE,
PEOPLE FROM THE COMMUNITY ARE
AWARE, THESE SOLICITATIONS FOR
ALLERGY AND ASTHMA STAT CENTER
OR TRANSPLANTATION RESEARCH,
STAT CENTER FOR OUR CLINICAL
TRIAL NETWORKS AND CLINICAL DATA
AND SAFETY MANAGEMENT CENTER.
THESE WERE INITIALLY CONSIDERED
BY COUNCIL PROBABLY A COUPLE
YEARS AGO AND THEN SOLICITED AS
CONTRACT PROPOSALS AND THERE
WERE SOME IRREGULATEARS IN THE
PEER REVIEW STAGE THAT LED TO
PROTESTS AND AS A RESULT WE ARE
REISSUING THESE NOW.
AND ANYBODY INTERESTED CAN GO TO
THESE WEB LINKS AND SEE THE
APPLICATION REQUIREMENTS.
SO, I WON'T GO INTO THOSE IN ANY
MORE DETAIL NOW.
AND WE WILL GO ON TO THE NEXT
SLIDE, I GUESS WHICH IS PROBABLY
GANG DONG'S FIRST SLIDE ON THE
KOFAR INITIATIVE.
>> WHY DON'T YOU INTRODUCE
YOURSELF AND GO THROUGH THE
INITIATIVES AND SAME FOR EACH OF
OUR STAFF WHO FOLLOW YOU ON THE
ADJUVANT DISCOVERY AND RADIATION
DISCOVERY PROGRAMS MANAGEMENT.
>> YEAH, SOMEHOW I JUST SAW MY
PRESENTATION AND I CAN'T--I CAN
NO LONGER SEE THEM.
MY SCREEN--
>> WE'RE NOT SEEING THEM EITHER.
>> CAN YOU SEE US RIGHT NOW?
>> NO, I WAS SEEING THEM WHEN
WE--I HAVE 1 MINITTOR, IS
THAT--YEAH, SO WITHIN THE ZOOM
WINDOW IF YOU SEE THE ZOOM
WINDOW YOUR COMMAND CONTROL
BUTTON IS AT THE BOTTOM OF THE
ZOOM WINDOW, YOU SHOULD SEE A
SHARE GREEN SCREEN BUTTON, DO
YOU SEE THAT, SO YOU WANT TO
SELECT THE GREEN SHARE SCREEN
BUTTON AND THEN SHARE THE
PRESENTATION THAT, YOU KNOW--
>> I DON'T SEE MY OPEN SLIDE
SET, THE POWER POINT.
>> ANNETTE DO YOU HAVE A
CONSOLIDATED VERSION YOU CAN
SHARE.
>> I WAS GOING TO SUGGEST WE DO
SRO A BACK UP JUST IN CASE.
>> THAT'S WAWE WERE EXECKING SO
WHY DON'T YOU GO AHEAD AND
PROJECT THAT.
>> STAND BY.
>> GANG IF YOU COULD LET THEM
KNOW NEXT SLIDE, THEY WILL MOVE
THAT FOR YOU.
>> OH, OKAY.
YEAH, I WAS SURPRISED.
THAT'S WHY WE HAVE THE BACK UP.
>> OKAY, SO SHOULD I WAIT
UNTIL--
>> PLEASE STAND BY.
PLEASE STAND BY.
, THEY WILL PUT IT UP FOR YOU.
>> BUT YOU CAN INTRODUCE
YOURSELF IN THE MEAN TIME GANG.
>> YEAH, HI, THIS IS GANG DONG
OFFICER FOR ASTHMA AIR WAY
BIOLOGY PROGRAM.
IF YOU NOTICED I AM LISTED TWICE
BUT ACTUALLY SINCE BOTH CONCEPT
CLEARANCE FOR THE SAME
CONSORTIUM SO I WILL PRESENT
THIS TOGETHER AS A SINGLE
CONCEPT CLEARANCE PRESENTATION
SO THE CONCEPT CLEARANCE
PRESENTING IS FOR THE RENEWAL
FOR CONSORTIUM FOR FOOD ALLERGY
RESEARCH, CO FAR.
NEXT SLIDE.
FOOD ALLERGY EFFECTS
APPROXIMATELY 8% OF CHILDREN AND
11% OF ADULTS IN THE U.S.
IT IS MOST FREQUENT CAUSE OF
EMERGENCY ROOM VISIT FOR
ANAPHYLAXIS.
THE SPECTRUM OF FULLY ENDORSE
THE IMMUNOLOGICAL DISEASES
CONTINUE TO EXPAND, AND ENCODE
ESO CENOPHILICI EOE AND FOOD
PROTEIN INDUCED ENTHUSIASMER O
COLITIS SYNDROME, FPIES
ALPHA-GAL SYNDROME, AGS.
THERE'S NO CURE FOR FOOD
ELSYNERGIES SO THEREFORE IN
2005, NIAID INITIATED CONSORTIUM
FOR FOOD ALLERGY RESEARCH, AIMED
TO CONDUCT CUTTING EDGE CLINICAL
TRIALS AND CLINICAL STUDIES TO
ADVANCE PREVENTION MANAGEMENT
STRATEGIES FOR FOOD ALLERGIES,
AND ALSO ENHANCE OUR KNOWLEDGE
ON THE ORIGE EPI-BLASTINS AND
THE PATHOPHYSIOLOGY OF IT
MEDIATED FOOD ALLERGY, NEXT
SLIDE, PLEASE.
>> AS I SAID BEFORE, CO FAR IS
ESTABLISHED IN 2005 AND RENEWAL
IN 2010, AND THE CURRENT CO FAR
IS RENEWED IN 2017, WE SUPPORTED
1 LEADERSHIP CENTER THAT
PROVIDED SCIENTIFIC LEADERSHIP
AND ADMINISTRATIVE STRUCTURE FOR
NETWORK WIDE TRIALS AND STUDIES
AND CO FAR ALSO SUPPORT
CURRENTLY SUPPORTING 7 CLINICAL
RESEARCH UNIT AS A SITE TO
IMPLEMENT NETWORK WIDE TRIALS
AND STUDIES.
NEXT SLIDE.
AND THEN LAST 17 YEARS CO FAR
HAS BEEN VERY SUCCESSFUL
COMPLETING MANY CLINICAL TRIALS,
NATURAL HISTORY STUDIES, AND
MECHANISTIC RESEARCH PROJECTS AS
IS LISTED, AS IS SHOWN IN THE
BAR AND CURRENT CO FAR, THERE
ARE 2 MAJOR STUDIES ONGOING, 1
IS CALLED OUTMATCH AND THE OTHER
IS SUN BEAM, WHICH WILL I
EXPLAIN IN THE NEXT COUPLE
SLIDES.
NEXT.
OUTMATCH IS A PHASE 3 CLINICAL
TRIAL ABOUT THE EFFICACY OF
ELOSE MAB WHICH IS THE
UN[INDISCERNIBLE] MONOCLONAL
ANTIBODY TO INCREASE THE AMOUNT
OF FOOD IT TAKES TO INDUCE THE
REACTION TO PEANUT AND OTHER
MAJOR FOOD ALLERGENS.
AND STUDY ALSO COMPARES
PROTECTION OF OMALIZUMAB
MONOTHERAPY TO FACILITATE THE
MULTIFOOD ORAL IMMUNOTHERAPY.
IF SUCCESSFUL, THIS STUDY MAY
LEAD TO FDA APPROVAL OF THE
FIRST BROAD SPECTRUM TREATMENT
FOR FOOD ELERGY.
NEXT SLIDE.
SUN BEAM IS THE FIRST COHORT
STUDY STANDS FOR SISS BIOLOGY
AND STUDY INITIATE INDEED
MARCH 2021 CONDUCTED BY CO FAR
NETWORK AND WITH PARTIC PAIGDZ
BY DIVISIONS--PARTICIPATION
FUNDED BY ATOPIC DERMA TITIS
RESEARCH NETWORK AND IMMUNE
TOLERANCE NETWORK, THE
OBJECTIVES IS TO IDENTIFY RISK
FACTORS FOR DISEASE PRODICTION
AND EARLY STAGE MECHANISMS IN
THE DEVELOPMENT OF ATOPIC
DERMATITIS AND FOOD ALLERGY AND
THE STUDY UTILIZE TD
MULTI-OMICs APPROACH TO
IDENTIFY DETERMINANTS OF ATOPIC
DISEASE IN VERY YOUNG CHILDREN,
FOCUSING ON FOOD ALLERGY AND
ATOPIC DERMA TITIS.
NEXT SLIDE.
