>> I'M DAN KASTNER
AN ACTIVE SENIOR INVESTIGATOR
FOR THE NATIONAL HUMAN GENOME
INSTITUTE IT'S AND MY PLEASURE
TO WELCOME YOU TO THE EAST COAST
UNITED STATES TIME THE SIXTH
INSTALLMENT OF THE 22nd YEAR OF
DEMYSTIFYING MEDICINE.
OF COURSE IT'S ESTABLISHED TO
BRIDGE THE EXCITING DEVELOPMENTS
IN BIOLOGY AND ENGINEERING WITH
ADVANCES IN MEDICINE.
AND WE HAVE THE ICON PHOTO OF
THE CONSTRUCTION OF THE BROOKLYN
BRIDGE WHICH IS SUPPOSED TO
CONVEY TO US THIS IDEA THAT WE
ARE BUILDING BRIDGES IN THIS
COURSE.
BRIDGES BETWEEN MEDICINE AND
SCIENCE MEDICINE AND ENGINEERING
AND BRIDGING THEM AND THE TWO
GUYS ON THE BRIDGE ONE FROM
BROOKLYN, ONE FROM MANHATTAN
ABLE TO DISCUSS THE LATEST
ISSUES OF THE 1870s WITH REGARD
TO SCIENCE AND MEDICINE.
TODAY, THIS AFTERNOON WE A
NATIVE NEW YORKER AND
TRANSPLANTED NEW YORKER.
WE'LL ALSO BE TALKING ABOUT THE
LATEST INTERESTS IN JAK
INHIBITERS AND AUTOIMMUNITY.
THE LEAD-OFF SPEAKER IS
DR. ANGELA CHRISTIANO THE
PROFESSOR OF DERMATOLOGY AND
DEVELOPMENT AT THE COLUMBIA
COLLEGE OF PHYSICIANS AND
SURGEONS.
SHE GOT HER BACHELOR'S, MASTER'S
AND Ph.D. DEGREES FROM RUTGERS
AND WENT TO PHILADELPHIA TO DO
HER POST-DOCTORAL TRAINING AT
JEFFERSON MEDICAL COLLEGE.
SHE'S WON A NORM NUMBER OF
AWARDS AND HONORS INCLUDING THE
WILLIAM MANTEGNA LECTURESHIP FOR
INVESTIGATIVE DERMATOLOGY AND
FROM THE NATIONAL ACADEMY OF
SCIENCE.
HER LABORATORY STUDIES INHERITED
SKIN AND HAIR DISORDERS IN
HUMANS AND MICE TAKING A
CLASSICAL GENETIC APPROACH THEY
ALSO WORK ON THE TRANSCRIPTIONAL
REGULATION OF ENDOGENS AND THEY
DO WORK ON THE GENETIC AND
CELL-BASED THERAPIES FOR SKIN
AND HAIR DISEASES.
THE SECOND SPEAKER IS THE GOOD
DOCTOR JOHN O'SHEA THE
SCIENTIFIC DIRECTOR AND CHIEF OF
IMMUNOLOGY AND INFORMATION
BRANCH AT THE NATIONAL INSTITUTE
OF ARTHRITIS AND MUSCULOSKELETAL
SKIN DISEASE AND DID HIS
TRAINING IN SYRACUSE AND
ALLERGY, IMMUNOLOGY SUBTRAINING
AT THE NIH.
HE'S PROUD TO SAY HE WAS THE
IRISH IMMUNOLOGIST OF THE YEAR
AND HAD THE PUBLIC LECTURE AWARD
SEVERAL YEARS AGO AND THE
RECIPIENT OF THE HOWLEY PRIZE
AND ROSS PRIZE AND MILSTEIN
PRIZE AND NATIONAL ACADEMY OF
MEDICINE AND DEMONSTRATED THE
ROLE OF JAK 3'S ROLE IN COMBINED
IMMUNODEFICIENCY DISEASE AND T
CELL DIFFERENTIATION AND
CYTOKINE SIGNALLING IN HEALTH
AND DISEASE AND THERAPEUTIC USE
OF JAK INHIBITERS IN AUTOIMMUNE
DISEASE.
TAKE IT AWAY.
>>WHAT A WARM WELCOME AND THANK
YOU TO DR. ARIAS AND FOR YOU FOR
HAVING US IN THIS SERIES.
WHAT AN HONOR.
WE'RE SO HAPPY TO BE HERE.
I USUALLY FOLLOW JOHN AND IT
MAKES MY JOB EASY AND TODAY HE
SUGGESTED WE CHANGE IT UP A BIT.
WE'LL DO A BIT OF A SPLIT TALK
AND I'LL INTRODUCE YOU TO A
DISEASE CLOSE TO MY HEART,ALL
ALOPICIA AREATA.
THIS IS WHERE THE BODY
RECOGNIZES ITS OWN HAIR DISEASE
AS FOREIGN AND AFFECTS ROUGHLY 7
MILLION PEOPLE IN THE
U.S. ALONE.
IT'S AN EQUAL OPPORTUNITY
DISORDER.
IT HAS NO GENDER BIAS.
IT AFFECTS ALL ETHNIC GROUPS
EQUALLY.
AND IT COMES IN A WHOLE SPECTRUM
OF SEVERITY RANGING FROM SMALL
PATCHES THAT BEGIN HERE ON THE
SCALP AND SOMETIMES ON THE BEARD
IN MALE PATIENTS THEY CAN GROW
LARGER.
THEY CAN COALESCE TO FORM LARGER
REGIONS HERE AND EVENTUALLY CAN
COVER THE ENTIRE SCALP OR BODY.
FOR MANY YEARS THE IMMUNE
INFILTRATE THAT SURROUNDS THE
HAIR FOLLICLE HAS BEEN A
MYSTERY.
WE KNEW IT WAS A COMPLEX SET OF
IMMUNE CELL TYPES AND BEGINNING
TO DISSECT WHAT THOSE CELLS DO
AND HOW THEY ACT.
THINK OF IT AS THE FRAMEWORK OF
THE LARGER FAMILY OF SKIN
AUTOMATIC DISEASE AND I'LL
INTRODUCE TO YOU ONE THE CONCEPT
OF IMMUNE PRIVILEGE BECAUSE IT'S
SOMETHING WE'LL TALK ABOUT
THROUGH THE REST OF TODAY AND
UNLIKE OTHER TISSUE SITES AND
THE HAIR FOLLICLE IN ITS NORMAL
STATE EXISTS IN A STATE OF
IMMUNE PRIVILEGE.
MEANING IT'S PROTECTED BY
RECOGNITION BY THE IMMUNE SYSTEM
BY OVER EXPRESSION OF WHAT IS
CALLED IMMUNE PRIVILEGE
GUARDIANS.
AND THE STATE OF IMMUNE
PRIVILEGE CAN BE DISRUPTED AND
LOWERS THE SHIELD ALLOWS AN
IMMUNE RESPONSE TO TAKE PLACE
WHEREBY THE HAIR FOLLICLE
RECRUITS IMMUNE CELLS FROM
BEYOND AND DRAWS THEM TO THE
ENVIRONMENT AND SETS UP THE
VICIOUS CYCLE WHEREBY DANGEROUS
SYMPTOMS ARE EXPRESSED THAT
RECRUIT IMMUNE CELLS WHICH ADD
TO THE FIRE AND SET UP THIS
VICIOUS CYCLE.
THERE'S SEVERAL PLACES WE CAN
THINK OF INTERVENING.
ONE IS AT THE LEVEL OF IMMUNE
CELLS AND AT THE LEVEL OF
RESTORING THE HAIR FOLLICLE BACK
TO THE STATE OF IMMUNE
PRIVILEGE.
WHEN WE THINK ABOUT
THERAPEUTICALLY TARGETING THE
DISEASE IT'S COMPLICATED BUT
IT'S ALSO ONE THAT'S RIPE WIN
OPPORTUNITY.
IMPORTANTLY, ALSO THE HAIR
FOLLICLE DOES NOT UNDER GO
PERMANENT DAMAGE IN THE DISEASE.
THE IMMUNE RESPONSE IS THE
BOTTOM OF THE HAIR FOLLICLE.
THE PART THAT TURNS OVER ON A
REGULAR BASIS.
THE STEM CELL COMPARTMENT IS
FAIR AND FOR PEOPLE WHO HAD
ALOPECIA AREATA FOR DECADES THE
HARDWARE OF THE HAIR FOLLICLE IS
IN TACK AND IN THEORY IF WE CAN
REVERSE THE IMMUNE RESPONSE
EVERYTHING NEEDED TO MAKE A HAIR
SHAFT IS INTACT AND HAS BEEN
SPARED IN THE DISEASE AND THAT'S
AN ADVANTAGE WHEN WE THINK OF
HOW TO GO ABOUT TAKING IT A
PART.
ALOPECIA AREATA COMES UP IN THE
NEWS BECAUSE IT'S A COMMON
DISORDER BUT WHEN CELEBRITIES OR
ACTORS OR ATHLETES EXPERIENCE
THIS THEY BEGAN TO EMBRACE IT
AND BE OPEN AND WHERE PEOPLE
WOULD WEAR A HAIR PIECE OR
PROSTHETIC TO DISGUISE IT.
WE TEND TO THINK THAT ALOPECIA
IS A RECENT DISCOVERY HOWEVER,
WHAT I WANTED TO DO TODAY IS
TAKE I BACK IN TIME AND NOT JUST
FOR OBSERVATIONAL PURPOSES BUT
CLUES FOR WHAT PEOPLE WERE ING
ABOUT ALOPECIA AREATA AND THIS
IS AN ARTICLE BY MY COLLEAGUE
WHO WROTE A BEAUTIFUL AND
ILLUSTRATED HISTORY OF ALOPECIA
AREATA AND SHARED WITH ME HIS
SLIDE.
THE EARLIEST KNOWN RECORDING OF
THIS IS 1500 B.C. AND YOU'LL
FIND PLANT MIXTURES OR ELIXIRS
THAT WERE THOUGHT TO BE APPLIED
THE FIRST APPEARANCE OF THE WORD
ALOPECIA IS HERE AND WE'LL TALK
ABOUT WHY IT'S CALLED THIS.
AND IF YOU LOOK AT THE
LITERATURE THE WORD COMES FROM
THE WORD FOR SNAKE AND YOU SEE
EARLY DESCRIPTION SAYING
WHATEVER IS DRIVING THIS DISEASE
IS NOT A PROBLEM OF A WESTERN
DIET.
FOR EXAMPLE BECAUSE IT'S EXISTED
LONG BEFORE MANY OF THE
ENVIRONMENTAL CHALLENGES WE
CURRENTLY KNOW AND THINK ABOUT
AND YOU SEE THERE WAS THOUGHT
THEY HAD BEEN TOUCHED BY AN EVIL
SPIRIT OR GHOST.
IT COULD BE A ROUND CIRCLE OR IN
THE SHAPE OF FINGER OR SNAKE.
IT'S NOT ITCHY.
THIS IS A QUIET INFLAMMATORY
STATE AP AND IT WAS DESCRIBED
TO LOOK LIKE A MANGY FOX AND
THIS WORLD ALOPECIA NOW REFERS
TO MANY TYPES OF HAIR LOSS BUT
THE PARTICULAR TYPE OF ALOPECIA
AREATA ARE SNEAKY PATTERNS OF
HAIR LOSS AND THIS NOW IS THE
WORD WE USE THAT FIRST APPEARED
1700 AS ALOPECIA AREATA.
THIS DISEASE GOES BACK IN
HISTORY AND KEVIN DID AN
EXTRAORDINARY JOB OF COLLECTING
THE HISTORICAL REPRESENTATIONS
IN THE MEDICAL LITERATURE FOR
YEARS.
THIS FROM 1817.
THE FIRST MODERN DESCRIPTIONS OF
THE DISEASE.
READ CAREFULLY.
PATCHES OF THAT SURROUND IT ARE
THICK.
THERE WERE ATTEMPTS TO EXPLAIN
WHAT MAY CAUSE THE DISEASE AND
NUTRITION, STRESS, INFLAMMATION
AND ENDOCRINE DISORDERS AND
FINALLY IN THE 1950s THE CONCEPT
OF MAYBE IT'S AUTOIMMUNE.
