>> IT'S MY GREAT PLEASURE TO
INTRODUCE DR. POLLY MATZINGER
FOR THE IIG SEMINAR, CHIEF THE T
CELL TOLERANCE AND MEMORY
SECTION.
IT'S JUST FITTING FOR THE WHOLE
DAY.
WITHOUT FURTHER ADO -- NO, WHAT
I WANT TO SAY, WE KNOW HER
DEGREE, B.S. IN BIOLOGY FROM
UC-IRVINE, THREE YEARS LATER
RECEIVED HER Ph.D., SO FOR
SOME OF US THAT TOOK 30 YEARS,
I'M IN AWE.
SHE DID FOUR YEARS OF POSTDOC
WORK AT CAMBRIDGE AND WAS A
SCIENTIST AT THE BASEL INSTITUTE
FOR SIX YEARS BEFORE COMING TO
THE NIH.
HER WORK ON T CELLS AND
DENDRITIC CELLS IS FUNDAMENTAL
TO UNDERSTANDING OF IMMUNOLOGY,
SPECIFICALLY T CELLS LICENSE
DENDRITIC CELLS AND TOLERIZEs
FOR THE THYMUS, HAS OVER 100
PUBLICATIONS, CHECKING BEFORE I
CAME DOWN HERE HAS MORE THAN
28,000 CITATIONS, AND COINED
TERMS SUCH AS PROFESSIONAL
ANTIGEN PRESENTING CELL, DANGER
SIGNAL, DAMP, WON AWARDS
INCLUDING AS A FILMMAKER FOR
SPECIAL EXCELLENCE IN
EDUCATIONAL FILMS FOR THE GERMAN
TRANSLATION OF IMMUNITY, THE
INSIDE STORY, AT THE 1986 FILM
FESTIVAL, SHE WAS INDUCTED AS
HONORARY LIFETIME MEMBER OF THE
SCANDINAVIAN SOCIETY OF
IMMUNOLOGY, IN 2002 DISCOVER
MAGAZINE RECOGNIZED POLLY AS ONE
OF THE 50 MOST IMPORTANT WOMEN
IN SCIENCE AND RECEIVED AN
HONORARY DOCTORATE, FOR THOSE
WHO HAVEN'T HAD THE PLEASURE OF
TALKING TO POLLY, WHAT I'LL TELL
YOU IS IT'S NEVER A DULL MOMENT,
SHE WILL CHALLENGE EVERY
ASSUMPTION OUT OF YOUR MOUTH,
AND MAKE YOU BACK THEM UP.
SO, WITH THAT I'M SURE WE'RE IN
STORE FOR A GREAT AND DIFFERENT
TYPE OF TALK, AND I HOPE
EVERYBODY ENJOYS IT.
POLLY?
[APPLAUSE]
>> I GOT MY Ph.D. IN THREE
YEARS BUT IT TOOK 11 TO GET A
BACHELOR'S DEGREE.
[LAUGHTER]
SO, WHAT YOU MAKE -- YOU KNOW,
THE BRITISH SAY STRAITS AND
ROUNDABOUTS.
THIS IS THE 30th YEAR, 30th
ANNIVERSARY OF THE PUBLICATION
OF THE DANGER MODEL.
AND IT'S BEEN AN INTERESTING 30
YEARS.
WHAT HAS BEEN MOST INTERESTING
TO ME IS HOW LONG IT IS TAKING
FOR PEOPLE TO ACTUALLY APPLY THE
MODEL.
SO, PEOPLE TELL ME THEY TEACH
DANGER.
AND SO I ASK THEM, WHAT DO YOU
TEACH?
THEY SAY, WELL, YOU KNOW, IN THE
CHAPTER ON ANTIGEN-PRESENTING
CELLS AND ANTIGEN PROCESSING WE
TALK ABOUT HOW YOU NEED TO
ACTIVATE THEM, WITH PAMP AND
DAMP, DAMAGE-ASSOCIATED
MOLECULAR PATTERNS.