>> SO FOR RENEWAL, WE STILL
USE--WE PROPOSED COOPERATIVE
AGREEMENT FOR 7 YEARS OF WORK
AND WE--WE WILL SUPPORT A
LEADERSHIP CENTER THAT PROVIDES
SCIENTIFIC LEADERSHIP AND
ORGANIZATION THOUGH AND THE
STRUCTURE AND THE LEADERSHIP
CENTER WILL GUIDE THE NETWORK
FOR CLINICAL TRIALS AND STUDIES
WITH EMBEDDED MECHANISTIC
STUDIES, SO OBVIOUSLY THIS--THE
LEADERSHIP CENTER, WE INCLUDE
STRUCTURE, ADMINISTRATIVE CENTER
AND CLINICAL ROPERATIONS CENTER.
AND WE ALSO SUPPORT 10 CLINICAL
RESEARCH CENTERS AS THE CENTERS
WILL SERVE AS THE SITE FOR
IMPLEMENT NETWORK WIDE TRIALS
AND STUDIES IN ADDITION EACH
SIDE WILL CONDUCT
CENTER-SPECIFIC SMALL CLINICAL
RESEARCH PROJECTS AND TOGETHER
THEY CONTRIBUTE TO DEVELOPMENT
OF NEW NETWORK-WIDE PROTOCOLS,
WITH MECHANISTIC RESEARCH WITH
THE HOPE THAT THIS--THE STUDY,
THIS PROJECT, THIS PROPOSAL MAY
BECOME, MAY LEAD TO THE NETWORK
WIDE PROTOCOLS; NEXT SLIDE.
SO THE OBJECTIVE OF THE PROFAR
RENEWAL WILL BE EXPANDED TO
INCLUDE THE MORE DISEASES, I
DESCRIBED IN THE INTRODUCTION WE
ALSO THE--INCLUDE THE OBJECTIVE
WILL IMPROVE DIAGNOSTIC
PROCESSES TO POTENTIALLY REPLACE
R04 CHALLENGES AND ASSESS
INCIDENCE AND PREVALENCE OF FOOD
ALLERGY IN THE U.S. AND WE
EXPECT THE CO FAR WILL CONDUCT
RESEARCH TO ELUC DATE
INTERACTIONS BETWEEN
IMMUNOLOGICAL, ENVIRONMENTAL,
GENETIC, EPIGENETIC FACTORS
UNDERLYING DEVELOPMENT OF FOOD
ALLERGY, MOLL LECULAR MECHANISMS
ASSOCIATED WITH DEVELOPMENT AND
CLINICAL PRESENTATION OF FOOD
ALLERGY RESPONSE TO THERAPY,
SEVERITY OF ALLERGIC REACTIONS
AND ANAPHYLAXIS IN FOOD ALLERGY.
NEXT SLIDE.
AND IN ADDITION THE CO FAR
RENEWAL CO FAR WILL HAVE A
RESPONSIBILITY TO COMPLETE THE
OUTMATCH TRIAL AND ALSO
CONTINUATION OF SUN BEAM BIRTH
COHORT STUDIES.
NEXT SLIDE.
SO CO FAR NETWORK WILL RECEIVE
SUPPORT FROM DIVISION FUNDED
OTHER CENTERS THAT INCLUDE THE
STATISTICAL SUPPORT, DATA
MONITORING AND MANAGEMENT,
CLINICAL SITE MONITORING,
MEDICAL MONITORING, REGULATORY
SUPPORT AND DSMB WHICH ARE
PROVIDED BY THE DIVISION OF
DAIT, I THINK THIS IS MY LAST
SLIDE AND I WILL BE HAPPY TO
ANSWER ANY QUESTIONS.
>> LOOKS GREAT.
>> SO THIS IS A 7 YEAR PROJECT
AND YOU ANTICIPATED IT WOULD GET
STARTED WHEN?
I SAW THOSE TIMELINES BUT WHEN
WOULD IT ACTUALLY GET FIRED UP?
>> THIS IS FOR 2024.
SO WE ANTICIPATE THE PROJECT
WILL START MARCH 2024.
THAT'S WHERE THE CURRENT CO FAR
PROGRAM WILL END.
>> OKAY.
>> DAVID ARE YOU STILL ON?
I DON'T SEE YOU.
DAN AND I HAVE HAD SOME
CONVERSATIONS OVER PAST FEW
MONTHS ABOUT BRINGING SOME OF
THE ININIVATIONS IN MUCOSAL
IMMUNOLOGY INTO THE FOOD ALLERGY
PROGRAM.
AND I'M WONDERING IF ANY
THOUGHTS FROM COUNCIL MEMBERS OR
OTHERS ON HOW WE CAN ACCELERATE
THAT IN THE CO FAR NETWORK
EITHER THROUGH OPPORTUNITY FUND
PROJECTS OR OTHERS.
>> WOULD THAT BE, DAN, A
SEPARATE MECHANISM THEN TO
INTEGRATE MAYBE THE PROGRAMS
BECAUSE IT SEEMS NATURAL.
I MEAN EACH WOULD BENEFIT FROM
THE OTHER.
AND IT'S A GREAT IDEA.
>> YEAH, I MEAN, WE ARE LIMITED
AS I ALLUDED TO EARLIER WHAT WE
CAN DO IN HUMANS VERSUS MICE, SO
THERE'S SOME LIMITATIONS THERE,
BUT BUT IT REALLY IS IMPORTANT
TO KEEP THESE CLINICAL NETWORKS
GROUNDED ON KIND OF THE
FUNDAMENTAL IMMUNOLOGY AND
CUTTING EDGE RESEARCH THAT FLOWS
FROM THE MORE BASIC SCIENCE THAT
THE EN--STRATEGIESITUTE
SUPPORTS.
>> COULD YOU ENVISION, YOU KNOW
IF YOU DID WANT TO MAKE THOSE
CONNECTIONS, WOULD YOU ENVISION
OFFERING LIKEN SILLARY TO THE
TRIAL OPPORTUNITY AS WELL OR DO
YOU THINK THAT'S NOT POSSIBLE?
I MEAN, I COULD IMAGINE WHILE
STUDYING HUMANS IS CHALLENGING,
YOU KNOW HUMAN TISSUE IMAGING,
YOU KNOW OF THE OCCASIONS WHEN
BIOPSIES ARE AVAILABLE, IS NOT
IMPABL AND CAN BE VERY
INFORMATIVE AND THEN THERE'S A
NUMBER OF THINGS JUST WITH
RESPECT TO NUCLEOTIDES T-REGENT
ABSORPTION THAT 1 CAN DO WITH
FOR EXAMPLE, STABILIZE O TAUPE
TRACER TYPE STUDIES AND I THINK
THERE ARE REALLY, I DON'T KNOW
POTENTIALLY COULD BE VERY
INTERESTING.
BUT YEAH, IN SOME CASES THERE'S
THE ANCILLARY STUDIES THAT
ASSOCIATES WITH TRIALS AND
PEOPLE CAN APPLY TO THOSE, DO
YOU THINK THAT'S POSSIBLE?
>> YEAH, THAT IS A POSSIBILITY.
IT'S ALSO WE ALWAYS REGARDED IT
AS A STRENGTH IF LEADERSHIP
CENTERS FOR THESE PROGRAMS BRING
IN BASIC SCIENTISTS OR KIND OF
ADVISORY GROUPS TO HELP STEER
THE RESEARCH OVER AND YOU KNOW
AS JUST COMMENTED, THIS IS A 7
YEAR PROGRAM.
SO IT'S NOT SO EASY TO
ANTICIPATE SOME OF THE
OPPORTUNITIES TO THAT MIGHT COME
UP.
>> RIGHT.
I GUESS MY OTHER QUESTION MIGHT
BE, HOW LIKELY IS IT THAT THE
CURRENT CO FAR GROUPS ARE THE
MAIN COMPETITORS FOR THE
RENUCLEOTIDESSAL BECAUSE I DON'T
KNOW THAT THERE ARE SO MANY
GROUPS POISED TO ADDRESS THESE
QUESTIONS?
>> WELL, IT'S USUALLY THE CASE
THAT THE INCUMBENT REAPPLIES BUT
ON MANY OF THESE CLINICAL
CONSORTIA WE HAVE HAD TURNOVER
EITHER IN THE LEADERSHIP CENTERS
OR IN THE CLINICAL RESEARCH
SITES.
WE ALSO HAVE I THINK IT WAS
MENTIONED EARLIER THAT THERE'S A
CONGRESSIONAL INTEREST IN OUR
EXPANDING CO FAR CLINICAL SITES
BEYOND THE CURRENT NUMBER AND
THERE COULD BE OPPORTUNITIES
THERE AS WELL.