BRIEFLY TO LOOK AT DO WE THINK
OF MICROBES OR FUNGAL INFECTIONS
AND CAREFULLY OBSERVING AND
WATCHING THE ONSET OF THE
DISEASE AS IT GOES ALONG WITH
VARIETAL TRIGGERS HERE AND
THEY'RE TALKING ABOUT NUTRITION.
WE KNOW IRON DEFICIENCY OR
HORMONE CAN INFLUENCE HAIR
GROWTH.
THINKING ABOUT ALL SORTS OF
THINGS THIS THEORY HAS BEEN
AROUND AND IN THE 1800s IT WAS
THOUGHT THIS COULD HAPPEN
OVERNIGHT OR BEING STRUCK BY
LIGHTNING OR TRAUMATIC BLOW TO
THE HEAD.
SOME LOCAL INFLAMMATORY RESPONSE
OR EVEN A PSYCHOSOCIAL SHOCK OR
TRAUMATIC INJURY AND IN HISTORY
WE KNOW THE MOST FAMOUS EXAMPLE
OF SOMETHING THAT'S CALLED
SUDDEN WHITENING OF THE HAIR
WHERE IT QUOTE TURNS WHITE
OVERNIGHT.
SOME OF THE EARLIEST DOCUMENTS
ARE IS MARIE ANTOINETTE WHOSE
HAIR TURNED WHITE BEFORE SHE WAS
EXECUTED.
WHEN WE THINK OF WHAT IS THE
AUTOREACTIVE T CELL AND IT'S
INTERESTING TO GO BACK TO THE
HISTORICAL ACCOUNTS AND THINK
WHERE THE NOTIONS IN THE FIELD
ORIGINATED.
THERE WAS AN IDEA THERE WERE
COMPULSIONS OR THINGS THAT COULD
TRIGGER ALOPECIAARY
THIS SHOWS INFILTRATE AND
INFLAMMATION AROUND THE HAIR
FOLLICLE.
THE FIRST THOUGHT OF IT BEING AN
INFLAMMATORY DISEASE CAME FROM
ITALY AND LEUKOCYTES BRINGING
THIS STRANGE INFILTRATION AND
AFFECTING THE HAIR FOLLICLE AND
CAREFUL OBSERVATIONS WE TOUCH ON
AND THEN IN THE 1950s STEVEN
ROTHMAN IN THE FIELD OF
DETERMINE -- DERMATOLOGY AND
LOOKED AT THESE ANTO GGENS AND
HAVE TREATMENTS WE'RE USING TO
THIS DAY IN ALOPECIA AND
REPROGRAMMING OR RESETTING THE
IMMUNE RESPONSE USING ANOTHER
KIND OF IRRITANT HAS AROUND 300
YEARS NOT A NEW IDEA.
THE NOTION OF STEROIDS GREW IN
THE 1950s BY DR. ROTHMAN AND
OTHERS WHO TREATED PATIENTS WITH
TOPICAL OR INJECTED STEROIDS AT
THE TIME AND GOT REGROWTH IN A
GENERIC WAY.
THIS LAID THE GROUND WORK FOR
THE GROUND WORK IMMUNOMODULATORY
AFFECTS ARE IN PLAY AND MAYBE
ALOPECIA AREATA IS A ONE OFF OF
PSORIASIS AND ECTOPIC DERMATITIS
AND THE APPROACH WAS TO TAKE A
NEWLY APPROVED DRUG AND TESTING
IT IN THIS AND HAVING THEM FAIL.
AND NONE OF THEM COULD CREATE
REVERSAL OF ALOPECIA AREATA AND
WHY IS THAT?
RIGHT NOW YOU'RE PROBABLY
FEELING LIKE I FELT WHEN I
ENTERED THE FIELD.
THERE'S SO MANY THINGS INVOKED
TO EXPLAIN WHY THE HAIR MAY BE
SUDDENLY FALLING OUT AND WHERE
THE DISEASE IS NOT SO OUTWARDLY
VISIBLE.
PEOPLE HAVE BEEN FASCINATED WITH
THE DISEASE FOR CENTURIES MAINLY
BECAUSE IT'S SO VISIBLE.
IT'S A DOUBLE-EDGED SWORD.
FOR PATIENTS IT'S A DISTRESSING
THING FOR THE WORLD TO SEE WHAT
THEY'RE GOING THROUGH AND FROM
THE SCIENCE SIDE IT MAKES IT
DIFFICULT TO DECIDE WHERE WILL
YOU ENTER THE CONVERSATION AND
TRY TO GET AN INROAD TO WHAT'S
HAPPENING AND THE DRUMBEAT GREW
LOUDER MOSTLY BASED ON CASE
REPORTS OF TWINS OR MULTIPLEX
FAMILIES WITH NUMEROUS FAMILY
MEMBERS AFFECTED NOT PARENT TO
CHILD TRANSMISSIONS BUT
IMMIGRATION IN THE LIVING ROOM
OF FIRST GENERATION A GIRS
DEGREE RELATIVE AND THINGS
ADVANCE THEY'D BEGAN TO PAY MORE
ATTENTION TO THE NOTION PERHAPS
THERE'S A GENETIC DRIVE AND THEY
LOOK AT THE TWIN STUDIES WHICH
SHOWED COULD BE CORDAN ANAN AAN
CONCORDANCE OF 21% AND THERE
MUST BE ANOTHER ENVIRONMENTAL
TRIGGERING AFFECT THAT BRINGS
THE GEEPT IN -- GEN
GENETIC FACTORS.
AND THEN IN THE '90s AND EARLY
2000s CANDIDATE GENES WERE
TESTED AND AS GENES WERE
IMPLICATED FROM OTHER
AUTOINFLAMMATORY AND AUTOIMMUNE
DISEASES THEY WOULD BE TESTED IN
A BIASSED WAY BY LOOKING ONE
GENE AT A TIME.
THE BEGINNINGS OF DISEASE
ASSOCIATIONS BEGAN TO GROW
DURING THAT TIME.
FOR ME THIS CHANGED MAY 10,
1996.
THE REASON IS BECAUSE I
DEVELOPED ALOPECIA AREATA.
THIS IS MY SCALP.
I EVENTUALLY DEVELOPED TEN SPOTS
LIKE THIS OVER THE COURSE OF A
TWO-YEAR PERIOD AND EVEN THOUGH
I HAD WORKED IN DERMATOLOGY AT
AS A POST-DOCTORAL FELLOW I
WORKED AND A DIFFERENT GROUP OF
DISEASES AND JUST MOVED TO
COLUMBIA TO SET UP MY OWN LAB
WAS LOOKING FOR WHAT I'D BE
DOING THE REST OF MY INDEPENDENT
CAREER AND THEN SIX MONTHS LATER
ALOPECIA AREATA CAME KNOCKING ON
MY DOOR AND I BECAME VERY
INTERESTED IN THE BACKGROUND
LITERATURE BECAUSE OF MY
TRAINING IN GENETICS WHEN I
LOOKED AT THIS AND I KNEW VERY
LITTLE.
THERE WERE NO LINKAGE OR GWAS
STUDY REALLY NOTHING TO BUILD
OFF OF.
AROUND THIS TIME AND WHEN THEY
WERE GETTING ATTENTION FOR THEIR
POTENTIAL IN IDENTIFYING DISEASE
RELEVANT PATHWAYS AND
POTENTIALLY MOVING DRUGS TOWARDS
THE CLINIC.
IT WAS VERY TEMPTING AS A YOUNG
FACULTY MEMBER TO DREAM OF THE
IDEA TO DO A GWAS STUDY IN
ALOPECIA AREATA SOME DAY.
THERE WERE NO COLLECTIONS
SITTING AROUND OF MULTIPLEX
FAMILIES AND NO LARGE CASES OR
CONTROLS TO BE DRIVEN OFF THE
SHELF AND IN 199 WE DIDN'T EVEN
HAVE A FULLY ANNOTATED GENOME SO
IT WAS EARLY DAYS.
I'M GRATEFUL TO NIAMS AND THE
NATIONAL ALOPECIA FOUNDATION
SAYING IF WE WANT TO MAKE A DENT
IN THE DISEASE WE'LL NEED A
COHORT.
THE NIH FOUNDED AND FUNDED A
REGISTRY FOR 10 YEARS.
WE WERE ONE OF FIVE SITES
TOGETHER TO ALLOW THE COLLECTION
AND ASCERTAINMENT OF 3,000
PATIENTS AND CONTROLS AS WELL AS
WE WERE ABLE TO USE AND ACCESS
TO A CONTROLLED DATABASE FROM
NEW YORK.
THIS WAS EARLY IN THE DAYS OF
GWAS THEY WERE DOING 1,000
PATIENTS VERSUS 1,000 CONTROLS
AND WAS NOT HOPEFUL WE'D FIND
ANYTHING.
TO OUR SURPRISE THE GWAS STUDY
WAS CLEAN.
THE REASON FOR THAT IS BECAUSE
THE PATIENTS WERE VERY CAREFULLY
PHENOTYPED FROM THE OUTSET.
THE SAME GROUP OF DERMATOLOGISTS
SAW AND COLLECTED ALL THE
SAMPLES AND THE PURITY OF THAT
INFORMATION LED TO THIS AND THEY
HAD EIGHT REGIONS AT THE
BEGINNING.
OF COURSE THE HLA BECAUSE WE
BELIEVE ALOPECIA AREATA IS AN
AUTOIMMUNE DISEASE AND THE
SECOND MOST SIGNIFICANT HIT IS
THE LOCUS CALLED PRDX5 AND
THEY'RE DANGER SIGNALS WHEN THEY
SAY COME IN AND KILL ME FROM THE
IMMUNE SYSTEM.
THEY CAPTURED OUR ATTENTION.
OTHER THINGS THAT WERE
DISCOVERED THAT WAS EXCITING
PEOPLE IS A GENETICISTS ALWAYS
LOVES WHEN WE GET WHAT WE CALL A
SMOKING GUN AND IF THIS WAS
THESE OTHERS NOT SO EXCITING BUT
THIS ONE WAS UNIQUE AND STILL
IS.
THERE'S NO OTHERS HAVE THE
LIGAND AS THEIR CANDIDATE LOCI
AND WERE EXCITED THIS WAS
LEADING US DOWN A PATH THAT WAS
DIFFERENT.
AND THE SECOND THING THAT CAME
FROM THE STUDY IS THE
REALIGNMENT OF WHAT ALOPECIA
AREATA MAY BE RELATED TO AND IT
MAY RESEMBLE VITILIGO AND
DERMATITIS BUT IT RESEMBLED
RHEUMATOID ARTHRITIS AND THERE'S
WORK ON THE DISEASES AND ALL ARE
UNITED BY THE FACT THEY'RE
DRIVEN BY SIMILAR CYTOKINE
SIGNALLING AND THE AXIS IS
CENTRAL TO ALL OF THEM.
THE GWAS STUDY WAS LATER
REPLICATED BY A LARGER COHORT
PUT TOGETHER WITH COLLEAGUES IN
GERMANY AND THEY'RE GETTING THE
CASE COUNTS UP CLOSER TO 3,000
AND EVENTUALLY 7,000 CONTROLS.
THEY WERE REP KATED AND THE
STRENGTH -- REPLICATED AND THE
STRENGTH OF THE SIGNAL SHOWED
THE UNIQUENESS OF THE GENES AND
THE STRENGTH OF THE SIGNAL WERE
TELLING US IT SEEMED LIKE A
FRUITFUL PLACE TO BEGIN TO LOOK.
WE SCANNED THE LITERATURE AND
WANTED TO LEARN EVERYTHING WE
COULD ABOUT THE LIGANDS IN THESE
DISEASES AND TURNED OUT IN
RHEUMATOID ARTHRITIS AND CELIAC
DISEASE THERE'S A RELATION IN
THE END ORGANS OF THESE
DISORDERS.
OUR QUESTION WAS DID WE SEE THE
SAME IN THE HAIR FOLLICLE.
THIS IS OUTLINED IN BLUE WITH
RED STAINING FOR THE LIGANDS
ULBP3 AND YOU SEE HERE A MASSIVE
UP REGULATION IN THE OUTER MOST
PART OF THE HAIR FOLLICLE AND
WE'LL TALK ABOUT THAT LATER.