I SAY, THAT'S GREAT, I'M GLAD
SOMEBODY'S TEACHING THIS.
WHAT DO YOU TEACH ABOUT WHY
MOTHERS DON'T REJECT THEIR
FETUSES?
AND THEY SAY, WE KNOW PREGNANCY
IS IMMUNOSUPPRESSIVE.
I SAY, NO, NO, THAT'S NOT THE
DANGER MODEL.
WE'RE CUTTING OFF TOO SMALL A
SLICE OF THE PIE, WHEN I WROTE
THAT IS I MEAN PEOPLE ACCEPTED
THE BASIC ASSUMPTION OF THE
DANGER MODEL, WHICH IS THAT, A,
YOU NEED TO ACTIVATE PRESENTING
CELLS IN ORDER TO INITIATE AN
IMMUNE RESPONSE, AND B, THAT ONE
OF THE THINGS, OR MANY OF THE
THINGS THAT ACTIVATE DENDRITIC
CELLS ARE DANGER SIGNALS,
ALARMIN
WHATEVER YOU WANT TO CALL THEM,
ALARM SIGNALS SENT BY INJURED OR
STRESSED CELLS.
YOU DON'T NEED A PATHOGEN.
YOU NEED AN INJURED CELL.
PEOPLE HAVE ACCEPTED THAT.
AND IN THE TRANSPLANTATION
FIELD, WE'RE TRYING TO APPLY IT.
IN TUMOR IMMUNOTHERAPY, THEY ARE
STILL STUCK WITH SELF, NON-SELF.
IN PREGNANCY STUCK WITH SELF,
NON-SELF.
I'M GOING TO PICK A FEW THINGS
THAT HAVE SOME NEW IDEAS THAT
COME OUT OF THE DANGER MODEL,
AND I'M NOT AN EXPERT IN ANY OF
THESE FIELDS.
I TEND TO THINK BROADLY, I DO
THINK ABOUT DETAILS, I'M SURE
EXPERTS WILL BE THROWING PIECES
OF PIE AND ROTTEN TOMATOES, BUT
I'M DO IT ANYWAY.
MEL KOEN WAS THE GREATEST
IMMUNOLOGY THEORYATICIAN,
INVENTED HELP FOR T CELLS OUT OF
THIN AIR.
HE SAID IF YOU GO OUT AND YOU'RE
CLEAR, IT'S IMPORTANT TO BE
CLEAR, AND YOU'RE WRONG, IT'S
OKAY.
BECAUSE PEOPLE WILL DO THE
EXPERIMENTS TO PROVE YOU WRONG.
IT DOESN'T MATTER IF YOU'RE
WRITE OR WRONG, SAY IT AND BE
CLEAR.
FIRST I'LL TALK ABOUT ALLERGY.
WHAT MAKES AN ALLERGEN AND
ALLERGEN.
A NORWEGIAN ASKED A QUESTION,
WHAT MAKES DUP P1 AND 2
ALLERGENSES AND THE OTHERS NOT,
THE PROTEINS A CAT CAN MAKE, AND
ALL THE OTHER THOUSANDS OF
PROTEINS THAT ARE NOT ALLERGENS.
WHAT MAKES AN ALLERGEN AND
ALLERGEN?
THE SHORT ANSWER IS AN ALLERGEN
IS AN IMMUNOGEN.
WHAT MAKES AN IMMUNOGEN?
THIS IS NOT NECESSARILY THE
TARGET OF AN ANTIBODY RESPONSE.
BUT SOMETHING THAT CAN INITIATE
AN IMMUNE RESPONSE.
ALLERGENS ARE IMMUNOGENS.
THEY ARE KIND OF INTERESTING.
SO DURP 1 IS A PROTEASE.
AND IT'S A PROTEASE THAT ATTACKS
THE SURFACE OF LUNG EPITHELIUM.