>> SO DAN, 1 THOUGHT THAT
CROSSED MY MIND IS WE USED TO
HAVE VIA NHLBI, THOSE CORE
GRANTS WHERE ACTUALLY THE BASIC
PROJECTS HAD TO BE BECAUSE OF A
REQUIREMENT TO BE SUPPORTED BY A
CLINICAL PROJECT AND THAT WOULD
KIND OF BE AN OVERARCHING THING
SO WOULD THAT BE A THOUGHT THAT
THE CO FAR PROJECTS HAVE?
LIKE INTEGRATED SOME MORE BASIC
PROJECT THAT COULD INVOLVE
IMAGING OF THAT GWEN POINTED OUT
BECAUSE IMAGING IS SO
[INDISCERNIBLE] WITH THE COMPLEX
IMAGING AND 1 CAN TOO WITH THE
SAMPLES SO WOULD THAT BE
SOMETHING FOR THE FUTURE TO
INCLUDE A BASIC WITH THE
CLINICAL, YOU KNOW?
>> I SEE, ALKIS JUST WENT OFF
MUTE, DID YOU WANT TO COMMENT ON
THAT.
>> YEAH, HI.
YEAH, THIS WOULD BE SOMETHING
VERY OF INTEREST TO US, NO
QUESTION ABOUT IT.
ONE OF OUR LIMITATIONS OF
COURSE, WE WOULD HAVE LOVED TO
BE ABLE TO HAVE ACCESS TO
TISSUE, BUT AS YOU ALL KNOW,
FOOD ALLERGY PRIMARILY AFFECTS
YOUNG CHILDREN AND IT BECOMES
QUITE DIFFICULT TO DO
EN'REENDOSCOPYS IN CHILDREN FOR
PURPOSES THAT HAVE TO DO WITH
RESEARCH.
THERE HAVE BEEN SOME ATTEMPTS IN
THE PAST FEW YEARS TO
INTRODUCEENDOSCOPY IN ADULTS OR
IN OLDER ADOLESCENTS WITH FOOD
ALLERGY AND THERE HAVE BEEN
QUITE INTERESTING FINDINGS
THERE.
SO, I THINK THAT THE FIELD IS
OPENING UP IN THIS DIRECTION.
IT'S JUST GOING TO TAKE A FEW
MORE YEARS, I THINK FOR
EVERYBODY TO FEEL COMFORTABLE
WITH THAT.
BUT OVER ALL THE IDEA BEHIND CO
FAR IS TO ALLOW FOR MECHANISTIC
STUDIES THAT WILL INTRODUCE NEW
CONCEPTS AND WE HOPE THAT WITH
THIS NEW STRUCTURE, WHICH MAKES
EACH 1 OF THE CLINICAL RESEARCH
SITES, DO ITS OWN SMALL PILOT
PROJECTS THAT SOME ADDITIONAL
IDEAS MECHANISTIC IDEAS WILL
COME OUT THAT WILL THEN BECOME A
SOURCE FOR APPLICATION TO LARGER
CLINICAL TRIALS AND STUDIES.
>> SORRY.
>> I WAS JUST GOING TO SAY SO
THOSE WHO ARE PART OF MIST IF
YOU HAVE IDEAS AND TO HAVE
POTENTIAL COLLABORATORS IN YOUR
OWN INSTITUTIONS OR ELSEWHERE
WHO WOULD BE APPLYING TO THIS
SORT OF STATION WHEN IT COMES
OUT THAT WOULD BE TERRIFIC.
>> GWEN--
>> GO,A HEAD.
>> OH NO I WAS JUST GOING TO ASK
ALKIS, IN THE CONTEXT OF THE
DIAGNOSIS OF THESE DIFFERENT
LIKE FOOD PROTEIN INDUCED
ENTERIC COLITIS OR EOE, WHAT IS
THE BASIS OF THE DIAGNOSIS FOR
THESE DIFFERENT SUBFEATURES?
IS THERE AN OPPORTUNITY THERE TO
USE THE DIAGNOSTIC SETTING, YOU
KNOW TO ALSO ACQUIRE MATERIALS
MORE BASIC ANALYSIS.
>> VERY MUCH SO FOR EOE THE
DIAGNOSIS IS TRULY A PATHOLOGIC
DIAGNOSIS SO THEY DO UNDERGO EGD
ON A REGULAR BASIS, IN FACT,
THESE PATIENTS.
SO YES THAT COULD BE TISSUE
AVAILABILITY FROM THE ESOPHAGUS
IN THE STOMACH AND PROBABLY FROM
THE DUDE NEM AS WELL FROM THESE
PATIENTS.
FOR [INDISCERNIBLE] THESE ARE
INFANTS, RARELY DO THEY GET
SCOPED, DIAGNOSIS IS MOSTLY
CLINICAL BECAUSE THE CLINICAL
PRESENTATION IS QUITE DRAMATIC.
SO IT'S PRETTY MUCH EASY TO PUT
THAT DIAGNOSIS ON, THAT--BUT YOU
KNOW THIS IS--WE ARE FOR
[INDISCERNIBLE], WE ARE AT WHAT
I WOULD CALL EMBRYONIC STAGE OF
RESEARCH.
WE WANT TO REALLY DO SOMETHING
ABOUT THIS CONDITION, WHICH
SEEMS TO BE INCREASING IN
INCIDENCE THESE DAYS.
>> OKAY, WITH THAT IF THERE ARE
NO OTHER COMMENTS OR QUESTIONS
WE SHOULD MOVE ON TO THE
ADJUVANT DISCOVERY PROGRAM.
>> I AM WOLF GANG AND I AM WITH
THE BASIC IMMUNOLOGY BRANCH
WHERE THE VACCINE ADJUVANT
DISCOVERY PROGRAM RESIDES AND I
OVERSEE THE VACCINE ADJUVANT
DISCOVERY PROGRAM AND ITED I'M
PRESENTING CONCEPT OF RENEWAL OF
THIS PROGRAM FOR ANOTHER 5
YEARS.
SO THE DISCOVERY PROGRAM IS JUST
1 COMPONENT OF A MUCH LARGER
ADJUVANT PORTFOLIO THAT SUPPORTS
A WIDE VARIETY OF ASPECTS OF
RESEARCH STARTS WITH DISCOVERY
WHICH ESTABLISHES A PIPELINE OF
NEW IMMUNO STIMUTORS BUT ALSO
IMMUNE SUPPRESSORS THAT CAN BE
FURTHER DEVELOPED INTO SIM
LATTERY OR TOLL-LIKE
RECEPTORRERATTIC ADJUVANTS
RESPECTIVELY.
WITH EACH NEW ROUND THE FOCUS
HAS CHANGED AND THIS HAS CHANGED
AS INSIGHTS INTO THE INNATE
IMMUNE PATHWAYS AND RECEPTORS
HAVE EVOLVED AND IN THE CONTEXT
OF THE DISCOVERY PROGRAM, WE
ALSO SUPPORT THE EXPLORATION OF
ADJUVANT COMBINATIONS TO BROADEN
THE RESPONSE.
NOW THE NIDE ADJUVANT PROGRAM IS
NOT JUST A PROGRAM DEVELOPMENT
BUT WE HAVE A RESEARCH COMPONENT
AND WE SUPPORT STUDIES INTO THE
MECHANISM OF ADJUVANT PROGRAMS
AND THE DISCOVERY OF CORRELATES
OF ADJUVANTISSITY AND THE
INVITRO CORRELATES OF
ADJUVANTISSITY.
SO AT THE JANUARY MEETING OF THE
ADVISORY COUNCIL, YOU HAVE HEARD
ABOUT THE ADJUVANT DEVELOPMENT
PROGRAM WHICH REACHES THE VERY
WIDE AND VERY DEEP GAP BETWEEN
ADJUVANT DISCOVERY AND THE FIRST
TRIAL OF VACCINE THAT USES A
NOVEL ADJUVANT.
AND 1 FOCUS AREA WITHIN OUR
ADJUVANT DEVELOPMENT AREA IS
HEAD-TO-HEAD COMPARISONS OF
ADJUVANTS TO FACILITATE AND
ACCELERATE ADJUVANT SELECTION
FOR CLINICAL STUDIES.
AND FINALLY OUR ADJUVANT PROGRAM
ALLOWS US TO ADVANCE DEVELOPERS
AND WE EXCEEDED THE PROGRAM TO
ADVANCE NAID PRIORITIES AND WE
CONNECT WITH THE GOAL OF GETTING
NEW ADJUVANTS INTO THE CLINIC.