WE WOULD HOPE WE SEE THE
RECEPTOR ON THE SURFACE OF T
CELLS SURROUNDING THE HAIR FOL
KALZ AND HERE YOU CAN SEE THAT'S
THE CASE WE HAVE COEXPRESSION OF
PD8 AND THE T CELLS SURROUNDING
THE HAIR FOLLICLE.
THIS WAS AN IMPORTANT MOMENT FOR
BECAUSE IT WAS THE FIRST TIME WE
HAD A BIT OF DEFINITION ABOUT
THE NATURE OF THIS INFILTRATE
AND I WAS WORKING WITH A
BRILLIANT IMMUNOLOGY COLLEGIATE
THE TIME AT COLUMBIA AND THEY
STUDIED THEM IN TYPE 1 DIABETES
AND CANCER.
AND THE FIELD KNOWS A LOT ABOUT
THE CELLS TOO ESPECIALLY WHAT'S
REQUIRED TO KEEP THEM ALIVE.
THEY REQUIRE IL15 SIGNALLING FOR
THEIR SURVIVAL AND WHEN
ACTIVATED IN ANGRY THEY CREATE
INTERFERON GAMMA.
AGAIN, THIS IS EARLY DAYS OF THE
LITERATURE BUT WE BEGAN TO
ALREADY THINK ABOUT HOW COULD WE
INTERRUPT THE SIGNALLING AND
RATHER THAN TAKE THE APPROACH OF
USING BLOCKING ANTIBODIES
BECAUSE ALOPECIA AREATA HAS A
COSMETIC DISEASE AND NO KNOWN
COMORBIDITY SAFETY WAS TOP OF
MIND AND THE THOUGHT OF
INTERVENING DOWN STREAM THE IL15
PATHWAY BECAME SOMETHING WE
FOCUSSED ON AND DOWN STREAM
YOU'LL LEARN IN A FEW MINUTES
VERY WELL ABOUT THE JAK
SIGNALLING PATHWAY.
BECAUSE WE KNEW WE HAD BOTH IL15
AND INTERFERON GAMMA AS OUR
CYTOKINE AXIS WE BEGAN TO FOCUS
ON TRYING TO IDENTIFY JAK
INHIBITERS TO TEST IN THE
DISEASE.
IL15 AND THE SIGNAL THROUGH JAK
1 OR JAK 2 OR JAK 3 AND THE TIME
THE DRUGS WERE COMING TO MARKET
AND YOU'LL NOTICE THIS GOES TO
THIS AND HE'LL TELL YOU ABOUT
THE JAK INHIBITORS IN HIS WORK
AND I'LL COME BACK WHEN HE'S
FINISHED AND TALK ABOUT HOW WE
BEGIN TO APPLY THAT KNOWLEDGE IN
THE SETTING OF ALOPECIA AREATA.
I'LL TURN IT OVER TO JOHN.
THIS IS ITHE 30th ANNIVERSARY
OF THE JAK STAT PATHWAY AND IT'S
BEEN A DECADE SINCE WE STARTED
HAVING JAK INHIBITERS AND MY
JOB IS TO TALK ABOUT CYTOKINE
SIGNALLING AND THE RATIONALE AND
HISTORY OF THIS JAKINIBS AND
THINK OF CYTOKINE SIGNALLING
WHICH STARTED IN THE LATE '80s
AND '90s AND HOW WE THINK OF
CYTOKINE SIGNAL.
THESE ARE REFERENCES OR IF YOU
HAVE TO GIVE LECTURES SEND ME A
NOTE I'M HAPPY TO SEND MY SLIDES
WITH MY CARTOONS TO GIVE ME TALK
AS WELL.
HERE'S ARE MY DISCLOSURES.
THE NIH HAS A PATENT ASSOCIATED
WITH JAK INHIBITERS AND I GET
ROYALTIES FROM THAT AND WE HAD A
LONG-STANDING COLLABORATION WITH
PFIZER WHICH ENDED.
AND WHEN YOU THINK BROADLY HOW
WE FACE ALL THE MANY TYPES OF
MICROBIAL PATHOGENS WE FACE WE
HAVE MANY CELLS INVOLVED WITH
HOST DEFENSE AND HOW DO THEY
COMMUNICATE WITH EACH OTHER?
ONE OF THE BIGGEST SOLUTIONS FOR
THE COMMUNICATION BETWEEN THE
CELLS AS ANGELA POINTED OUT,
HAVE LOADS AND LOADS OF
CYTOKINES PRODUCED BY DIFFERENT
CELLS AND THEY RESPOND TO THE
CYTOKINES AND THEY'RE IMPORTANT
FOR HOST DEFENSE BUT A NUMBER OF
THINGS TO THINK ABOUT.
IT'S IMPORTANT FOR THINK OF
EFFICACY AND ADVERSE EVENTS.
CYTOKINE IS A HISTORICAL TERM
AND DOESN'T REFER TO A
PARTICULAR STRUCTURAL CLASS OF
LIGANDS OR RECEPTORS AND USED
WIDELY FOR THINGS AND IT'S
IMPORTANT FOR HOST DEFENSE AND
CYTOKINES ACT ON CELLS AND
EVOLUTIONARY ALL CELLS START
FROM INVERTEBRATES HAVE A NEED
TO COMMUNICATE WITH ONE ANOTHER
AND THE LIKE AND SO IN FACT
CYTOKINES GO BACK TO
INVERTEBRATES AND THE JAK STAT
PATHWAY IS EVIDENCED IN INSECTS.
THIS WAY OF TALKING AMONGST
CELLS IS AN ANCIENT ASPECT OF
CELL-CELL COMMUNICATION.
IT'S CRITICAL FOR HOST DEFENSE
AND REPAIR AND HOMEOSTASIS AND
I'LL GET TO THAT IN A MOMENT.
THIS IS MY WAY OF THINKING OF
CYTOKINES AND THIS IS ONE WAY OF
CATEGORIZING CYTOKINES.
THERE'S TYPE 1 AND TYPE 2
CYTOKINES.
AND YOU SEE RECEPTORS AND THIS
IS AN ANCIENT PATHWAY GOING BACK
TO INVERTEBRATES AND EVEN PLANT
HAVE SOME ASPECTS OF THIS
PATHWAY.
17 RECEPTOR ALSO IN
INVERTEBRATES THEN THERE ARE
SOME CYTOKINES THAT USE RECEPTOR
AND KINASES AND SEVEN TRANS
MEMBRANE RECEPTORS ARE OTHER
RECEPTORS FOR CHEMOKINES.
AND YOU'LL SEE RHEUMATOID
ARTHRITIS CLOSE TO ALOPECIA
AREATA AND THERE'S CYTOKINES
INVOLVED IN THE PATHOGENESIS.
IF YOU THINK ABOUT THIS EVERY
DAY AND THINK ABOUT HOW TO WE
CAN USE THIS INFORMATION ON A
DAILY BASIS IT JUST SEEMS LIKE A
MORASS OF NUMBERS AND THE LIKE.
THERE'S PROBABLY MORE THAN 200
OR SO THINGS YOU CAN CALL
CYTOKINES IN THE GENOME.
IT'S IMPORTANT THEY DRIVE
AUTOIMMUNE DISEASE AND
CYTOKINES' NAMES ARE SOMETIMES
MISLEADING IN BROAD FUNCTIONS
AND CYTOKINE CAN INCLUDE GROWTH
FACTORS AND INTERLEUKINS AND
STIMULATING FACTORS.
IT DIDN'T MISS OR INDUSTRY
DIDN'T MISS THE EXPLOSION OF
CYTOKINE RECEPTORS AND LED TO
NOT JUST THE MOLECULAR BIOLOGY
REVOLUTION OF DISCOVERY BUT ALSO
BIO ONICS IN TERMS OF TARGETING
CYTOKINES AND I'M GIVING
EXAMPLES OF DIFFERENT CLASSES
SHOWN HERE.
DESPITE THE EFFICACY OF THESE
DRUGS, THEY'RE REALLY
EXTRAORDINARILY EFFICACIOUS AND
I'LL RETURN TO THE CLASS OF TNF
RECEPTORS AND NOT ALL PATIENTS
RESPOND TO THE DRUGS.
I'LL FOCUS ON CYTOKINE RECEPTOR
AND THIS IS ME ON THE RIGHT AND
DAN CAN TELL YOU THE STORY
LATER.
AND I WENT TO A LOT OF MEETINGS
WITH PEOPLE LIKE AND BECAME
INTERESTED IN PHOSPHORYLATION
AND ARD AND I REMEMBER VIVIDLY
HEARING PRESENTATIONS ABOUT
PEOPLE WHO STUDY GROWTH FACTORS
LIKE INSULIN AND OTHER FACTORS
AS WELL THESE RECEPTORS HAVE
INTRINSIC KINASE AND THE
RECEPTORS WITH KINASE ACTIVITY
INTRINSICALLY AND INDUCED
PHOSPHORYLATION OF SUBSTRATES IN
THE CELL.
I WAS INTRIGUED BY THE IDEA
CYTOKINES DID THIS AND THE
PATHWAY AT THE TIME WAS NOT
CLEAR.
THE FIELD BLEW UP BY PEOPLE AND
THE LAB OF GEORGE STARK WITH
SANDRA AND JIM DARNELL.
AND THE APPROACH MANY OF US TOOK
WE STARTED SCREENING LIBRARIES
FOR KINASES TO SEE IF THEY FIT
THE BILL FOR SIGNALLING AND THEY
GENERATED CELL LINES THEY USE TO
THIS DAY FOR CELL LINES
INSENSITIVE TO INTERFERONS.
AND THIS KINASE RESTORED
SIGNALLING IN THE INTERFERON
SENSITIVE LINE.
AROUND THE SAME TIME THEY USED
THE SAME STRATEGY THINKING ABOUT
LOCI THAT ARE RESPONSIVE TO
INTERFERONS AND HE USED
PROMOTERS FROM THE GENES AS BAIT
TO LOOK AT INTERFERONS AND
DISCOVERED THE STAT PATHWAY AND
STANDS FOR SIGNAL TRANSDUCER AND
ACTIVATOR OF TRANSCRIPTION.
ACTUALLY WHEN JIM CAME HOME AND
SAID TO HIS WIFE, I DISCOVERED
THESE THINGS THAT GIVE THIS
RAPID RESPONSE TO INTERFERONS
AND WAS THINKING I DON'T KNOW
WHAT TO CALL IT AND THIS IS A
TRUE STORY AND HIS WIFE SAID
WHAT DO YOU GUYS SAY WHEN
SOMETHING HAPPENS QUICKLY, YOU
SAY STAT.
IT'S QUICK.
AND JIM THEN TOOK STAT AND USED
THIS AS AN PATHWAY AND IT'S USED
BY CYTOKINES AND THE POWER OF
THESE LINES GENERATED BY GEORGE
STARK WAS OBVIOUSLY VERY CLEAR
WE DIDN'T KNOW THE IN VIVO
CRITICALITY OF JAK AND YOU WOULD
THINK PEOPLE WOULD MAKE VARIOUS
KNOCKOUT MICE WHICH WAS DONE BUT
THE IN VIVO CRITICALITY CAME
ABOUT A DIFFERENT WAY.
WE WERE TRYING TO CLONE KINASES
AND I FOCUSSED ON KINASES AND
LEUKOCYTES IN CATOLYTIC CELLS
AND WE CLONED JAK 3 AND NOTICED
IT WAS HIGHLY EXPRESSED IN
IMMUNE CELLS.
THAT GOT ME THINKING TO WHAT
MIGHT IT BE USED FOR.
AND A COLLABORATOR FOR A LONG
TIME FOUND THE CYTOKINES, HERE
SIGNAL THROUGH THIS RECEPTOR SUB
UNIT REFERRED TO AS THE COMMON
GAMMA CHANGE AND IT UNDER LIE
THE DISEASE IMMUNODEFICIENCY OR
THE BUBBLE BOY DISEASE.