AND ALSO OF B CELLS.
DURP 2 LOOKS LIKE MD 2, AND
ENHANCES LPS RESPONSES.
SO THIS IS THE FIRST CATEGORY.
THE ALLERGEN ITSELF CAUSES
DAMAGE.
CATEGORY 1.
CATEGORY 2, THE ALLERGEN MIMICS
OR HELPS AN ENDOGENOUS OR
EXOGENOUS ALARM SIGNAL.
CATEGORY 3, THE ALLERGEN IS
PACKAGED WITH SOMETHING THAT
CAUSES DAMAGE.
HERE WE HAVE B VENOM, A MOLECULE
CALLED MELOTIN, A PEPTIDE THAT
INSERTS INTO MEMBRANE AND CAUSES
PORES AND CAN DESTROY RED CELLS
AND FOR NON-RED CELLS IT CAUSES
A CYTOPLASM TO COME OUT, LIKE
PYROPTOSIS.
WHEN CYTOPLASM COMES OUT IT'S
GOING TO ACTIVATE YOUR LOCAL
APC. 3.
CATEGORY 4, YOU'VE GIVEN AT THE
SAME TIME AS DAMAGE.
MY FAVORITE IS PEANUT.
PEANUT ALLERGY DIDN'T EXIST IN
AMERICA UNTIL THE 1990s AND
DOESN'T EXIST WHERE PEOPLE EAT A
LOT, VERY RARE IN INDONESIA,
HOLLAND, I GREW UP UNTIL 7 IN
HOLLAND.
WE ATE PEANUT BUTTER EVERY
MORNING.
WE DIDN'T GET ALLERGIES.
WHAT CAUSES PEANUT ALLERGY?
TURNS OUT THAT PEANUT OIL IS A
WONDERFUL EMOLLIENT, AND YOU
FIND IT IN SKIN CREAMS.
BECAUSE IT'S JUST GREAT AT
MAKING SKIN SOFT AND HAPPY.
CANADIANS BANNED PEANUT OIL
RECENTLY IN BABY CREAMS.
BABIES WHO HAVE RASHES, ECZEMA,
BE ATOPIC VERY OFTEN, THEY
BECOME ALLERGIC TO PEANUTS AND
THEN OTHER NUTS.
SO WHAT'S HAPPENING THERE?
HERE'S WHAT I THINK IS
HAPPENING.
YOU'VE GOT SKIN THAT IS DAMAGED.
YOU'VE GOT LOCAL
ANTIGEN-PRESENTING CELLS
ACTIVATED, AND YOU'RE SLATHERING
IT WITH PEANUT OIL.
IT'S A COMPLETE RECIPE FOR
TURNING ON AN IMMUNE RESPONSE.
SO, THE EXCEPTION THAT MIGHT
PROVE THE RULE, MIGHT, ACTUALLY
HAPPENED HERE, SO CAT AND DAN
BARBER HAD A SON WITH ECZEMA,
WERE CAREFUL NOT TO USE PEANUT
OIL.
AND SO THEY DIDN'T.
AND WHEN HE WAS A YEAR AND A
HALF OLD, HE ANAPHYLAXED IN DAY
CARE WHEN THEY FED HIM HUMMUS,
SESAME OIL USED IN HUMMUS IS
ALSO USED IN CREAMS.
SO, IF WE COULD STOP USING
PEANUT OIL ON BABIES WITH BAD
SKIN WE MIGHT BE ABLE TO STOP
THIS EPIDEMIC OF PEANUT ALLERGY
IN AMERICA.
JOHNSON'S BABY OIL IS MINERAL
OIL.
WHY NOT USE THAT?
IT'S EASIER TO STAY AWAY FROM
MINERAL OIL THAN PEANUTS.
SO, THE FIFTH CATEGORY IS IT'S
GIVEN AT THE WRONG TIME.
THESE ARE BOTH TIME.