SO THIS NEXT SLIDE SUMMARIZES
THE VARIOUS PROGRAMS WITHIN OUR
ADJUVANT PORTFOLIO THAT WE USE
TO ACCOMPLISH THE GOALS I JUST
OUTLINES.
THE DISCOVERY PROGRAM IS THE
OLDEST 1 WITHIN THE PORTFOLIO,
IS IT STARTED IN 2003 AND THIS
IS THE PROGRAM I'M PRESENTING
FOR RENEWAL TODAY.
THIS PROGRAM IS COMPLEMENTED BY
AN ANNUAL SBIR SOLICITATION
THAT'S ON THE STREET RIGHT NOW,
AND THAT SUPPORTS THE DISCOVERY
OF NOVEL ADJUVANTS COMPANIES,
BASIC RESEARCH ON ADJUVANTS IS
SUPPORTED THROUGH THE MOLECULAR
MECHANISM OF COMBINATION
ADJUVANTS PROGRAM, AND SEEKS TO
GAIN INSIGHTS INTO THE HOW
ADJUVANTS WORK ON A MOLECULAR
LEVEL, THE ACC PROGRAM, TO
ESTABLISH THE PRINTS OF
ADJUSTICE ACCESS RANTS, NOW THE
DEVELOPMENT PROGRAM, NIAID
SUPPORTS PRECLINICAL STUDIES
THAT ARE NEEDED TO TO GET
VACCINES THAT ARE FORMULATED
WITH NOVEL ADJUVANTS TO THE
CLINIC OR CLOSER TO THE CLINIC.
THE AVAR-T PROGRAM WHICH JUST
STARTED LAST WEEK IS DESIGNED TO
IDENTIFY OPTIMAL ADJUVANTS FOR
VACCINES THROUGH SYSTEMATIC
COMPARISON AND PROFILING
STUDIES.
AND FINALLY I MENTIONED OUR GOAL
TO MAKE NOVEL ADJUVANTS MORE
ACCESSIBLE TO VACCINE
DEVELOPERS, THIS IS OUTLINED IN
THE NIDE STRATEGIC PLAN AND
RESEARCH AND 1 OF THE TOOLS WE
USE FOR THIS PURPLES IS THE
VACCINE ADJUVANT COMPENDIUM OR
VAC, THIS IS AN ONLINE
SEARCHABLE DATABASE WE LAUNCHED
LAST YEAR WHICH IS DESIGNED TO
CONNECT VACCINE AND ADJUVANT
DEVELOPERS.
NOW, TALKING SPECIFICALLY ABOUT
THE ADJUVANT DISCOVERY PROGRAM
CHA HAS BEEN ACCOMPLISHED SO
FAR, THE PROGRAM HAS SUPPORTED
THE SCREENING OF MORE THAN
3 MILLION COMPOUNDS INVITRO, BUT
OVER THE YEARS, WE'VE ALSO ADDED
INSILIC O EFFORT AND MORE THAN
10-24th COMPOUNDS HAVE BEEN
EVALUATED INSILICO, THE LEAD
COMPOUNDS THAT COME OUT OF THESE
SCREENS TRIGGER A WIDE VARIETY
OF PATHWAYS AND THE TLRs,
CLRs, AND SO ON AND SO ON,
FOLLOWING UP ON DR. HERBERT'S
PRESENTATION, I WANTED TO POINT
OUT THAT 1 OF OUR CURRENT
CONTRACTORS IS ALSO CONDUCTING A
SCREEN OF SMALL MOLECULES TO
IDENTIFY IL1 RECEPTOR AGONIST AS
NOVEL ADJUVANTS SO INSTEADY OF
USING THE WHOLE CYTOKINE THEY'RE
LOOKING FOR SMALL MOLECULE
INSTEADY.
EVEN THOUGH THIS IS AN EARLY
STAGE PROGRAM THAT IS MEANT TO
PRIME THE ADJUVANT PIPELINE,
LEAD CANDIDATES FROM ADJUVANT
CONTRACT HAS BEEN TESTED IN MORE
THAN 10 CLINICAL TRIALS SO FAR,
THESE TRIALS ARE SUPPORTED BY
NIAID PROGRAMS OR WITH OWDZ
FUNDING.
AND THEY'RE USE INDEED A WIDE
VARIETY OF VACCINES, FOR
INFLUENZA FOR ALLERGY, VACCINES
FOR SUBSTANCE ABUSE AND OTHERS.
A NUMBER OF ADJUVANTS FROM THE
PROGRAM HAVE BEEN AND ARE
CURRENTLY BEING USE INDEED
PRECLINICAL COVID VACCINE
STUDIES, 2 OF THEM HAVE MADE IT
INTO APPROVED VACCINES, 1 OF
THEM IS ALHYDROXY QUIM 2, A
TLR7/8 AGONIST USED IN COVAXIN,
SECOND 1 IS A NOVEL COMBINATION
ADJUVANT CONSISTING OF A
CARBOHYDRATE BASED STIMULATOR
AND A TLAGONIST THAT CAME OUT OF
1 OF THOSE SCREENS WHICH I AND
THIS COVAX 19 WHICH IS ON THE
MARKET UNDER THE NAME SPIKOGEN.
THE PROGRAM FEEDS INTO OTHER NIH
AND NIAID PROGRAMS, I MENTIONED
INFLUENZA WHO SUPPORT THE
INFLUENZA VACCINE PROGRAM
INCOLLABORATION WITH THE NIAID
WITH COLLEAGUES IN THE NIAID
DIVISION OF MICROBIOLOGY AND
INFECTIOUS DISEASES.
WE HAVE AN ONGOING OPIOID
VACCINE PROGRAM IN COLLABORATION
WITH THE NIH INSTITUTE FOR DRUG
ABUSE ANDAD JUSTICE ACCESS VANTS
ARE BEING PROVIDED TO THE NIAID
DIVISION OF AIDS FOR HIV
VACCINES.
NOW WHAT DOES THE OVERALL GOAL
OF THE PROGRAM, IT HASN'T
CHANGED, IT IS TO SUPPORT THE
DISCOVERY OF NOVEL IMMUNE
STIMLATTORY, IMMUNOMODULATORY OR
COAL O GENIC COMPOUNDS AND THEIR
PRECLINICAL EARLY STAGE
EVALUATION AS VACCINE ADJUVANTS
AND THEN THREEZ NOVEL LEAD
COMPOUNDS WOULD BE FED INTO
OTHER ADJUVANT PRESENTLYS
ESPECIALLY THE ADJUVANT
DEVELOPMENT PROGRAM.
WHAT IS OBVIOUSLY NOT SUPPORTED
BECAUSE THIS IS AN EARLY STAGE
PROGRAM IS CLINICAL TRIALS.
AND JUST TO SHOW YOU THE OVERALL
PROGRAM STRUCTURE, EACH PROJECT
STARTS WITH A HIGH THROUGH PUT
SCREENING, LIBRARIES, THE SCREEN
CAN BE CONDUCTED EITHER INVITRO
OR INSILIC O OR A COMBINATION OF
BOTH, LEAD COMPOWBDS UNDERGO
MECHANISM OF ACTION STUDIES AND
THEY ALSO UNDERGO OPTIMIZATION
STUDIES WHICH INTERNAL AUDIT
VOLVE STRUCTURE ACTIVITY
RELATIONSHIP OPTIMIZATION TO
OPTIMIZE THE ACTIVITY AND THEN
FINALLY THE COMPOUNDS ARE TESTED
AND THROW THE SELECTED TO IN
VIVO VACCINE HIM OWN O
GENERATEDISSITY AND EFFICACY
STUDIES.
FOR THIS PROGRAM WE'RE PROPOSING
WE WOULD LIKE TO USE THE
CONTRACT AND RENEW FOR ANOTHER 5
YEARS AND WE I WOULD BE HAPPY TO
TAKE ANY QUESTIONS.
>> SO I HAVE A QUESTION ABOUT
THE CURRENT PROGRAMS.
ARE THEY-OF DO THEY MAINLY
INVOLVE THE LAST STEP THAT YOU
SAID, IN VIVO TESTING, LARGELY
IN MOUSE MODELS OR AS WOULD BE
APPROPRIATE, I GUESS FOR THE
PROGRAM.
>> YEAH, I THINK I KNOW WHAT
YOUR CONCERN IS.