AND WE WERE THINKING MAYBE IT
ASSOCIATED WITH THIS RECEPTOR
AND PROPOSE IF MUTATIONS TO THE
COMMON GAMMA CHAIN AND YOU GET
THIS DISEASE MAYBE IF YOU HAD
MUTATIONS THIS DISEASE AFFECTS
BOYS BUT YOU MIGHT IMAGINE AND
THERE WERE GIRLS WHO HAD A
SIMILAR DISEASE MUTATIONS OF JAK
3 MAY CAUSE A SIMILAR DISEASE
AND TURNED OUT TO BE TRUE AND WE
IDENTIFIED PATIENTS WITH JAK 3
MUTATIONS AND LAUREN AND I
COLLABORATED WITH A LAB AT DUKE
AND SHE ALSO HAD A COHORT OF
PATIENTS.
THIS WAS THE FIRST KNOCKOUT IN
THE JAK STAPP STAT PATHWAY AND A
NUMBER OF GROUPS MADE VARIOUS
KNOCKOUT MICE.
IN THE PAPER WE PROPOSED IF YOU
GENERATED A NEW CLASS OF DRUGS
YOU'D HAVE A NEW CLASS OF
IMMUNOEXPIMMUNO
EXPRESS SUPPRESSANTS AND THAT
WAS BOLD AND WHEN I FIRST DID
THIS IN 1993 THIS WAS A MEETING
WHEN I FIRST PRESENT THE CLOTH
AND RAN INTO PAUL.
AND WE HAD BEEN COLLABORATORS ON
DIFFERENT PROJECTS BEFORE HE
MOVED TO PFIZER.
AND PAUL WAS LOOKING FOR
POTENTIALLY TARGETS FOR PFIZER
TO START A PROJECT ON.
AND THIS IS DEPOSITED TO START
SIGNALLING.
THIS IS THE CHALLENGE AHEAD OF
US.
YOU MIGHT IMAGINE IF WE SAID TO
YOU RIGHT NOW WE WANT TO MAKE
DRUGS THAT TARGET ATP, YOU MIGHT
THINK THAT'S PRETTY FOOLISH.
BUT THAT FIELD AND THERE WAS MET
WITH PLENTY OF SKEPTICISM BACK
IN THE MID 90s OR SO.
A NUMBER OF DRUGS HAD REVERSIBLE
PHOSPHORYLATION.
AT THE TIME PEOPLE DIDN'T KNOW
THE BIO CHEMISTRY AND LOOKING AT
BIOLOGICS GENERATED FROM
PRODUCTS AND BACTERIAL PRODUCTS
ETCETERA.
WE DIDN'T KNOW THE DRUGS WERE
ALTERING PHOSPHORYLATION BUT IT
TOOK TARGETED THERAPY OF KINASES
AND THAT'S THE WORK AND TARGETED
THESE IN CML AND GENERATED A
DRUG THAT SELECTIVELY TARGET THE
KINASE AND YOU MAY THINK
TARGETING ATP WOULD BE A GOOD
IDEA THIS FLIPPED THE SWITCH AND
TARGETING KINASES IN THIS MANNER
BECAME A VERY ACTIVE AREA.
THIS IS WHAT HAPPENED WITH JAK
INHIBITERS.
FIRST JACK INHIBITERS WERE
APPROVED IN 2012.
AND THERE'S MANY JAK INHIBITERS
FOR ARTHRITIS IN CHILDREN AND
ULCERATIVE COLITIS AND
DERMATITIS AND ALOPECIA AREATA
AND PLAQUE SORIASIS AND THIS IS
ASSOCIATED WITH DAN CASTNER'S
EXTENDED LAB.
THIS IS LEO 6 YEARS OLD WAS WELL
UNTIL THREE YEARS BEFORE HE
PRESENTED TO THE NIH AND RASH
AND ITCHING AND SCRATCHING AND
TREATED WITH STEROIDS AND GOT
PUT ON A JACK INHIBITOR AND YOU
SEE LEO THREE WEEKS AFTER BEING
TREAT.
THIS IS TO REMIND YOU THERE IS
IN FACT JAK CANINE INHIBITERS AS
WELL AS HUMAN.
MANY DISEASES BEING TESTED AND A
LOT OF ACTIVITY AT THE NIH AND
WHERE PEOPLE STUDY ARE DIFFERENT
DISEASES.
THERE'S INTERESTING WORK FROM AN
NIH ALUM NOW IN NEW YORK WHO
POINTED OUT NERVES HAVE CYTOKINE
RECEPTORS AND JAK INHIBITERS CAN
RAPIDLY AFFECT ITCH AND THEY
ALSO IMPACT PAIN.
THIS IS AN IMPORTANT AREA GOING
FORWARD TO BE THINKING ABOUT NOT
JUST CYTOKINE RECEPTORS ON
IMMUNE CELLS AND NON-IMMUNE
CELLS AND HOW IT PARTICIPATES IN
OTHER ASPECTS OF DISEASE
ASSOCIATED WITH INFLAMMATORY AND
IMMUNE MEDIATED DISEASE.
AGAIN, DRUGS ARE TYPICALLY
ASSOCIATED WITH ADVERSE EVENTS
AND JAK INHIBITERS ARE NO
EXCEPTION.
THE THING WE EXPECTED EARLY ON
IS SEEING SERIOUS INFECTION WITH
JACK INHIBITORS AND IN
PARTICULAR HERPES ZOSTER IS A
DISEASE THAT CAN BE IN PATIENTS
TREATED WITH JACK INHIBITERS AND
YOU SEE CYTOPENIA AND
HYPERLIPIDEMIA AND PULMONARY
EMBOLI AND THE IDEA THEY'RE
BLOCKING GAMMA AND THE AFFECT OF
IMMUNE CELLS THAT ARE KEEPING
CANCER UNDER CONTROL SO THERE'S
CONCERN THERE'S ASSOCIATION WIN
CANCER AND MANY DISEASES ARE
ASSOCIATED WITH INFLAMMATION ARE
ASSOCIATED WITH ACCELERATED
CARDIOVASCULAR DISEASE AND
CANCER AS WELL.
THERE'S A LOT OF WORK TO
UNDERSTAND THE ISSUES AND THIS
IS THE BIGGEST TRIAL AND IT
INCLUDED MORE THAN 4,000
PATIENTS AND WAS A FOUR-YEAR
OPEN LABEL NON-INFERRIORITY
TRIAL AND THE DATA SHOWED THE
RISK OF CARDIOVASCULAR EVENTS
AND VENUS THROMBOSIS IN CANCER
AND THERE WAS A GREATER
LIKELIHOOD THAN TNF INHIBITERS
AGAIN IN A NON-INFERIORITY TRIAL
AND THE CONFIDENCE INTERVAL
EXCEEDED 1.7.
SO IN THIS CASE IT WAS A BROAD
RANGE OF RISKS.
BUT THE WAY THE TRIAL WAS DESIGN
NON-INFERIORITY WAS FAILED AND
THAT'S THE WAY THE TRIALS WORK
AND I'M NOT A STATISTICIAN SO WE
CAN DISCUSS THAT HEARD.
SERIOUS INFECTION IS WHAT A
THOUGHT BASED ON PATIENTS WITH
SKID AND IT TURNS OUT IT THIS
WAS SIMILAR TO TNF INHIBITORS
AND IF YOU LOOK DEEPLY YOU SEE
THE SITUATION WITH INDIVIDUALS
WHO ARE GREATER THAN 65 OR
SMOKED THEY HAVE HIGHER RISK
FACTOR WITH JAK INHIBITERS
VERSUS TNF INHIBITERS AND IF YOU
LOOK AT OTHER SUBJECTS YOUNGER
THAN AGE 65 AND DIDN'T SMOKE
THEIR INCIDENTS OF
CARDIOVASCULAR EVENTS WERE MUCH
DIFFERENT.
HAVE IMPORTANT TO THINK WHO IS
GETTING THE DRUGS AND PART OF
THE TRIAL WAS THAT THERE WAS NO
IN OF UNTREATED CONTROL GROUPS.
THESE DISEASES ARE ASSOCIATED
WITH INCREASED CARDIOVASCULAR
EVENTS AND RHEUMATOID ARTHRITIS.
WE DON'T REALLY KNOW THEY HAD
FEWER SIDE EFFECTS WITH THESE
WITH RISK FACTORS BUT WERE THEY
EFFECTIVE AND MAYBE TNF
INHIBITERS WERE NOT AS EFFECTIVE
IN PREVENTING THE RISK.
LET ME REPEAT.
THE QUESTION IS WHETHER JAK
INHIBITERS COULD IMPROVE RISK
BUT NOT AS GOOD AS TNF INHIBITOR
IN MINIMIZING THE EVENTS IN
PATIENTS WITH RHEUMATOID
ARTHRITIS WITH INCREASED EVENTS
INCLUDING CARDIOVASCULAR EVENTS
AND CANCER.
WE'RE STILL IN THIS UNCLEAR TIME
WHERE IT'S NOT GOING TO SHOW
WHAT POPULATION WILL BENEFIT
MOST FROM JAK INHIBITORS.
AND WE DON'T HAVE A FULL
UNDERSTANDING OF THE MECHANISM
OF CARDIOVASCULAR DISEASE AGAIN.
OR VENOUS THROMBOSIS AND THEY
MAY OR MAY NOT RELATE TO JAK
INHIBITERS.
WHAT CAN WE DO ABOUT GETTING
BETTER INHIBITERS AND BETTER
COMBINATIONS AND MAYBE BETTER
PATIENT SELECTION.
CAN WE IMPROVE SELECTIVELY AND
CAN WE AVOID JAK 2 INHIBITION AS
THE SIGCYTOKINES IMPACT
HEMATOPOIETIC CELLS.
AGAIN, THESE ARE THE FOUR JAKS,
1, 2 AND 3 AND THE FIRST JAK
FAMILY MEMBER AND SOME ARE
IMPORTANT FOR MULTIPLE CYTOKINES
AND SOME LIKE JAK 3 ARE
IMPORTANT FOR A LIMITED NUMBER
OF CYTOKINES.
YOU THINK MAYBE IT'S A GOOD
THING TO BLOCK CYTOKINES TO GIVE
EFFICACY IN DISEASES BUT CAN
ALSO GIVE MORE SIDE EFFECTS AND
IT'S IMPORTANT FOR A LOT OF
CYTOKINES SHOWN HERE AND HORMONE
LIKE CYTOKINES AND GROWTH
HORMONE AND ETCETERA.
ARE ARE THE CYTOKINES THAT USEK
AND A FIRST GENERATION JAK
INHIBITOR THAT HAVE THE CAPACITY
TO BLOCK ALL THE 57 CYTOKINES IN
PRINCIPLE.
NOW WE HAVE THESE SELECTIVE JAK
2 AND JAK 3 INHIBITORS AND WE
HAVE THE CAPACITY TO TARGET
LIMITED NUMBERS OF CYTOKINES AND
COMPARE AND CONTRAST THE
EFFICACY AND SAFETY WITH THE
DIFFERENT DRUGS.
THIS IS THE DRUG AND YOU SEE IT
BLOCKS IN THE SAME SITE BUT HAS
THE CAPACITY TO SELECTIVELY BIND
WITH SOME KINASES AND NOT
OTHERS.
WE HAVE OTHER OPTIONS.
AND FINALLY AFTER 30 YEARS WE
NOW HAVE THE COMPLETE STRUCTURE
OF KINASES AND THAT WAS SHOWN AT
THE END OF 2022.
THIS IS WHAT THE STRUCTURE LOOKS
LIKE.
THIS IS THE KINASE AND NAME OF
JAK INHIBITERS AND SEE THE
FUNCTION OF THE KINASE DOMAIN
WHICH MAKES IT HANDSHAKE WITH
THE OTHER JAK.
THAT'S HOW IT TRIGGERS
SIGNALLING IN CELLS.
IN PRINCIPLE YOU THINK
UNDERSTANDING THE JAK STRUCTURE
WE'LL BE ABLE TO MAKE BETTER
DRUGS.
WE TARGET THE DOMAIN AND YOU NOW
THEY HAVE ALLOSTERIC DOMAINS AND
THAT INCLUDES LIKE A JAK 1
INHIBITOR.