THIS ISN'T NECESSARILY A TIME
WHEN THERE'S DAMAGE ALREADY.
THOSE OF OF YOU AS OLD AS ME MAY
REMEMBER THAT BEFORE WE GOT ALL
EXCITED ABOUT LPS AND THOSE
KINDS OF ADJUVANTS, PEOPLE WERE
USING ANOTHER ADJUVANT, THERE
WAS A PERIOD OF TIME WHEN PEOPLE
WERE USING CASEIN, BOVINE, AN
ADJUVANT.
IF YOU INJECT IT INTO A MOUSE
YOU'LL KILL THE MOUSE.
IF YOU INJECT YOU WILL BE ABLE
TO ISOLATE HIGHLY INFLAMMATORY
MICRO PHAGES OUT OF THE PER KNEE
UM.
IT IS NOT MEANT TO BE SYSTEMIC.
AND YET WE FEED IT TO NEWBORN
BABIES AT A TIME WHEN THEIR GUTS
HAVE NOT COMPLETELY HEALED UP.
FIRST 24, 48 HOURS OF BIRTH THE
INTESTINAL EPITHELIUM IS LEAKY.
YOU FEED MILK, CASEENI GETS INTO
THE BLOOD AND YOU'VE JUST GIVEN
A SYSTEMIC ADJUVANT WITH OTHER
MILK PROTEINS.
IS IT ANY SURPRISE THAT SOME
BABIES GET MILK ALLERGIES?
I WOULD LIKE TO SUGGEST THAT
HOSPITALS SHOULD BANK HUMAN
MILK.
OBVIOUSLY IN HUMANS, HUMAN MILK
GIVEN AT BIRTH DOES NOT DO THIS.
SO, GET SOME DONORS, BANK SOME
HUMAN MILK, GIVE IT TO YOUR
PREEMIES AND THE OTHER BABIES
WHO FOR SOME REASON CAN'T GET
HUMAN MILK FROM THEIR MOTHERS.
STOP GIVING COW'S MILK WHICH HAS
THIS NATURAL ADJUVANT IN IT, TO
A BABY WHOSE GUTS HAVEN'T YET
LINKED UP.
PROTEINS THAT DON'T DO ONE OF
THESE THINGS, MOLECULES THAT
DON'T DO ONE OF THESE THINGS
TEND NOT TO BE ALLERGENS.
YOU CAUSE DAMAGE, YOU MIMIC
ENDOGENOUS OR EXOGENOUS ALARM
SIGNAL, YOU'RE PACKAGED WITH
SOMETHING THAT CAUSES DAMAGE, B
VENOM ALSO HAS PHOSPHO-LIPAAST
A2, YOU GIVE IT WHEN YOU ALREADY
HAVE SOME DAMAGE.
OR YOU'RE GIVING AT A TIME
DAMAGING MOLECULE THAT GETS INTO
THE WRONG PLACE.
SO THAT'S WHAT MAKES AN ALLERGEN
AN ALLERGEN, BY THE DANGER
MODEL.
SO THE SECOND QUESTION IN
ALLERGY, WHICH IS REALLY A
COMBINATION OF TWO QUESTIONS, IS
WHY DO SOME PEOPLE RESPOND TO
THESE ALLERGENS AND OTHER PEOPLE
DON'T?
WHY DO THESE INDUCE A Th2
RESPONSE?
I THINK THAT THAT'S NOT QUITE
THE RIGHT QUESTION.
WHEN YOU'RE ASKING THE WRONG
QUESTION, YOU'RE GOING TO GET
THE WRONG ANSWER.
I THINK THE RIGHT QUESTION HERE
ISN'T WHY DO SOME PEOPLE RESPOND
AND OTHERS NOT.
MOST PEOPLE WILL RESPOND TO
THESE ALLERGENS.
FREDERICKA SOLUSTO IN THE '90s
SHOWED PEOPLE WHO ARE NOT
ALLERGIC MAKE IgG OR IgA
RESPONSES TO A POTENT ALLERGEN.