THE DIFFERENCE BETWEEN THE
DIFFERENT SPECIES AND IN
ORDER--YES, THE FINAL EVALUATION
IS FREQUENTLY DONE IN THE MOUSE
MODEL SIMPLY BECAUSE IT'S--WE
HAVE THE TOOLS, WE HAVE THE READ
OUTS, IN ORDER TO AVOID ANY KIND
OF IDENTIFICATION OF SPECIES
SPECIFIC ADJUVANTS, THE PROGRAM
STARTS WITH THE REQUIREMENT TO
DO THE SCREEN IN BOTH HUMAN
CELLS AND CELL TYPE FROM THE
SPECIES THAT THE ADJUVANT WILL
BE TESTED IN INVITRO.
AND THIS WAY WE'RE SCREENING OUT
OWL THE COMPOUNDS THAT ARE IN
THIS CASE, JUST MOUSE SPECIFIC.
>> IT BECOMES A CHALLENGE AND OF
COURSE WHEN WE'RE TALKING ABOUT
IMMUNE RESPONSE TO HAVE JUST 1
TYPE OF CELL, I MEAN THAT'S
WHERE I GUESS, ARE THEY PROGRAMS
THAT ARE INCLUDING ORGANOIDS OR
OTHER FORMS OF STRUCTURES TO
COMPLEMENT THE STUDIES.
>> I DO,A GREE WITH YOU.
THE CHALLENGE IS WITH ORGANOID
CULTURES YOU CANNOT DO HIGH
THROUGH PUT SCREENING SO DO YOU
NEED SOME KIND OF SYSTEM THAT
ALLOWS YOU TO GO THROUGH 10S OF
HUNDREDS OF THOUSANDS OF
COMPOUNDS.
I SHOULD HAVE A POINT OUT THAT
OVER THE YEARS, THE PROGRAM HAS
MOVED FROM THE USE FROM THE
RELIANCE ON REPORTER CELLS WHICH
ARE, YOU KNOW AS YOU POINTED OUT
SINGLE CELL TYPE.
THEY CAN BE RATHER ARTIFICIAL
TOWARDS PRIMARY CELLS, PBMCs,
AND HAS BEEN--SOME OF THE
FAILURES, SOME OF THE COMPOUNDS
THAT DID NOT TRANSLATE
TO--COMPOUNDS THAT HAVE ADJUVANT
ACTIVITY IN VIVO WERE DUE TO THE
USE OF REPORTER CELLS THAT
IDENTIFY FALSE-POSITIVES, THAT
IS BEING ADDRESSED THROUGH THE
USE OF PBMCs.
IN THE--IN THE PROGRAM I
MENTIONED BEFORE, THE
ACC PROGRAM, THE ADJUSTICE
ACCESS HAVEN'T CHARACTERIZATION
PROGRAM, THAT PROGRAM DOES
INVOLVE THE USE OF ORGANOID
CULTURES TO CHARACTERIZING
RESPONSES INDUCED BY DIFFERENT
ADJUVANTS BUT IT'S MEANT TO BE A
VERY LOW THROUGH PUT APPROACH.
>> THANK YOU.
THANK YOU.
>> OKAY BEING IF THERE ARE NO
OTHER COMMENTS OR QUESTIONS WE
SHOULD MOVE ON.
LANYN YOU HAVE 2 INITIATIVES TO
DISCUSS.
>> YES, I DO AND LET ME SHARE MY
SCREEN.
NCAN YOU SEE THE RIGHT SCREEN.
>> YES, IT'S CORRECT.
THANK YOU.
>> SO TODAY, MY NAME IS
LANYN TALIAFERRO, AND I AM A
PROGRAM WOF WITH THE DAITs,
AND I WILL TALK ABOUT 2 STUDIES
FOR APPROVAL.
THE FIRST AND ENTITLED
DEVELOPMENT OF RADIATION
NUCLEOTIDES CLER MEDICAL
COUNTERMEASURES AND BIODOSIMETRY
DEVICES AND THIS IS MAKING USE
OF OUR AGENCY ANNOUNCEMENT BROAD
CONTRACT VEHICLE.
SO TO GIVE YOU A BIT OF
BACKGROUND, THE INITIATIVE WAS
DEVELOPED AND IT WAS FOR TRIAGE
AND TREATMENTS IN THE EVENT OF A
RADIATION PUBLIC EMERGENCY FOR
RADIATION.
NIAID WAS ASKED ABOUT THESE
PLANS AND ESTABLISHED CRMCP AND
OUR PRIORITIES INCLUDE TWEPPING
COUNTERMEASURES FOR AXIEWT AND
RADIATION INJURIES AND ALSO
DEVELOPMENT OF INCORPORATED
AGENTS AND FINALLY, DEVELOPING
TRIAGE TOOLS TO INSURE WE CAN
SORT A LARGE POPULATION OF
PEOPLE FROM THE [INDISCERNIBLE].
SO THE RNCP EXPANDS BASIC
DEVELOPMENT TO RESEARCH AND I
WILL TELL YOU ABOUT WHAT WE DO
AND HOW WOE DO IT.
UNDER THE BASIC RESEARCH PREMISE
WE HAVE SOME NECKIMISMS OF
ACTION STUDIES, WE HAVE STUDIES
THAT ALSO FOCUS ON THE TARGETS,
THAT WE CAN USE TO MITIGATE SOME
OF THE RADIATION INJURIES, ALSO
INVITRO IN SMALL ANIMAL ANIMAL
EFFICACY IS ARE DONE.
UNDER THE PRECLINICAL
DEVELOPMENT THAT HELPS PUSH
THINGS ALONG THE PIPELINE, WE
HAVE LEAD OPTIMIZATION WHERE WE
ARE FIGURING OUT DOSING AND
ADMINISTRATION OF LEADING AND WE
ALSO USE LARGE ANIMAL EFFICACY
MODELS, USING CANINES AND PIG
MODELS, THESE STUDIES ARE DONE
UNDER THIS AREA, WE CAN ALSO
FORMULATE DRUGS AND FORMULATION
FOR OUR VRCOs AND
PK/PD STUDIES AND TOX.
WE HAVE MOVED INTO SOMEWHAT OF A
PHASE 1, PHASE 3 CLINICAL TRIAL,
WE'RE STILL KIND OF IN INFANCY
THERE BUT HOPING THAT WILL BE
MORE FREQUENT AND EVENTUALLY,
YOU KNOW WE HELP WITH THE
LICENSURE AND PROCUREMENT OF
THESE DRUGS.
ON SO HOW DO WE DO THIS?
UNDER THE BASIC RESEARCH
COMOPPOSITE BEHAVIORIAL
PHENOTYPE AND THEN THE UMBRELLA
WE HAVE GRANTS AND COOPERATIVE
AGREEMENTS AS WELL AS
INTERAGENCY GREAPTS THAT HELP US
MOVE THAT PATH ALONG AND IN
PARTICULAR, THIS PATH HERE, THAT
KIND OF VALID BETWEEN THE BASIC
AND ADVANCE DEVELOPMENT IS
REALLY SPEARHEADED BOO I THE
BROAD AGENCY ANNOUNCEMENT
CONTRACT IS WHAT WE'RE SHOWING
HERE AND THIS IS A FOA WE ISSUE
ONCE EVERY 2 OR 3 YEARS AND
THEY'RE AWARDS AND OFFERS ARE
EXPECTED TO [INDISCERNIBLE]
WORK, SINCE THERE IS REALLY A
BROAD AGENCY ANNOUNCEMENT TO
KIND OF CAPTURE A LOT OF THE NEW
MEDICAL COUNTERMEASURES THAT MAY
BE COMING DOWN THE PIPELINE OR
MAYBE EVEN SOME OF THE
BIOINDUSTRY TOOLS.
SO THE CORE THAT'S IN CHARGE
WILL WORK WITH THE CONTRACTOR AT
HAND TO DEVELOP THIS CRITICAL
PATH TO LICENSURE TO MAKE SURE
WE CAN PUSH IT DOWN THE ADVANCED
DEVELOPMENT PIPELINE.
AND WHEN THAT HAPPENS WE WORK
WITH A PRODUCT DEVELOPMENT IQ
CONTRACT OR WITH BARTA AS WELL
AS FDA TO HELP PUSH THAT ALONG.
SO GIVEN THIS MOVEMENT OR
PIPELINE, WE HAVE TO HAVE
SUCCESS AND HAVE PRODUCTS
APPROVED FOR THE SPACE, 4 OF
THOSE PRODUCTS HAVE BEEN
APPROVED UNDER THE U.S. FDA
ANIMAL RULE AND 3 OF THEM HAVE
BEEN FUNDED UNDER OUR UMBRELLA
SO IN 2017, [INDISCERNIBLE] WAS
FUNDED BY NAID AND WE PUSHED IT
THROUGH LICENSURE AND BARTA WAS
ABLE TO ACQUIRE IT AT THE END.