YOU IMAGINE WE GET MORE
SPECIFICITY WITH THESE DRUGS AND
AND SOME AVOID TICK 2 AND USING
OTHER INHIBITERS YOU GET MORE
SPECIFICITY.
TO UP THE TALK THIS IS HOW WE
SAW THINGS IN THE '90s IN THE
JAK STAT PATHWAY AND DIDN'T
INCLUDE ALL THE INFORMATION
LEARNED WITH THE DISCOVERY OF
THE HUMAN GENOME AND ONLY 2%
WERE GENES.
AND THE PROPOSAL WAS MAYBE THE
REST OF THE GENOME IS JUNK AND
WHAT WE NOW KNOW IS IT GOES
BEYOND TRANSCRIPTION FACTORS
GOING TO THE LIMITED PARTS OF
THE GENOME.
INSTEAD MUCH IS ACTIVE AND
THERE'S THOUSANDS OF ENHANCERS.
MUCH OF THE GENOME IS
TRANSCRIBED IN NON-CANONICAL
GENES THAT DON'T ENCOAT PROTEIN
SO WE LOOK AT ENHANCER DEFINED
BY DIFFERENT FACTS AND CHIP SEQ
AND THEN WHAT WE ALSO KNOW IS
HAVE THIS IN PERIMETER AND
HERE'S THIS TINY GENE AND ALL
AROUND ARE REGULATORY ENHANCERS
AND DEFINED BY P300 AND
ENHANCERS ARE PRESENT IN TH1
CELLS AND THIS IS ALL PRETTY
VACANT HERE.
HERE'S REFERRED TO INTERFERON
GAMMA A AND DESCRIBED IN THIS
DIRECTION.
ENHANCERS ARE ENRICHED WITH THE
LINK RNAs.
THIS IS LINKED TO IBD IN HUMANS
AND WE FOUND IF WE DELETE THIS
YOU HAVE INCREASED
SUSCEPTIBILITY TO INFECTION AND
DECREASED PRODUCTION AND THE
WORK WAS DONE HERE IN MY LAB.
WE FOUND YOU SEE THIS IN
PATIENTS WHO HAVE BEEN
VACCINATED WITH YELLOW FEVER 10
YEARS AFTER THEIR VACCINATION.
SO WE HYPOTHESIZE THE PRODUCTION
OF THIS ENCODING RNA IS RELEVANT
ACUTELY AND POSSIBLY IN MEMORY
AND VACCINES, ETCETERA.
THE YOU HAVE THE INTERACTIONS
AND THE STRUCTURE MATTERS IN
TERMS OF EXPRESSION OF GENES
THIS IS WITH IL22 AND AN
INVESTIGATOR WAS INTERESTED HOW
THE ORGANIZATION OF THE GENOME
CHANGES WHEN YOU TAKE NAIVE
CELLS AND POLARIZE THEM TO
INTERFERON GAMMA AND YOU SEE
REORGANIZATION OF THE HUMAN
GENOME AND NOTICED THE PEEK OF
THE ARCHITECTURAL PROTEIN
BINDING IN PROXIMITY OF THE
WHOLE CYTOKINE LUCAS TO THE
ENCODING RNA BEYOND THIS
CYTOKINE AND THEY THOUGHT WHAT
HAPPENS IF WE TAKE OUT THIS
PIECE OF RNA AND WHAT HAPPENS IS
YOU ALTER THE ARCHITECT TURE OF
THIS LOCUS AND IT SPARES
INTERFERON PRODUCERS IN CD8 T
CELLS BUT BLOCKS THE PRODUCTION
OF GAMMA IN DEVELOPING TH1
CELLS.
THIS IS WHAT WE WERE HOPING TO
SEE.
ARCHITECTURE IS IMPORTANT BUT
IT'S IMPORTANT IN THE CELL
SPECIFIC MANNER.
THIS IS THE LAST STORY I'LL TELL
YOU NOW THAT WE HAVE INCREASED
ABILITY TO SEQUENCE LOTS OF
PATIENTS YOU CAN BEGIN LOOKING
AT PATIENTS WITH SEVERE ALLERGIC
DISEASE.
THIS SAY WORLD WIDE
COLLABORATION AND THROUGHOUT THE
WORLD HE HAD GAIN OF FUNCTION
MUTATIONS AND THIS IS A STATIN
MOLECULE AROUND DNA AND THIS
GIVES YOU GAIN OF FUNCTION
ACTIVITY AND THAT RESULTS OF A
VARIETY OF ALLERGIC DISEASES
ESPECIALLY SEEN IN YOUNG
CHILDREN AND THAT GIVES US THE
OPPORTUNITY TO TREAT THESE
PATIENTS WITH BIOLOGICS AND JAK
INHI
INHIBITERS.
YOU CAN THINK OF BIOLOGICS AS AN
ON AND OFF SWITCH YOU CAN BLOCK
THE CYTOKINE.
THE DAMAGE IS THAT IT'S VERY
SPECIFIC THERE'S MANY SWITCHES.
AND WHEN YOU THINK OF THE INPUTS
THAT TURN ON THE CYTOKINE GENES
WE KNOW SOME OF THE MOST
EFFECTIVE ARE COMBINCOMBINATORI
WE CAN CAPITALIZE AS WE
UNDERSTAND THE GENE EXPRESSION.
IT WOULD BE NICE IF WE CAN
MEASURE THESE IN PATIENTS AND
NOW OVER TO YOU, ANGELA.
>>I THINK YOU CAN SEE WHY WE
WERE SO EXCITED WHEN WE GOT TO
THE POINT OF REALIZING THESE
WERE BEING DRIVEN BY CYTOKINE
PATHWAYS AND THIS WAS AROUND
WHEN THE INHIBITERS WERE
APPROVED.
AND THERE'S A ROBUST ANIMAL
MODEL.
WE WERE INVITED TO BEGIN THE
EFFICACY OF THE DRUGS IN THE
MOUSE MODEL.
AND THEN TO SEE THIS ONLY 15% OF
FEMALES WILL DEVELOP SPONTANEOUS
ALOPECIA AREATA AND THAT'S A
LONG TIME AND UNPREDICTABLE
MODEL.
TO GENERATE A MORE STEREOTYPED
MORE RAPID MODEL OF ALOPECIA
AREATA AND THEY GRAFTED AND IF
YOU WAIT SIX WEEKS OR SO THE
MICE BEGIN TO LOSE THEIR HAIR.
AND THEY CAN LOSE HAIR ALL OVER
THE BODY AND USED THESE AS
MODELS FOR ALOPECIA AREATA AND
LATE MORE SEVERE ALOPECIA AND WE
CAN USE IT IN A NUMBER OF WAYS.
IF WE GIVE THE DRUG AT THE SAME
TIME WE ADMINISTER THE GRAFT, WE
CAN MEASURE WHETHER THE DRUG
PREVENTS THE DEVELOPMENT OF
ALOPECIA AREATA.
THAT'S THE EASY EXPERIMENT.
AND THEN IN THE TREATMENT
CONTEXT IF WE GRAFT AND WAITFUL
THE -- WAIT UNTIL THE MOUSE
BEGINS TO LOSE ITS HAIR WE'RE
TALKING DISEASE REVERSAL WHICH
IS HARDER TO DO AND MIMICS THE
HUMAN SITUATION YOU MAY
ENCOUNTER WITH A PATIENT.
THE MOUSE MODEL'S BEEN
INCREDIBLY USEFUL TO US TO
ENABLE TO US LOOK AT JAK
INHIBITERS.
MICE GIVEN THIS AS A PREVENTION
EXPERIMENT AT THE TIME OF
GRAFTING ALL KEPT THEIR HAIR AND
THE ONES THAT GOT IT DOWN HERE
ALL LOST THEIR HAIR AND SO AND
THE PROTECTED MICE HAVE HAIR
FOLLICLES STILL IN THE CYCLE
WITH A LITTLE BIT OF IMMUNE
INFILTRATE AND THE MICE WHO LOST
THEIR HAIR HAVE DYSTROPIC
FOLLICLES.
THE LYMPH NODE AND SPLEEN OF THE
MICE REMAINED THE SAME AS THE
NORMAL MICE AND THE SAME IS TRUE
FOR MICE GIVEN THESE AND WERE
PROTECTED AND YOU SEE THE NICE
THICK FOLLICLES AND THE MICE
WITH PBS HAVE A DENSE LAYER ON
THE FOLLICLES AND SUGGESTING THE
DISEASE NEVER GOT STARTED WE
SWITCHED THEM TO SYSTEMIC
DELIVERY AND WANTED TO SEE IF
THIS COULD INDUCE PREVENTION.
THESE ARED MICE COMPARED TO
UNTREATED AND LOOKING AT
STAINING AND THIS IS COMPARED TO
THE ANTIBODY.
AND BOTH JAK INHIBITERS PUT IT
BACK IN THE CYCLE.
THIS IS BEGINNING TO GO DOWN.
YOU CAN SEE IN THE TREATED MICE
WE'RE RESTORING THE IMMUNE
PRIVILEGE.
WE'RE NORMALIZING THE HAIR
FOLLICLES AND THE CELLS ARE
ABSENT FROM THE TREATED MICE
SUGGESTING THEY NEVER GET START
ED FROM THE TIME OF GRAFTING
COMPARED TO 20% IN THE UNTREATED
MICE.
IT'S A MASSIVE AM OF CELLS AND
BEGINNING TO GIVE A WINDOW OF
WHAT A THERAPEUTIC RESPONSE MAY
LOOK LIKE.
HERE WE'RE LOOKING AT TOPICAL
TREATMENT AND NOW WE'RE LOOKING
AT THE MICE TREATED WITH A JAK
INHIBITOR WITH ONE AND TWO
MONTHS AND SEE ROBUST AIR GROWTH
WITH EITHER ONE OF THESE JAK
INHIBITERS.
WE SEE THE INFLAMMATORY SIGNALS
IN THE FOLLICLE.
THE RETURN OF THE HAIR FOLLICLE
INTO THE CYCLE AND CLEARANCE OF
THOSE 20% OF CD8 POSITIVE T
CELLS FROM THE SKIN.
SO FAR WE DON'T HAVE A HUMAN JAK
INHIBITER THAT WORKS FORR ALR
OWE -- FOR ALOPECIA AND YOU CAN
CLEAR THE DISEASE AND GIVEN WE
HAD AN EXTRAORDINARILY FORWARD
LOOKING CLINICAL PARTNER AT
COLUMBIA ON THE BASIS OF OUR
MOUSE DATA THEY STARTED CLINICAL
STUDIES USING OFF LABEL FOR
THESE PHARMACEUTICALS AND THEY
ONLY HAD 30% AND THEY REGREW
THEIR SCALP, FACIAL AND BODY
HAIR AND WE HAVE PATIENTS WITH
LONG STANDING DISEASE, NINE YEAR
WITH NO HAIR AT ALL HAD COMPLETE
REGROWTH.
AND WE CONDUCTED A SIMILAR TRIAL
WITH TOFACITINIB AND PATIENTS
HAD TO HAVE A DOSE ESCALATION
BUT ON THE HIGHER DOSES HAD
ROBUST NEAR COMPLETE WITH THE
INHIBITOR AND THIS IS A TIME
COURSE.
THIS SHOWS NICELY THE HAIR
ESSENTIALLY GOES BACK INTO CYCLE
UNIFORMLY ACROSS THE SCALP.
IT DOESN'T FILL IN IN PATCHES
HERE AND THERE SUGGESTING THAT
BY REMOVING THE IMMUNE RESPONSE
WE LATER SHOWED HAVING A DIRECT
EFFECT ON THE FOLLICLE YOU CAN
STIMULATE RAPID ONSET OF
PATIENTS UNDERGOING TREATMENT.
THESE STUDIES WERE DONE EARLY IN
2016.