I'VE BEEN ASKING ALLERGISTS FOR
ABOUT A DECADE NOW TO DO THE
FOLLOWING EXPERIMENT, IF THERE'S
ANY ALLERGISTS OUT THERE THAT
WILL DO IT, PLEASE DO IT.
TAKE LARGE FAMILIES WERE SOME
KIDS ARE ATOPIC AND ALLERGIC TO
ANTIGENS, OTHER KIDS ARE NOT.
IT HAS FAMILIES, IN THE SAME
ENVIRONMENT.
MY SISTER IS ALLERGIC TO SAGE
BUT LIVES IN IDAHO AND BECAME
ALLERGIC LATER.
I'M NOT ALLERGIC TO SAGE BUT
I'VE NEVER LIVED IN THE
ENVIRONMENT.
SAME ENVIRONMENT, KIDS AND
FAMILY.
PREDICTION IS THE ATOPIC KIDS
ARE MAKING IGE TO WHATEVER
ALLERGEN YOU TEST, THEY ARE
ATOPIC TO, AND NON-ATOPIC KIDS
WILL BE MAKING IgG OR IF IT'S
A FOOD ALLERGEN, IgA.
IT'S NOT THAT ATOPIC PEOPLE
RESPOND.
AND NON-ATOPIC PEOPLE DON'T
RESPOND.
IT'S THAT ATOPIC PEOPLE MAKE
IGE, I'M JUST TALKING ABOUT THAT
HERE, NON-ATOPIC MAKE THE NORMAL
RESPONSE.
AND I DON'T HAVE AN ANSWER TO
WHY SOME PEOPLE MAKE IGE AND
SOME PEOPLE DON'T.
THAT'S-- THE DANGER MODEL IS HOW
DO YOU INITIATE AN IMMUNE
RESPONSE.
IT'S NOT ABOUT HOW DO YOU
DETERMINE WHAT CLASS OF RESPONSE
YOU MAKE.
I HAVE SOME IDEAS.
ONE OF THEM COMES FROM A MAN
NAMED FERNANDO MARTINEZ, WHO
STUDIES ATOPIC PEOPLE, AND HE
HAS THE FOLLOWING IDEA, SOUNDS
LOGICAL AND COULD BE RIGHT THAT
NEWBORNS, BECAUSE THEY JUST
ENCOUNT ERRED OXYGEN HAD TO MAKE
MUCOUS AND MOLECULES, ARE
DEALING WITH NEWLY ARRIVED
OXYGEN.
WHEN THEY MAKE AN IMMUNE
RESPONSE, YOU DON'T WANT TO MAKE
AN IMMUNE RESPONSE THAT'S GOING
TO GIVE YOU MORE OXYGEN
RADICALS.
YOU DON'T WANT TO MAKE A Th1
RESPONSE.
SO HE SUGGESTS THAT NEWBORNS ARE
KIND OF BIASED TO MAKE
NON-INFLAMMATORY POTENTIALLY IGE
AND IgG 4 RESPONSES.
THAT MAY BE TRUE, I DON'T KNOW
HOW TO TEST IT.
SO, IN SHORT, ALLERGY, DANGER
MODEL CANNOT TELL YOU WHY SOME
PEOPLE MAKE IGE AND OTHERS DON'T
BUT PREDICTS THAT PEOPLE WILL
RESPOND TO THE SAME ALLERGENS
JUST IN A DIFFERENT WAY.
IT SAYS AN ALLERGEN IS AN
ALLERGEN BECAUSE IT RAISES ALARM
SIGNALS IN ONE WAY OR THE OTHER.
BY THE WAY, IF YOU HAVE
QUESTIONS OR ARGUMENTS, IF
SOMETHING I SAY DOESN'T FIT,
RAISE YOUR HAND.