IN 2018, LUKINE WAS ACQUIRED
BY--SORRY WAS PUSHED DOWN THE
PIPELINE BY BARTA, AND IT HAS
BEEN ACQUIRED SINCE THEN.
BOTH OF THESE STIMULATE BONE
MARROW TO INCREASE NUTRIFILLS SO
IT CAPTURES THAT PART OF THE
[INDISCERNIBLE] ERA HOWEVER
THERE WAS NOT ANOTHER COMPONENT
THAT WAS NOT TAKEN CARE OF AND
THAT ALLEVIATED BY THE PUSH WITH
ANTI[INDISCERNIBLE] THE PRODUCT
DEVELOPMENT PIPELINE.
AND THIS WAS REALLY NIAID'S PUSH
AND BARTA PARTNERED UP UP WITH
US AT THE END TO HELP US PUSH IT
ALONG TO THE LICENSURE.
AND THIS DRUG INCREASES
PARTICIPATE IN A TRIALLETS
STIMULATING CARIO SIGHTS.
SO ULTIMATELY WE HAVE HAD 4
SUCCESSFUL DRUGS COME DOWN THE
PIPELINES FOR [INDISCERNIBLE],
HOWEVER, RADIATION HAS MANY
RADIATION ORGAN INJURIES WE HAVE
TO WORRY ABOUT, GI, LUNG AND
SKIN BEING THE TOP 3 THAT WE'RE
FOCUSING ON NEXT.
SO A LITTLE BIT ABOUT THE
[INDISCERNIBLE] AND HOW IT
HELPED US ALONG THE WAY, SINCE
FISCAL YEAR 2010 BONDS WERE PART
OF OUR PROGRAM TO GET THINGS
MOVING ALONG AND TO THE ADVANCE
DEVELOPMENT REALM AND YOU CAN
SEE WE HAD 9 FACILITATIONS SO
FAR, WHERE 24 CONTRACT VS BEEN
AWARDED AND THESE SPAN A VARIETY
OF RADIATION INDUCED DISEASES,
BEGINNING FROM GHAST ROW
INTESTINAL INJURIES TO LUNG, TO
BIODISSYMMETRY AND CUTEAINIOUS
RADIATION INJURY.
THE ACHIEVEMENTS ARE PRETTY
GOOD.
WE'VE HAD 3 FDA INVESTIGATIONAL
NEW DRUGS UNDER THESE CONTRACTS,
SO, YOU COMPANIES THAT HAVE
BYE-BYE WORKING WITH US HAVE
BEEN ABLE TO OBLIGATIONS STAIN
THOSE, WE'VE HAD 12 FDA PRIOR
IND MEETING THIS FAR AND
DEFINITELY PUSHING THE UMBRELLA
AND PUSHING THAT AGENDA TO GET
THEM TO FDA AND GET THESE
PRODUCTS TRANSITIONED AND LOOK
THOSE LINES WE'VE ALSO HAD
PRODUCTS TRANSITION TO BARREDDA.
--BARDA.
THE FISCAL YEAR 23, AWARDS ARE
CURRENTLY UNDER, I GUESS
NEGOTIATIONS, SO THERE'S NOT
MUCH WE CAN SAY ABOUT THOSE BUT
THEY ARE BEING NEGOTIATED AS WE
SPEAK.
PROPOSED BOND INITIATIVE, WE
WANT TO BECAUSE IT PROET MODEL
CITIZENS ACCELERATION OF
PRECLINICAL AND MCMs AND
BIODOS IMPEDIMENTSETRY ASSAY
DEVELOPMENT FOR RADIATION
INJURY, WE WANT TO HAVE A
MECHANISM THAT WILL TAKE THESE
YOU KNOW MEDICAL COUNTER
MEASURES AND BIOCHEMISTRY
DEVICES ALL THE WAY THROUGH THE
ADVANCE DEVELOPMENT AND THIS
REALLY KIND OF SPANS THAT IN
BETWEEN.
SO WE HOPE TO SUPPORT SOME LARGE
ANIMAL EFFICACY STUDIES, AND
ALSO SUPPORT ANY IND AND IUO
ENABLING STUDIES FOR ANY FDA
LICENSURE APPROVAL OF THESE
DEVICES.
WE EXPECT ABOUT 8-10 PROPOSALS,
FOR THIS PARTICULAR BOND AND WE
HOPE TO AWARD 2-3 YEAR AWARDS
FOR THIS BOND.
ANY QUESTIONS?
IF THERE ARE NONE I WILL
CONTINUE ON TO THE NEXT
INITIATIVE.
>> JUST REAL QUICK ONCE YOU GET
THESE PRODUCTS FOR THESE AND ARE
THOSE--THE NEXT STEP ANTICIPATED
TO WHERE, PRODUCTION OF THOSE
DEVICES OR--HOSPITALS AND
DOCTORS ALL AROUND THE WORLD, SO
IN THAT CASE, WE HAVE WHAT THEY
CALL [INDISCERNIBLE] INVENTOR
EXPE THAT HAS BEEN ACQUIRED BY
THE BARDA, THEY ARE THE 1S THAT
DEAL WITH THAT SIDE OF THE HOUSE
AND WE'RE JUST REQUIRING THEM.
AS FAR AS SOME OF THE NEWER
DRUGS THAT MAY NOT BE OUT THERE,
THEN THAT'S A LITTLE BIT MORE
DIFFICULT, BUT WE'RE--WE'RE
HOPING TO [INDISCERNIBLE] FACT
CALL THEM IN SOME WAY SHAPE OR
FORM AND BARDA USUALLY WORKS
WITH THE COMPANIES TO TRY TO AT
LEAST PUSH FORWARD A PRIMARY
IMPLICATIONS WHERE THEY SUPPORT
THE USE OF THESE DRUGS NOT JUST
WITHIN THE RADIATION SPACE THAT
WAS IN THE CLINICAL.
>> RIGHT.
>> THANK YOU.
>> OF COURSE THE BIODOSEMITRY
TOOLS ARE MORE SPECIFIC TO THE
OUR AREA BUT SOME OF OF THE
PEOPLE DEVELOPING THE TOOL
TRYING NOT TO DEVELOPMENT JUST
FOR OUR INDICATION BUT THINGS
THEY CAN USE FOR CLINICAL
INDICATION AS WELL.
ANY OTHER QUESTIONS?
OKAY, WELL MOVING ON TO THE NEXT
1 THAT WE'RE HOPING TO GET
APPROVED.
OUR NEXT INITIATIVE IS ENTITLED
SEX DIFFERENCES IN RADIATION IN
NUCLEAR RESEARCH MODELS WHICH
LOOKS AT UNDERLYING PATHWAYS,
BIOMARKERS OF INJURY AND MEDICAL
COUNTERMEASURES RESPONSES THAT
ARE AFFECTED BY DIFFERENCES IN
SEX.
SO WHY DOES THIS MATTER?
WELL WE KNOW THAT SEX AND AGE
CAN AFFAIRS TEAM LEADERRER
RESPONSES TO RADIATION DRUG AND
EFFICACY AND IN GENERAL 8-10
PRESCRIPTION DRUGS WERE DRAWN TO
THE MARKET FOR DANGEROUS SIDE
EFFECTS IN WOMEN COMPARED TO MEN
AND THIS WAS IN A
[INDISCERNIBLE] AUDIT BACK IN
97.
THERE'S A HIGHER INCIDENCE OF
ADVERSE EVENTS IN WOMEN THAT
INCLUDES ISSUES SUCH AS HIGHER
BLOOD CONCENTRATIONS OF DRUGS,
LONGER TIME FOR CIRCULATION, ON
THE HISTORICALLY EXCLUSION OF
FEMALE ANIMALS IN PRECLINICAL
ANIMAL MODELS, LED TO SOME OF
THESE PROBLEMS AND WE CONTINUED
TO SEE SOME OF THOSE
RAMIFICATIONS.
SO WHY DO WE NEED THIS
INITIATIVE.
WELL, IN OUR CASE RADIATION
INDUCED SEX DRVESS HAPPEN BUT
WE'RE NOT SURE WHY, AND WE'RE
TRYING TO FIGURE OUT WHY THIS IS
HAPPENING AND UNFORTUNATELY
HISTORICALLY A LOT OF THE WORK
HAS BEEN DONE AND HAS BEEN DONE
IN MALES SO WE'RE JUST BEGINNING
TO REALLY PUSH THE GETTING MORE
FEMALES--MORE FEMALE ANIMALS
INTO THE SPACE AND
UNFORTUNATELY, THERE'S JUST NOT
ENOUGH NUMBERS FOR US TO REALLY
SAY, YOU KNOW THESE TRENDS
REALLY HAVE A STATISTICAL
SIGNIFICANCE SO WE'RE TRYING TO
REALLY HELP PUSH THAT NOTE
ALONG.