SINCE THAT TIME THERE'S MANY
REPORTS AND OPEN LABEL STUDIES
AND WE WERE EXTREMELY FORTUNATE
AS A FIELD THE PHARMACEUTICAL
INDUSTRY TOOK NOTE OF OUR EARLY
WORK AND BECAME INTERESTED IN
PURSUING THIS BECAUSE THERE WAS
NO FDA APPROVED TREATMENT AND
RUXOLITINIB RECEIVED APPROVAL
LAST YEAR AND BACICITNIB IS
EXPECTED TO BE APPROVED THIS
YEAR AND THESE ARE DRUGS FOR HAS
BEEN APPROVED AND
>>IT EXEMPLIFIES AS A FIELD TO
MOVE IT INTO THE REALM OF BONA
FIDE AUTOIMMUNE DISEASE IS
LOOKING AT THE UNMET NEED.
IT'S BIN EXTRAORDINARY YEARS FOR
THE PATIENT COMMUNITY AND
HOPEFULLY SOME TOPICALS AS WELL.
I WANT TO CLOSE BY AMPLIFYING ON
THE THEME HOW CAN WE DO IT
BETTER?
THOSE ARE THE INITIAL GENERATION
OF JACK INHIBITERS AND WANTED TO
MAKE THE WINDOWS OF EFFICACY
MORE SPECIFIC AND NEARO.
NARROW AND WE WENT BACK TO THE
DATA AND TOOK JOHN'S QUESTIONS
TO HEART, HOW CRITICAL IS JAK 2
INHIBITION IN REVERSAL AND CAN
WE LIVE WITHOUT IS AND STILL
MAINTAIN EFFICACY?
WE NEVER SAW EVIDENCE FOR A
STRONG JAK 2 IF ANY IN OUR BULK
DATA IN SKIN AND THE NOTION IS
HOW NARROW CAN WE GET AND STILL
MAINTAIN THE ALOPECIA REVERSAL.
I'LL SHOW THE BROAD INHIBITERS
YOU JUST SAW.
WE HAVE SOME WORK NOW USING THE
ISOFORM SPECIFIC ONES.
ONLY JAK 1, ONLY JAK 2 AND JAK 3
AND USING THE TOTALS IN THE
MOUSE MODEL WE'VE BEEN ABLE TO
ESTABLISH JAK 2 IS DISPENSABLE
FOR REVERSAL OF ALOPECIA.
OUR PAPER'S IN THE LITERATURE
NOW BUT WE MAINTAIN THIS WITH
THE JAK 3 SELECTIVE OR
PREFERENTIAL INHIBITOR BUT THEY
HAVE NO EFFECT ON REVERSING
ALOPECIA AREATA.
THIS IS IMPORTANT CLINICALLY
BECAUSE MANY OF THE HEMATOLOGIC
SIDE EFFECTS COME FROM THE JAK 2
INHIBITION MAY LIMIT POTENTIAL
FOR SOME OF THE SIDE EFFECTS
WE'D RATHER NOT HAVE BLOCKING
THE GAMMA CYTOKINES WAS
SUFFICIENT TO REVERSE THESE.
WE WERE SURPRISED BY THIS AND
GAVE US THE CHANCE TO TEASE A
PART WHAT'S THE CHICKEN AND EGG.
THE CYTOKINE SIGNALLING IS
ENOUGH TO REVERSE DISEASE.
IT SAYS TO US PERHAPS AN IMMUNE
RESPONSE IS THE PLACE TO START
AND WE WERE AWE STRUCK BY THE
REVELATION.
THE RECENT EXPERIENCE OF THE
ALOPECIA COMMUNITY GOING THROUGH
TRIALS WITH JAK INHIBITERS HAS
UNCOVERED I THINK AND INVITED
NEW CLINICAL QUESTIONS BASED ON
WHAT'S COMING OUT OF THE TRIALS.
WHAT I MEAN BY THAT IS CAN WE
FRAME SOME OF THE OBSERVATIONS
INTO KNEW QUESTIONS.
FOR EXAMPLE, NEARLY EVERYONE TO
TAKE A JAK INHIBITOR WILL
RELAPSE WHEN THEY STOP AND WHAT
CAN WE DO TO PROTECT THE NEWLY
RECOVERED HAIR FOLLICLES FROM
ATTACK DURING THE NEXT CYCLE.
WE KNOW THE JAK INHIBITERS ARE
NOT A CURE, SO TO SPEAK BUT THE
QUESTION IS ONCE WE REGROW, HOW
CAN WE COME AT THIS PROBLEM TO
MITIGATE RELAPSE AND GET DURABLE
RESPONSES?
I'LL SHOW YOU WHAT WE'RE
THINKING.
FOR PEOPLE WHO DON'T RESPOND AND
FOR THE 65% THAT DO RESPOND, ONE
THIRD -- ONE-THIRD THAT DON'T
WANT WE LOOK AT THE INITIATING
EVENTS WITHIN THE HAIR FOLLICLE
CAN WE STOP THEM IN PATIENTS
WHO'S WE RECEIVER AND USE
BLOCKADE OF THE INITIATING EVENT
TO AVOID RE.
AND THERE'S SOME THOUGHTS ON
ENVIRONMENT.
SOME WILL FLARE AND IS THIS AN
INDICATION OF AN VIESHLTAL
FACTOR THAT'S IMPEDING --
ENVIRONMENTAL FACTOR THAT'S
IMPEDING RESPONSE AND WE TALKED
ABOUT THE MICROBIOME AND
EXPANDED THINKING BEYOND THE
DISEASE BEYOND THE IMMUNE
PRIVILEGE PART TO START SAYING
IS THIS MORE OF A THREE-LEGGED
PARADIGM WHERE WE HAVE THE HAIR
FOLLICLE PART AND WE'LL TALK
ABOUT THIS AND FINALLY SOME
ENVIRONMENTAL TRIGGER AND THE
ONE WE FOCUS MOST ON LATELY HAS
BEEN THE GUT MICROBIOME AND
THERE'S INTRINSIC DEFECTS IN THE
HAIR FOLLICLE WHICH CAN BE A
CONTRIBUTING FACTOR IF THE
DISEASE AND THOUGH WE WERE
FOCUSSED ON THIS PATHWAY WE
STARTED TO THINK OF HOW TO STOP
THIS.
THERE'S UNPUBLISHED DATA HOW THE
T CELLS GET IN THE HAIR
FOLLICLES DURING THE ATTACK AND
HOW DO THEY GET BACK OUT.
THIS IS OUR THINKING AGAIN OF
HOW DO WE THINK ABOUT RELAPSE.
THESE ARE MICROSCOPY IMAGES OF
NORMAL MOUSE FOLLICLE AND ONE
BEING ATTACKED BY THE YELLOW T
CELLS.
THIS IS A MASSIVE AMOUNT OF
INFILTRATING T CELLS.
AND WE'VE DONE WORK TO WATCH THE
ATTACK ON THE HAIR FOLLICLE.
AND THIS IS SHOWING WHERE THE
CELLS ARE BEGINNING TO DIE ONCE
THEY'RE ATTACKED.
YOU CAN SEE THE CELLS START
LAUNCHING THEIR ATTACK AND THE
FOL
FOLLICLE BECOMES CLEARED OF T
CELLS UNTIL WE TAKE A DEEP ER
LOOK AND THE T CELLS NEVER TRULY
EXIT AND ONCE IT'S REGRESSED AND
SHRUNKEN DOWN WE FIND T CELL
MEMORY CELLS LODGED INSIDE THE
HAIR FOLLICLE EPITHELIUM POISED
AND READY TO ATTACK IF THE HAIR
GOES BACK IN THE CYCLE AND WE
ARE NOT ONLY CLEARING THE CELLS
BUT WE HAD A HUNCH THEY WOULD
LEAVE AND GO BACK TO THE
SURROUNDING DERMIS BUT THAT'S
NOT WHAT'S HAPPENING HERE.
OUR KILLERS ARE SETTING UP SO
ANY ATTEMPT TO A NEW HAIR
FOLLICLE WOULD MAKE THEM SUBJECT
TO THE SAME ATTACK.
YOU CAN SEE THESE ARE RESIDENT
MEMORY T CELLS WHO ARE IN THE
RIGHT PLACE TO LAUNCH A NEW
ATTACK ON NEWLY REGROWN HAIR
FOLLICLES.
IT'S A CHALLENGE FOR US AND
RAISED THE BAR IN OUR WAYS OF
THINKING ERADICATING THEM AND
GETTING THEM CLEATLY --
COMPLETELY AND WE'VE DONE
STUDIES TO SHOW HOW THE HAIR
FOLLICLES ARE PENETRATED BY THE
ATTACKING T CELLS.
IF YOU FOLLOW THE STAGED TIMED
IMAGES YOU CAN FOLLOW THE PURPLE
T CELL CRAWLING THROUGH THE BLUE
LAYER OF THE HAIR FOLLICLE AND
ENTERING INTO THE FOLLICLE
EPITHELIAL LAYERS.
IF WE FOLLOW THAT OVER TIME
INTERESTINGLY THE T CELLS WILL
KEEP GOING AND KEEP CRAWLING IN
THE FOLLICLE UNTIL THEY HIT ONE
SPECIFIC LAYER.
THEN THEY REORGANIZE AND SET UP
AN IMMUNE SYNAPSE AND GET READY
TO KILL THE CELL THEY SET THEIR
SIGHT ON AND YOU CAN SEE THE
COMPONE
COMPONENTS IT SETS UP AND
TARGETS AND KILLS CELL KILLING
WITHIN THE LAYER SHOWN HERE.
REMEMBER IN THE HUMAN WE CALLED
OUR DANGER SIGNAL ULBP3 AND IN
THE MOUSE THE LIGAND SIGNAL IS
CALLED H60.
IN WHITE THE LAYERS OF THE MASS
HAIR FOLLICLE THAT EXPRESSES THE
H60.
IT LOOKS AS THOUGH THE T CELLS
CRAWL TOWARDS THE LAYER THAT
EXPRESS THE LIGANDS AND THEY
STOP THERE AND SET UP AN IMMUNE
SYNAPSE AND KILL AND TARGET THE
LAYER OF THE FOLLICLE.
IT'S BEEN SURPRISE BEING THE T
CELLS SEEM TO BE ON A MISSION TO
GET TO THAT PLAYER AND ONCE THEY
GET THERE THEY STOP AND KILL AND
THEN SET UP CAMP AND STAY THERE
UNTIL THE NEXT HAIR CYCLE BUT IT
GIVES US ANOTHER CLUE.
IF WE KNOW THEY MAKE THE SYNAPSE
THERE ARE DRUGS TO TARGET THE
FORMATION OF THAT IMMUNE
SYNAPSE.
THERE WAS A DRUG TAKEN OFF THE
MARKET DUE TO MANY SIDE S BUT
THE GOAL WAS TO BLOCK THE
FORMATION OF THE IMMUNE SYNAPSE.
SINCE THE TIME IT'S BEEN OFF THE
MARKET INTERESTINGLY THERE'S
TOPICAL SMALL MOLECULE DEVELOPED
FOR DRY EYE DISEASE AND IT'S TO
BLOCK THE FORMATION OF THE
IMMUNE SYNAPSE.
GIVEN WE HAVE THE OPPORTUNITY TO
WORK ON THIS WE BEGAN TO REVISIT
THE BLOCKING OF SYNAPSE AND WE
HAVE EXCITING DATA THIS MAY
WORK.
AND PERHAPS NOT IN THE PRIMARY
MEANS OF REVERSING DISEASE BUT
PERHAPS AT THE ADJUNCT WHEN IT'S
REGROWN WITH A JAK INHIBITOR
COULD BE A WAY TO MAINTAIN THAT
AND PREVENT THE SUBSEQUENT HAIR
FOLLICLE FROM BEING ATTACKED.
I WANT TO COME BACK TO THE IDEA
OF WHAT THE GENES ARE TELLING US
IN THIS DISEASE.
THE GWAS POINTED AT THE IMMUNE
CELLS.
WE HAD NO GWAS SIGNAL THAT
INDICATED THIS AND THE STUDY IS
DESIGN TO GIVE COMMON VARIANTS.
AND THIS SHOULD GIVE US INCLUDE
WHAT IT MAY BE OTHER THAN THE NK
LIGAND.
WE WENT BACK TO THE DRAWING
BOARD AND WANTED TO DO DIFFERENT
GENETIC STUDIES TO SAY WHAT IS
THE CONTRIBUTION OF RARE
VARIANTS.