DON'T WORRY ABOUT MICROPHONES,
I'LL REPEAT FOR THE PEOPLE
WATCHING.
IF YOU HAVE A QUESTION IN THE
MIDDLE, PLEASE ASK IT.
I FOUND WHEN PEOPLE GET CONFUSED
OR DISAGREE THEIR THOUGHTS GO
SOMEWHERE ELSE AND EVENTUALLY
THEY GO TO SLEEP.
I THROW THINGS, I'M KNOWN FOR
THROWING THINGS AT PEOPLE WHO GO
TO SLEEP.
[LAUGHTER]
AND I HAVE A BAD AIM.
[LAUGHTER]
WHICH MEANS IF YOUR NEIGHBOR IS
FALLING ASLEEP IT'S A GOOD IDEA
TO WAKE THEM UP.
OKAY, THAT'S ALLERGY.
LET'S DO PREGNANCY.
SO PREGNANCY WAS ONE OF THE
FIRST PROBLEMS THAT THE SELF,
NOT SELF-MODEL RAN INTO.
IF YOU RESPOND TO THINGS THAT
ARE FOREIGN, MOTHERS OUGHT TO
REJECT THEIR FETUSES.
PETER MEADOWAR WHO WON THE NOBEL
PRIZE FOR THE EXPERIMENT THAT
PUT THE MODEL ON THE MAP -- GO.
>> (INAUDIBLE).
>> THE QUESTION IS ABOUT THE
HYGIENE HYPOTHESIS AND WHAT DO I
THINK ABOUT IT.
IT'S INTERESTING, YOU KNOW, FARM
KIDS DON'T HAVE AS MANY
ALLERGIES.
I THINK THAT IS TRUE, IF YOU GET
YOUR THINGS IN A NORMAL WAY,
YOU'RE UNLIKELY TO GET ALLERGIC
TO THEM.
AGAIN, THE EXCEPTION IS MILK IN
THE FIRST 24 OR 48 HOURS.
FEED THEM PEANUTS.
HERE'S ANOTHER THING PEOPLE
DON'T THINK ABOUT.
I HAVE A FARM, I HAVE A WELL, I
DON'T HAVE CHLORINE IN MY WATER.
AND WHEN YOU TAKE A SHOWER IN
CHLORINE, CHLORINATED WATER, YOU
ARE BREATHING HOT CHLORINE.
WHAT IS THAT DOING TO YOUR
LUNGS?
WHEN YOU BATHE YOUR LITTLE BABY
IN CHLORINATED WATER WHAT ARE
YOU DOING TO ITS LUNGS?
THAT WATER IS STEAMY.
SO, THERE ARE THINGS THAT WE
NEED TO THINK ABOUT IN THE
HYGIENE HYPOTHESIS, NOT JUST
ABOUT BEING EXPOSED TO LOTS OF
DIRTY THINGS.
AND THAT'S ALL WE HAVE TIME FOR
ON THAT ONE.
MAYBE AFTER I TALK WE CAN DO A
LITTLE MORE.
WHY DON'T MOTHERS REJECT THEIR
FETUSES?
MEADOWAR, KNOWING THIS WAS A
PROBLEM AND BEING SMART AND ALSO
AMAZINGLY STUPID, WROTE A PAPER
WHERE HE SUGGESTED THREE THINGS.
A, FETUSES IMMUNOSUPPRESS THEIR
MOTHERS.
THIS IS AN EVOLUTIONARILY SMART
THING TO DO, TAKE THE
INDIVIDUALS THAT ARE CARRYING
THE NEXT GENERATION AND TURN
THEM INTO AIDS PATIENTS.
[LAUGHTER]
SO, I'VE DISCOVERED IN MY CAREER
MOST THINGS THAT ARE
EVOLUTIONARILY DUMB GENERALLY
TEND NOT TO BE TRUE AND IF NOT
TRUE HOW MANY OF YOU CARRIED
FETUSES?
DID YOU HAVE TO LIVE IN A
BUBBLE?