UNTIL RECENTLY WE ONLY HAD A
VERY SMALL NUMBER OF FEMALE
NONHUMAN PRIMATES IS AVAILABLE
WHICH IS A VARIETY OF REASONS
WHY THAT HAPPENS NOT ONLY WAS IT
A MALE DOMAIN NATIVE AMERICANS
NATIVE AMERICANS
IN THE NORTHERNED RESEARCH
COMPONENT BUT ALSO SOME OF THESE
THINGS ARE LIKE THAT BECAUSE OF
BREEDING THAT SORT OF THINGS, SO
CHALLENGES IN THE EFFECTS OF
NONHUMAN PRIMATES, SO WE NEED TO
MAKE USE OF THESE ANIMAL MODELS
AND IF WE DON'T HAVE THEM AND
THE DON'T HAVE THE RIGHT, YOU
KNOW CORRELATION BETWEEN MALES
AND FEMALES THEN WE CAN'T USE
THEM FOR WHAT WE WANT AND/OR
WHAT WE NEED.
AND YOU KNOW WE'VE BEEN LOOKING
AT THESE SEX DIFFERENCES, THERE
HAS BEEN A LOT OF RESEARCH DONE
AND LOTS OF NEW FINDINGS THAT
HAVE COME TO BEAR.
IN 2021, THE RADIATION RESEARCH
SOCIETY MEETING WHICH IS A VERY
IMPORTANT MEETING FOR OUR SPACE
HAD A SYMPOSIUM JUST ABOUT THE
EFFECT ABOUT RADIATION AND
BIOLOGY AND MEDICINE CAN THERE
WERE OVER 27 THAT WERE PRESENTED
AT THIS MEETING.
FOLLOWING THAT WE DECIDED TO DO
AND HOST A TRANS-AGENCY WORKSHOP
WHERE NIAID LED THE WORKSHOP
WITH PARTNERS IN THE U.S. GENE.
WE ALSO PUT OUT REQUEST FOR
RESEARCH AND WE'VE HAD MULTIPLE
RESPONSES TO THIS AREA.
SO WHAT IS THE GOAL OF THIS
INITIATIVE?
WE WANT TO EXPLORE THE SEX
RELATED DIFFERENCES IN RADIATION
RESPONSES BUT WHY?
WE WANT TO IMPROVE THOSE ACROSS
THE STUDY PORTFOLIO, WE WANT TO
MAKE SURE WE HAVE MEDICAL
MEASURE DEVELOPMENT.
WE HAVE PRECLINICAL AN MODELS
AND THEY MAKE SENSE TO HELP US
UNDERSTAND WHAT THOSE LITTLE
DETAILS THAT WE'VE BEEN MISSING
SHOW.
WE UNDERSTAND--WANT TO
UNDERSTAND THESE UNDERLYING
CAUSES AND ULTIMATELY INCREASE
SAFETY AND EFFICACY OF OUR
MEDICAL COUNTERMEASURES THAT MAY
BE GOIVEN PEOPLE WHO DOT
NONAPOPTOTIC HAVE ANY DAMAGE IN
A CASE OF A MASS CASUALTY EVENT.
WE WANT TO IDENTIFY WHAT THESE
SEX DIFFERENCES ARE, EMERGING
DECKNOLOGYS AND WORKING ON THE
CHIP, SO, THESE ARE ALL THE KIND
OF IDEAS THAT WE HAVEON BOARD
WITH THESE SEX DIFFERENCES AND
THE SEX DIFFERENCE INITIATIVE
AND WE WANT TO ADVANCE
BIOMARKERS THAT ARE ROBUST AND
SEX DEPENDENT SO WE CAN DETECT
WHETHER OR NOT SOMEBODY HAS BEEN
EXPOSED TO RADIATION REGARDLESS
WHO THEY ARE.
AND ULTIMATELY THE FDA ANIMAL
RULE LICENSURE XEBTS ADEQUATE
REPRESENTATION FROM BOTH SEXES
SO THEREFORE WE HAVE A NEED FOR
THIS DEMAND OF HAVING BOTH
SEXES.
SEX RELATED RADIATION ASSOCIATED
EEIVETS HAVE BEEN DOCUMENTED FOR
DECADES, YET MUCH REMAINS TO BE
LEARN BODY THE BASIS FOR THESE
EFFECTS AND IN FACT IN 2006, WE
HAD THE NATIONAL ACADEMIES
PREPORT ON OCCUPATIONAL AND
ACCIDENTAL RADIATION EXPOSURES,
THE SURVIVORS OF CHIRN OBSESSIVE
ILLEGALS AND OCCUPATIONAL
EXPOSURES AND AS YOU CAN SEE
THERE'S PLENTY OF DISEASE STATES
THAT WERE FOUND BETWEEN MALES
AND FEMALES, HOWEVER, WHEN
YOU'RE LOOKING AT THE
DIFFERENCES, THERE ARE MANY
DIFFERENCES HERE, PROMINENCE OF
DISEASES THAT ARE BASED ON SEX,
NOT NECESSARILY THE FACT THAT
THEY'RE HUMAN, THERE'S CANCER
RATES THAT ARE INCREASED BUT NO
CANCER IS--1 THAT IS PREDOMINANT
THAN THE OTHER, THERE'S VERY
DIFFERENCE ACUTE DIFFERENCES
BETWEEN THE 2 SEXES.
FURGT MORE WE'VE SEEN
DIFFERENCES IN OUR STUDIES WHERE
WE HAD THE RESPONSES FOR
READYIATION DONE ON NONHUMAN
PRIMATES SPECIAL AND WE SEE THAT
THE FEMALE MONKEYS ARE MORE
SENSITIVE TO RADIATION, AS YOU
CAN SEE ON THE LEFT HERE WE HAVE
2 FEMALE DOSE RESPONSE CURVES TO
HAVE BEEN DONE IN DIFFERENT
PLACES AND FEMALE DOSE RESPONSE
CURVE DONE IN DIFFERENT
LOCATIONS AND AS YOU CAN SEE
THEY REPEAT THEMSELVES PRETTY
EQUALLY AND IN DIFFERENT PLACES,
HOUR, WHEN YOU ARE LOOKING AT
THEM SEPARATELY, YOU CAN SEE
THOSE DIFFERENCES BETWEEN THE
MAIL AND THE FEMALE WHERE THE
FELL MALE IS MUCH MORE--FEMALE
IS MUCH MORE SENSITIVE THAN THE
MALE.
WE ALSO LOOKEDDA THE OTHER
MEDICAL COUNTERMEASURES THAT ARE
COMING TO OUR PORTFOLIO WHERE WE
SEE PRETTY GOOD EFFICACY,
PROFILES IN THE MALES AND THEN,
THE FEMALE IN THIS CASE, SHOWS
NO PROMISE.
AND SO, AGAIN, IT COULD BE A
MATTER OF DOSING--DOSE
OPTIMIZATION, IT COULD BE A
MATTER OF DETERMINING WHY THAT
IS, BUT WE--WE ARE AT THIS POINT
WE CAN'T REALLY DETERMINE WHAT
THOSE DIFFERENCES WILL BE.
SO BECAUSE OF ALL THESE FINDINGS
AND THESE DIFFERENT I GUESS
PROBLEMS THAT WE HAVE BEEN
SEEING, IS WE WANTED TO
UNDERSTAND THE STATE OF THE
SCIENCE IN OUR RADIATION SPACE
AND SO WE HOSTED THE NIAID
WORKSHOP IN 2022 AND THIS WAS
PARTNERED WITH THE NIH OFFICE OF
RESEARCH OF WOMEN'S HEALTH, IF,
DA OFFICE OF WOMEN'S HEALTH AND
BIOMEDICAL ADVANCE RESEARCH
AUTHORITY OR BARDA.
WE HAD OVER 24 PRESENTERS AND
OUR MEETDING GOALS WERE TO
EXAMINE SEX DIFFERENCES IN
PRECLIENAL PRODLES AND IDENTIFY
SEX DIFFERENCES AND BIOMARKERS
FOR AND TO ASSESS RADIATION
INJURIES AND EXPLORE CHALLENGES
IN MEDICAL RESEARCH LACKING
REPRESENTATION FROM BOTH SEXES
AND TO DISCUSS REGULATORY
POLICIES THAT INCLUDE WOMEN IN
RESEARCH.