WHAT THAT MEANS IS GWAS STUDIES
LOOK AT VARIANTS AND EACH ADDS
ON TO SUSCEPTIBILITY.
IN THIS DIRECTION THESE ARE MORE
RARE DISEASE TYPE GENES FOUND
ONLY IN FAMILIES.
THESE ARE DONE IN FAMILIES AND
THESE ARE DONE ACROSS THE
POPULATION IN GWAS AND THE ONE
IN THE MIDDLE ARE DESIGN TO
OVERLIE THESE VARIANTS AND THE
JAK INHIBITERS WERE ELIMINATED
BY THE GWAS STUDY BUT WANTED TO
FOCUS TO SEE IF THERE WAS A
LAYERING OF GENETIC AFFECTS AND
THE PARADIGM IS ECTOPIC
DERMATITIS WHERE THERE'S GWAS
ASSOCIATED GENES AND THERE'S A
MAJOR GENE THAT INTRODUCES A
MAJOR EFFECT ON THE SKIN
BARRIER.
WE HAD THE GOAL OF DISCOVERING
THE VARIANTS AND THESE IS
DIFFERENT THAN THE
GWAS APPROACH AND TAKE THE
MUTATIONS THAT COULD BE DETECTED
AND PULL THEM TOGETHER.
WE HAVE ALL THE BAD VARIANTS AN
GIVEN AND ADDS TO OUR POWER TO
BE ABLE TO DO THAT ON A GENE
BASIS BY PULLING VARIANTS
TOGETHER.
WHEN WE DO THAT UNEXPECTEDLY WE
GOT ONE SINGLE GENE
SIGNIFICANTLY ASSOCIATED WITH
ALOPECIA AREATA AND TO OUR
SURPRISE IT WAS HAIR KERATIN A
SPECIFIC ONE, 82.
IT'S ONE LAYER FROM THE LAYER WE
WERE JUST TALKING ABOUT IN THE
MOUSE FOLLICLE.
AND THERE WAS A SPLICING
MUTATION IN THE GENE.
THAT'S AN ENORMOUSLY HIGH
NUMBER.
THESE ARE NOT SUBTLE MUTATIONS.
A LOSS OF FUNCTION.
MANY BEING MUTATIONS SUGGEST THE
AFFECT IS SIGNIFICANT.
AS IT DAMAGING THE PROTEIN IN
THE NON-SUBTLE WAY.
IT'S EXPRESSED IN A VERY NARROW
AND THAT CUTICLE PROTECT THE
INNER HAIR SHAFT AND
INTERESTINGLY THAT SAME CUTICLE
LAYER WHEN WEAKENED IS DAMAGING
IN A MORPHOLOGY.
THEY LOOK LIKE HAIRS UPSIDE-DOWN
AND THICKER ON THE TOP THAN
TOWARDS THE SCALP.
A
AND IT'S KNOWN THAT A FRACTURED
CUTICLE IS ONE OF THE THINGS
THAT IS CHARACTERISTIC OF AN
EXCLAMATION MARK AND WHAT IS
MORE ENTICING AND THERE'S BEEN A
MOTION AND WE HAVE LOOKED AT
ANTIBODIES FOR THIS AND OTHERS
IN THE FIELD SHOWING THESE
PROTEINS AS AROUND THE SAME
RANGE AS KERATIN 82 CAN BE SHOWN
TO DETERMINE WHETHER THIS LOSS
OF FUNCTION IN THE HUMAN PATIENT
MAYBE ASSOCIATED WITH THE
BEGINNINGS OF AUTOIMMUNITY AND
WE THINK PERHAPS NOW IT WILL
GIVE US AN INSIGHT INTO THE
INITIATING DAMAGE THAT MUST GO
ON WITHIN THE HAIR FOLLICLE THAT
PRECIPITATES THE IMMUNE RESPONSE
AND AIL CLOSE WITH FORWARD
LOOKING ASPIRATIONS TO LOOK AT
THE ENVIRONMENTAL FACTORS IN
ALOPECIA AREATA.
OUR FOCUS HAS BEEN ON THE
MICROBIOME AND MUCH OF OUR WORK
FOCUSSED ON THE GUT MICROBIOME.
WE HAVE SHOWN COMPOSITIONAL
CHANGES AND NOT IN THE SKIN
MICROBIOME ARE ASSOCIATED WITH
THE ONSET OF ALOPECIA IN THE
MOUSE AND IF WE PUT THEM IN A
GERM-FREE ENVIRONMENT ALOPECIA
AREATA ESSENTIALLY DOES NOT
DEVELOP.
THE GUT MICROBIOME ITSELF
APPEARS TO BE REQUIRED TO INDUCE
THE DISEASE IN THE MICE.
WE NARROWED IT DOWN TO ONE
SPECIES IN THE MOUSE.
OUR MOUSE HAS A SINGLE SPECIES
APPEARS TO BE OVER REPRESENTED
IN THE GUT OF MICE WITH ALOPECIA
AND IT'S A LACTOBACILLUS AND
IT'S NOT FOUND AS A COMMENSAL IN
HUMANS BUT IT IS IN MICE AND AN
OVERREPRESENTING GROUP SEEMS TO
BE DRIVING THE DYSBIOSIS IN THE
ALOPECIA MICE AND REQUIRED FOR
THE ONSET OF DISEASE AND
RECENTLY WE'VE SHOWN BLOCKING
THAT BY REMOVING THE MICROBIOME
CAN MODULATE AND ATTENUATE THE
ARE RECRUITMENT OF AFFECTED T
CELLS IN THE SKIN.
IT'S SHOWED DYSBIOSIS UNDER
REPRESENTATION AND THE MORE
INTERESTING DATA COMES FROM
THESE STUDIES IN THE LITERATURE
THAT PATIENTS TO HAVAL HAVE ALO
AREATA THAT RECEIVED A
TRANSPLANT MAINTAINED HAIR FOR
MORE THAN A TWO-YEAR PERIOD.
THIS INDEPENDENT STUDY HAD
ANOTHER PATIENT WHO HAD RECEIVED
AGAIN FECAL MICROBIOME
TRANSPLANT FOR THIS AND MAIN
MAINTAINED AND REGREW THEIR
HAIR.
THE THINKING IS IN PATIENTS THE
GUT MICROBIOME NOT THE SKIN
MICROBIOME MAY BE A
PRECIPITATING ENVIRONMENTAL
FACTOR FOR ONSET OF ALOPECIA
AREATA AND POTENTIALLY ONSET
ROLE IN FLARE OR DURING OR AFTER
REGROWTH.
I JUST WANTED TO SHOW THIS AGAIN
TOLL GIVE YOU THE SENSE OF THE
DIFFERENT PARTS OF THE DISEASE
WE HAVE BEGUN TO WORK WITH AND
CAN CONTROL THE IMMUNE RESPONSES
AND BEGIN TO ADDRESS THE
FACTORS.
WHEN WE STARTED THE WORK WE WERE
NAIVE WE WOULD BE ABLE TO MAKE
INROADS IN THE DISEASE AND WITH
A SMALL COHORT OF OUR GWAS STUDY
THE FACT WE FOUND ANY ASSOCIATED
WITH ALOPECIA WAS REMARKABLE AND
THE FACT THAT ONE LED US TOWARDS
THE INNOVATION OF USING JAK
INHIBITERS IS A FORTUNATE SERIES
OF EVENTS AND SQUARES ON THE
SHOULDERS OF THOSE WHO SAW AND
COLLECTED PATIENTS AND THOSE WHO
DID MOST THE PRE CLINICAL WORK
AND THE EMBRAVINGS OF THE DATA
BY INDUSTRY TO BE EXCITED ABOUT
ALOPECIA AREATA AND GIVE THE
PATIENT COMMUNITY THEIR FIRST
APPROVED DRUGS.
WE SHOWED THIS AT THE BEGINNING
ABOUT AND I WANTED TO SAY I HAVE
TREMENDOUS RESPECT FOR THE
PEOPLE WHO OBSERVED AND YET
DESPITE THAT THERE'S KEEN POWERS
OF OBSERVATION AND DOCUMENTING
AND LISTENING AND WATCHING
PATIENTS AND OBSERVE ING
INFLAMMATION.
RIGHT NOW OUR TOP THREE AREAS MY
GROUP IS INTERESTED IN IS HERE
AND IF YOU LOOK DOWN THE LIST
THE CONCEPTS ARE STILL THERE.
INFECTIOUS AGENTS AND VACCINES
AND PLENTY OF PATIENTS WHO
DEVELOPED ALOPECIA AREATA EITHER
FROM COVID OR COVID VACCINE OR
HEPATITIS B VACCINE AND WE DON'T
KNOW ABOUT THE TRIGGERS.
AND STRESS IS A FACTOR BUT WE
HAVE LOOKED AT PSYCHOLOGICAL
STRESS AND EVERY PATIENT WILL
TELL YOU THEY'VE HAD
PSYCHOSOCIAL STRESS.
THERE'S MORE WORK TO BE DONE.
THIS IS AN EXTRAORDINARY DISEASE
AND IT'S RARE TO HAVE A MOUSE
MODEL TO RECAPITULATE SO MUCH OF
THE DISEASE STATE.
PLEASE JOIN US.
THE FIELD IS OPEN FOR NEW IDEAS
AND PEOPLE.
I HOPE BY THE END OF THE TALK
YOU FEEL LIKE YOU'RE BEGINNING
TO GET CLARITY ON MAJOR BUCKETS
OF FACTORS THAT CAN INFLUENCE
DISEASE.
I ALWAYS MARK 1996 AS THE
BEGINNING OF MY INTEREST IN THIS
DISEASE AND EVERYTHING THAT'S
GROWN FORWARD FROM THAT AGAIN
WITHOUT THE PARTICIPATION OF THE
FOUNDATION AND WITH NIAMS
SUPPORT IT'S LED TO RECENT
APPROVALS.
FOR US WHAT WAS TRULY
TRANSFORMATIONAL IS THE P50 THAT
ENABLE WILL US TO BLOW THIS OPEN
AND CATALYZE THE WORK THAT
NEEDED TO BE DONE.
I'LL SAY A WORD OF THANKS TO
THOSE INVOLVED AND MANY WHO WILL
HOPEFULLY SET UP THEIR OWN
CLINIC.
THANK YOU FOR THE OPPORTUNITY.
>>THREW
>>THANK YOU FOR THE SPECTACULAR
PRESENTATIONS.
IT'S BEEN A REAL TREAT HAVING
YOU PRESENT IN THIS TAG TEAM
FASHION.
SO WE USUALLY GO UNTIL 6:00.
I THINK THEY TURN OFF THE
INTERNET AT 6:01 AND WE HAVE
LOTS AND LOTS OF QUESTIONS.
WE HAVE SOMETHING LIKE 25
QUESTIONS.
WE MAY GET TO 20 OR WHATEVER.
WHY CAN ALOPECIA AREATA BE SO
LOCALIZED?
DON'T MOST AUTOIMMUNE DISEASES
AFFECT THE WHOLE BODY?
WHY WOULD THIS AFFECT JUST PART
OF THE SCALP.
WHAT'S PROTECTING THE UNAFFECTED
AREAS.
>>GREAT QUESTION.
IT AFFECTS GROWING HAIR
FOLLICLES THEY HAVE TO BE IN
THEIR GROWTH STATE TO BE
ATTACKED AND MOST ARE IN THEIR
RESTING PHASE AND GROW A QUARTER
INCH AND STOP WHEN THEY'RE NOT
SUSP
SUSCEPTIBLE AND SOME GO THROUGH
A SHORT RESTING PHASE.
THE PREFERENCE IS THE FACT THEY
SPEND MOST THEIR TIME GROWING.
HAIR FOLLICLES ON A HUMAN EXCEL.
THEY'RE INTERMIXED.
WE DON'T KNOW WHY A PATCH STARTS
HERE AND WHERE ELSE IT MIGHT GO
AND THE FOLLOW-ON IS WHEN
SOMEBODY REGROWS THEIR HAIR
ALMOST ALWAYS FALLS OUT ON THE
EXACT SAME PATCH WORK AS THE
FIRST TIME.
THEY DON'T HAVE THE RESIDENT T
CELL S AND T CELLS ARE STUCK AND
REACTIVATE.
WE DON'T HAVE AND IF WE LOOK AT
PATIENTS WITH PATCHY DISEASE AND
THEIR BULK RNA GENE EXPRESSION
SOMETIMES THEY'RE SCALP LOOKS
LIKE A NORMAL CONTROL AND
SOMETIMES IT LOOKS SO CLOSE TO
LESIONAL SCALP IT LOOKS POISED
TO FALL OUT.
I WISH I HAD A BETTER ANSWER.
MAYBE NEXT TIME.
>>THE NEXT QUESTION FROM OUR
AUDIENCE IS THIS PERSON MUST
HAVE DONE THEIR HOMEWORK.
THERE ARE 400 CASE REPORTS OF
ALOPECIA AREATA FOLLOWING COVID
VACCINE IN CDC.
THESE ARE SELF-REPORTED AND NOT
ALL CONFIRMED.
THIS SEEMS A LARGE NUMBER FOR A
COMMON DISEASE AN REASON TO
THINK mRNA VACCINE MAY GENERATE
MORE CYTOKINES THAN OTHER
DISEASE.
>>THERE'S A HISTORY OF ALOPECIA
AREATA CASES BEING REPORTED
ESPECIALLY THE MOST COMMON IS
THE HEPATITIS B VACCINE.
THERE'S A CASE WHERE THERE'S 75
OR SO CASES.
ALOPECIA AREATA IS NOT UNCOMMON
IF YOU LOOK AT THE PREVALENCE
REPORTS ARE DONE FROM DOCTOR
OFFICE VISITS OR MEDICAL RECORD.
MOST WHO HAVE A SINGLE PATCH OF
DISEASE IN THEIR BEARD OR SCALP
DON'T EVEN GO TO DETERMINATION
AND THE NUMBERS ARE A BIT
MISLEADINGLY LOW.
THE REASON WHY THEY'RE PERHAPS
MORE OF AN ASSOCIATION AND THE
FLAVOR OF THE CYTOKINE STORM
INDUCED BY COVID IS REMARKABLY
SIMILAR TO THE FLAVOR OF THE
CYTOKINES THAT ARE ACTIVATED IN
ALOPECIA AREATA.
IT'S THAT COINCIDENCE THAT
BARCITINIB IS APPROVED FORRAL --
FOR ALOPECIA AND NOW APPROVED
FOR COVID.
>>IT MAY TURN OUT THERE'S MORE
CASES OF ALOPECIA AREATA WHEN
PEOPLE ARE VERY STRESSED.
THEIR HAIR IT TURNING WHITE.
I THINK ONE HAS TO BE HUMBLE AND
CAUTIOUS.
YOU SAID IMMUNE CHALLENGES LIKE
VACCINES MAY PRECIPITATE
ALOPECIA AREATA.
MAYBE THE STRESS CAN TRIGGER.
AND SCIENTIFICALLY THE MOST
EXCITING PART TO ME IS WHAT I
WAS REFERRAL TO AND THINKING HOW
THE IMMUNE SYSTEM WORKS AND ALL
THESE COME TOGETHER AND NERVE
HAVE CYTOKINE RECEPTORS.
THE TRUTH IS WE HAVE TO STUDY
THESE THINGS RIGOROUSLY AND
COMPREHENSIVELY.
>>ANOTHER QUESTION FROM THE
AUDIENCE, WHAT ARE THE CAUSES
FOR LOSS OF FUNCTION OF KRT82
FROM THE ALOPECIA AREATA
PATIENTS?
>>THE OVERWHELMING MAJORITY OF
THE VARIATIONS ARE LOSS OF
FUNCTION.
MOST KERATIN DISEASES ARE
AFFECTED BY THE ABILITY TO FORM
NORMALLY.
THE MUTATIONS THEMSELVES THERE
SEEMS TO BE A HOT SPOT THAT'S
FOUND IN MORE THAN HALF THE
PATIENTS.
THAT'S TYPICAL FOR A KERATIN
MUTATION.
MANY OCCUR AT ARGININE BECAUSE
OF THEIR ABILITY AND IT'S
BASICALLY FITTING THE PROFILE OF
WHAT A KERATINOPATHY PATTERN
SHOULD LOOK LIKE.
WHAT WE DON'T YET KNOW AND WILL
BE DIFFICULT TO MODEL IS THE
AFFECT ON THE FUNCTION AND
STRUCTURE OF THE FOLLICLE IS IT
MORE EASILY PENETRATED BY IMMUNE
T CELLS?
A LOT FOR US TO THINK ABOUT.
IT'S A DIFFICULT KERATIN TO WORK
WITH BECAUSE IT'S A HARD
KERATIN.
IT'S INTRACTABLE TO WORK WITH
BUT WE'RE TRYING OUR BEST.
IT'S A SURPRISE TO FIND A
KERATIN THAT'S A MAJOR LOCUS BUT
WE LOOK AT IT AS A WEAKNESS IN
THE SKIN BARRIER THAT THEN
OVERLAYS ON THE BACKGROUND OF
THEIR IMMUNE RESPONSE AND THE
MICROBES.
>>
>>CAN I ASK A FOLLOW-UP
QUESTION?
>>AS I RECALL, ANGELA, ONE OF
YOUR PAPERS ARGUED JAK
INHERITORS CAN PROMOTE HAIR
GROWTH.
DO I REMEMBER THAT CORRECTLY?
>>ABSOLUTELY.
>>DO YOU WANT TO COMMENT ON
THAT?
>>IT'S AN OBSERVATION DURING
TREATING THE ALOPECIA AREATA IN
MICE.
AND TO OUR EYE IT APPEARED THE
MICE WHO RECEIVED TOPICAL JAK
INHIBITERS REGREW BETTER THAN
THOSE WHO RECEIVED IT
SYSTEMICALLY.
WE MOVED IT OUT OF ALOPECIA
AREATA AND JUST TO MICE AND
ASKED IF YOU TAKE A BLACK THICK
MOUSE IN RESTING PHASE AND APPLY
A TOPICAL JAK INHIBITOR CAN YOU
INDUCE A HAIR CYCLE.
IT SEEMS AS THOUGH THERE'S A
BLOCK THAT'S MEDIATED BY JAK
SIGNALLING AND WHEN YOU APPLY
THE INHIBITOR YOU LOWER THE
THRESHOLD FOR THE FOLLICLE TO
REENTER THE GROWTH PHASE.
THAT WAS A FINDING WE THINK IS
AN ADDED BENEFIT OF THE JAK
INHIBITION IN ALOPECIA AREATA
YOU TAKE AWAY THE IMMUNE AFFECT
AND ALLOW THEM TO REENTER THE
HAIR CYCLE.
IT WAS NOT SOMETHING WE EXPECTED
AND MORE TO DO TO FIGURE OUT HOW
IT WORK IT WAS UNEXPECTED.
>>SO A COUPLE FOLLOW-UP
QUESTIONS ON THE DISCUSSION YOU
GUYS HAVE BEEN HAVING.
ONE IS IN STUDIES OF JACK
INHIBITERS IN RHEUMATOID
ARTHRITIS ARE OTHERS TREATED
WITH A JAK INHIBITOR.
DO ANY OF THEM EXPECT TO START
TO GROW MORE HAIR?
THE HAVE UNDIAGNOSED ALOPECIA
AREATA?
>>THERE'S REPORTS OF PATIENTS
WHO ARE RA AND TAKE THE JAK
INHIBITOR AND THERE'S REPORTS
THEY REGREW AND THERE'S SOME FOR
MEDICATIONS AND IF THEY RESPOND
AS IN THE CASE OF PSORIASIS ARE
OUT THERE.
I THINK YOU'RE ASKING IF YOU SEE
AN EFFECT OF CONVENTIONAL
PATTERN HAIR LOSS?
>>I HAVEN'T SEEN LITERATURE
LIKE THAT AND IN OUR HANDS IN
THE MICE WE NEVER SAW THAT
SYSTEMICALLY IN THE PUMP ONLY
WITH SUPER HIGH LOCAL DELIVERY
ON TO THE SKIN INTO THE FOLLICLE
IN THE MICE.
MY HUNCH IS WHATEVER THE AFFECT
IS IT HAS TO HAVE A HIGH ENOUGH
CONCENTRATION IN THE FOLLICLE
ITSELF.
I DON'T KNOW THE SYSTEMIC DOSES
WILL GET THERE BECAUSE WE DIDN'T
SEE IT HAPPEN IN THE MICE AND IT
SEEMS TO ONLY BE DONE TOPICALLY
AND I THINK OF TOPICAL
INHIBITERS BECAUSE THE TARGET
FOR STIMULATING THE FOLLICLE
IT'S SUPERFICIAL COMPARED TO
WHERE YOU NEED TO TARGET FOR
ALOPECIA AREATA.
IT'S HARD TO GET THE DRUG TO
PENETRATE LOW IN THE SKIN AND
THEN STOP AND NOT KEEP GOING IN
THE CIRCULATION.
IT'S EASIER THE HIGHER UP YOU
ARE IN THE SKIN.
SOME OTHER FORMULATIONS LIKE
ECTOPIC DERM AND PSORIASIS MAY
HAVE A BETTER CHANCE OF REACHING
THE UPPER LAYERS THAN THE
CHALLENGES FACED SO FAR WITH
ALOPECIA AREATA.
>>THERE WAS A QUESTION ABOUT
THE PATCHY NATURE OF THE
LESIONS.
ANY THOUGHTS ABOUT SOMATIC
MUTATION.
HAVE YOU LOOKED FOR THAT?
>>I WISH I COULD.
>>WE'D LOVE TO EXPLORE IT
FURTHER AND FIGURE OUT WHAT IT
DOES.
>>THE WAY WE THINK OF
PATCHINESS AND THE FIELD AFFECT
IN THE DERMAS AND INDEPENDENT OF
THE CYCLE AND TALKING ABOUT
COMPETENCE OF A REGION TO ENTER
THE HAIR SCALP VERSUS SOMETHING
THAT BLOCKS THE DERMIS FROM
ENTERING.
THE PATCH WORK YOU CAN SEE IN
THE MICE BY THINKING ABOUT
FACTORS BUT I LOVE THE QUESTION
WHETHER THERE COULD BE REGIONAL
OR PATCHY DECEMBER THAT WOULD DO
THAT.
WE DON'T KNOW IF WE CAN STUDY
PLUCKED HAIRS YET BUT
FASCINATING QUESTION.
THANK YOU.
>>THESE ARE FASCINATING
QUESTIONS IN GENERAL.
YOU GUYS ARE DONE A WONDERFUL
JOB OF REALLY FASCINATING US AND
DEMYSTIFYING MEDICINE FOR SURE.
NOW, AS IT TURNS OUT SOMEWHERE I
GUESS IN EUROPE IT'S NOW
MIDNIGHT AND BECAUSE OF THAT OUR
CARRIAGE IS TURNING INTO AING
UP.
-- TURNING INTO A PUMPKIN AND
THANK YOU FOR THE WONDERFUL
PRESENTATIONS AND I DO HAVE
PLENTY OF OTHER QUESTIONS I CAN
RELATE TO YOU LATER.
YOU CAN SPEND THE NEXT WEEK
ANSWERING THE QUESTIONS FOR US.
NEXT WEEK WE ARE GOING TO HAVE
THE GREAT HONOR AND PLEASURE OF
HEARING ABOUT THE HUMAN GENOME
AT AGE 20 BUT IN THE MEANTIME
ANYONE WHO MISSED THE VIDEO
PRESENTATION IT'S VIDEO ARCHIVED
AND I ENCOURAGE EVERYONE TO BO
BACK TO THE WEBSITE AND CATCH
THE SNIPPETS YOU DIDN'T QUITE
HEAR CAREFULLY.
ANYWAY, THANK YOU GUYS VERY
MUCH.
THANK EVERYONE FOR PARTICIPATING
THIS AFTERNOON, THIS MORNING,
THIS EVENING, WHATEVER TIME IT
IS TO YOU AND REMEMBER THAT IF
YOU WANT CME CREDIT AND ENTER
THE NUMBER 45382.
THANK YOU ALL VERY MUCH AND
WE'LL SEE YOU NEXT WEEK.