AND FOINALLY TO EXPLORE THE REAL
WORLD SCENARIOS OF RADIATION AND
HOW THESE CAN IMPACT THE REAL
LIFE SCENARIO.
THERE ARE MANY.
WE SHOWED MANY GAPS IN THE
UNDERSTANDING OF THESE
DIFFERENCES AND WE THINK WE NEED
TO EXPLORE MORE AND HEPATITIS E
TO CAPTURE MORE OF THAT WITH THE
THIS INITIATIVE.
SO WE HOPE TO USE THE YEAR 1
COPRAATIVE AGREEMENTS SO THAT WE
CAN DO MORE WITH THE BASIC
RESEARCH THAT'S NECESSARY IN THE
SPACE.
BUT WE ALSO WANT TO HAVE THAT
PROGRAM ATDIC INPUT SO THAT IT'S
NOT JUST AN RO-1 THAT'S NOT
BEING, YOU KNOW I GUESS GUIDED
BY PROGRAM.
SO WE WANT TO DISCUSS MAYBE
POTENTIALLY CO FUNDING SOMETHING
WITH THE NIH OFFICE OF RESEARCH
ON WOMEN'S HEALTH AND THAT'S
STILL UP IN THE AIR BUT WE ARE
INTERESTED IN IT.
WE HAD A GOOD OPPORTUNITY TO
WORK WITH THEM AND THEY WERE
GREAT PARTNERS, AND WE HOPE THAT
THESE WILL BE 3 YEAR AWARDS.
AND WE EXPECT ABOUT 30
APPLICATIONS, AND 17 AWARDS
ANTICIPATED AND THAT'S IT.
ANY QUESTIONS?
>> GREAT PRESENTATIONS, IT'S
PRETTY OBVIOUS, THE NEED.
>> JUST 1 THING I'M WONDERING,
YOU SHOWED OR MENTIONED
DIFFERENCES IN HUMANS LIKE AFTER
CHERNYOBOL, AND THEN NONHUMAN
PRIMATE STUDIES, ALLUDED TO AS
WELL AS MOUSE, HOW IN THE MOUSE
STUDIES WHICH, YOU KNOW ARE
REALLY UNIVERSAL AND BASIC
RESEARCH LABORATORIES, HOW MUCH
OF A CORRELATE DO YOU THINK
THERE IS FOR, YOU KNOW FEMALE
MICE BEING AFFECTED AND THAT
ALSO BEING TRUE IN SAY HUMAN?
I MEAN THERE ARE GOOD EXAMPLES
OF SCENARIOS WHERE YOU KNOW
FEMALE AND 1 SPECIES IS SOMEHOW
ANALOGOUS TO YOU KNOW FEMALE
HUMAN?
>> SO WHAT WE FIND IS THAT IT
CAN BE VERY DEPENDENT ON WHAT
MODEL IT IS, SO, FOR INSTANCE,
WE HAVE TOTAL BODY RADIATION
MODELS, WE HAVE THE RADIATION
MODELS AND IN SOME CASES WE HAVE
PEOPLE THAT SHOW THE FEMALES ARE
MORE SENSITIVE AND IT LOOKS LIKE
THE NONHUMAN PRIMATE SCENARIO,
BUT IN SOME CASES IT'S OPPOSITE
SO WE'RE TRYING TO FIGURE THAT
OUT BECAUSE THERE'S NO
DIFFERENCES AND IT COULD BE ALSO
DUE TO THE SOURCE OF RADIATION
THAT THEY'RE USING IN SOME CASES
SO THERE'S A LOT OF QUESTIONS
THERE, BUT CERTAINLY WE SEE
DIFFERENCES IN SEXES.
WHY THOSE DIFFERENCES ARE
OCCURRING, WE'RE STILL FIGURING
THAT OUT AS WE GO.
NOTHING ELSE?
THANK YOU SO MUCH, I APPRECIATE
YOUR TIME AND HOPE THAT WAS
PRETTY CLEAR.
>> THANK YOU.
OKAY, THANK YOU.
LET'S THEN ASK FOR A APPROVAL,
RECOMMENDATION TO PROCEED WITH
THESE AND A SECOND.
AND WE WILL DO THAT ON BLOCK.
>> JUST REAL QUICK, SO DOCTOR
ARE YOU OKAY WITH THE ADJUVANT
PROGRAM, THE REQUESTY ABOUT--
>> YEAH, YEAH, WE RECOGNIZE IT
WAS MORE A QUESTION.
IT'S THE SAME QUESTION FOR THE
NEXT 1 AS WELL.
THE RADIATION SO WE ARE A LITTLE
HAND STRONG WITH THE WEAR WE
COMPARE HUMANS AND MICE, YES,
ABSOLUTELY.
>> YEAH, THANK YOU FOR BRINGING
THAT UP, IF ANYBODY HAS CONCERNS
WE SHOULD DISCUSS THESE
INDIVIDUALLY BUT I DIDN'T TAKE
THAT FROM THE DISCUSSION AFTER
EACH OF THEM THAT THERE WERE
CONCERNS THAT ROSE TO THAT
LEVEL, BUT IF HAVE YOU CONCERNS,
LET US KNOW, IF NOT WE SHOULD
MOVE AHEAD.
>> MOVE TO ADOPT THEM ALL.
>> SECOND,.
>> SECOND?
I HAVE A QUESTION ABOUT THE
VOTING SHOULD WE ALSO VOTEOT
ELECTRONIC COUNCIL BOOK?
>> YES.
>> PLEASE DO.
>> I THINK THE ANSWER IS YES
BUT--
>> YES, ABSOLUTELY, PLEASE VOTE.
>> GOOD.
>> WELL, THAT WRAPS US UP THEN
FOR THE DAY AND I JUST WANT TO
THANK YOU ALL FOR STICKING WITH
US AN EXTRA 10 OR 11 MINUTES AND
ALSO FOR YOUR ACTIVE
PARTICIPATION THROUGHOUT THE DAY
AND GWEN AND ANURADHA, AND
ELLING AND THANK YOU TO YOUR
SERVICE TO THE INSTITUTE AS
COUNCIL MEMBERS I REALLY REGRET
THAT MOST OF THAT TIME HAS BEEN
BY ZOOM AND THAT'S CHALLENGING
BUT HOPEFULLY, WE WILL HAVE THE
OPPORTUNITY TO SEE YOU IN PERSON
AT UPCOMING MEETINGS.
>> THANK YOU.
>> THANK YOU TO THE ENTIRE TEAM
THERE, I MEAN I KNOW THERE'S A
LOT OF PEOPLE IN THE BACKGROUND,
PRESENTATIONS ARE EVERY MEETING
ARE JUST FANTASTIC.
>> YES.
>> THERE'S ALWAYS ANTICIPATION,
SEEMS LIKE ANTICIPATE QUESTIONS
WE MIGHT HAVE AND BRING THEM UP
ON THE PRESENTATION, JUST, I
HAVE TO SAY IT'S BEEN MORE THAN
A PRIVILEGE TO BE ON THIS
COUNCIL AND I REALLY APPRECIATE
THE HARD WORK THAT EVERYBODY AND
THE TEAM THERE DOES TO MAKE IT
ALL HAPPEN.
THANK YOU.
SNSHES TOTALLY.
>> WELL, WE APPRECIATE THE HARD
WORK YOU DO.
THERE'S ALSO A LOAT BEHIND THE
SCENES THAT YOU ALL DO WITH THE
GRANTS THAT DON'T EVEN GET
DISCUSSED HERE BUT REQUIRE SOME
LEVEL OF REVIEW ON YOUR PART.
OKAY, WITH THAT I THINK THAT
WRAPS IT UP.
GWEN--
>> NO, NO I WAS SAYING THANKS IS
ALL.
ADDING IT ON.
WHAT A TIME TO BE ON COUNSEL
THOUGH RIGHT?
AND THEN WE GOT TO SEE COVID AND
EVERYTHING.
>> I KNOW, I KNOW.
>> ALTHOUGH MOST OF THE TIME WE
DID SEE THE TRANSITION, IT'S
QUITE MEMORABLE.
>> YEAH AND YOU WITNESSED TONY'S
LAST COUNCIL.
>> YEAH.
AT LEAST AS THE HEAD OF THE
INSTITUTE, I HOPE, YOU KNOW, I'M
SURE SOMEBODY WILL INVITE HIM
BACK TO GIVE TALKS ON THIS OR
THAT AT SOME POINT, AND IT'S
HISTORIC.
ALL RIGHT, WELL THANK YOU AND
ENJOY THE REST OF THE DAY AND
HOPE TO SEE YOU ALL SOON.