NO!
DO MY 200 SHEEP HAVE TO LIVE IN
BUBBLES WHEN PREGNANT?
NO.
NOW, IT'S THROUGH THERE ARE SOME
PARASITES THAT TAKE ADVANTAGE OF
THE PREGNANT STATE, THE ONE THAT
USED TO KEEP BEING THROWN IN MY
FACE WAS MALARIA BECAUSE IN
ENDIMMIC AREAS WOMEN IN FIRST
PREGNANCIES IF THEY GET MALARIA
DO VERY BADLY.
FETUSES DIE, IF THEY DON'T DIE
THEY GET LOW BIRTH WEIGHT.
THE MOTHERS SOMETIMES DIE.
IT TURNS OUT IT'S NOT BECAUSE
THEY ARE IMMUNOSUPPRESSED.
IT'S BECAUSE THERE'S A VARIANT
OF MALARIA THAT ONLY GROWS IN
PREGNANT WOMEN, IT HAS A
PARTICULAR RECEPTOR THAT USES TO
BIND ON THE PLACENTA.
THIS PARTICULAR VARIANT GOES TO
THE PLACENTA AND USES UP THE
BLOOD.
THAT'S NOT GOOD FOR THE FETUS OR
THE MOTHER.
BUT IF THAT MOTHER MAKES IT, BY
HER SECOND PREGNANCY, SHE'S
BETTER, BY THE THIRD SHE'S FINE.
AND LARS HAVID, LOOK HIM UP,
HE'S COOL, BLED A BUNCH OF
PEOPLE IN MALI, I THINK, AND
FOUND THAT EVERY WOMAN EVER
PREGNANT HAD ANTIBODIES TO THIS
VARIANT, AND ALMOST NO MEN DID.
WHAT THIS SAYS IS THAT THAT
13-YEAR-OLD GIRL WHO HAS NEVER
SEEN THIS VARIANT BEFORE BECAUSE
SHE WASN'T PREGNANT, AND IS
GOING THROUGH HER FIRST
PREGNANCY, THE FIRST TIME SHE'S
MAKING A PRIMARY RESPONSE.
WHICH IS SLOW, NOT EFFECTIVE,
BUT IF SHE MAKES IT BY THE
SECOND PREGNANCY SHE'S MAKING A
SECONDARY RESPONSE AND BY THE
THIRD SHE'S FINE.
WHICH SAYS YOU CAN MAKE A
PRIMARY EFFECTIVE IMMUNE
RESPONSE WHILE YOU'RE PREGNANT.
PREGNANCY IS NOT
IMMUNOSUPPRESSIVE.
IT'S JUST THAT PARASITES ARE
PRETTY GOOD AT TAKING ADVANTAGE
OF IT.
SO THAT WAS THE FIRST THING.
THE SECOND, ALSO STILL WRITTEN
IN TEXT BOOKS, I'M STILL HEARING
PREGNANCY IS IMMUNOSUPPRESSIVE,
IN TEXT BOOKS, IT'S IN THE
NEWSPAPERS, IT'S ON NPR, SECOND
ONE WAS THAT THE PLACENTA IS A
PHYSICAL AND IMMUNOLOGICAL
BARRIER BETWEEN MOTHER AND
FETUS.
ALSO PRETTY DUMB.
MEANS IF YOUR FETUS GETS
INFECTED, YOU AND IT ARE DEAD
BECAUSE YOU CAN'T DO ANYTHING
ABOUT IT.
AND ALSO NOT TRUE.
RIGHT?
WE KNOW THERE'S TRAFFIC FROM
FETUS TO MOTHER.
PEOPLE ACTUALLY NOW ISOLATE
THOSE CELLS OUT OF MATERNAL
BLOOD, IN ORDER TO DO A
NON-INVASIVE PRENATAL DIAGNOSIS.
AND THERE'S TRAFFIC FROM MOTHER
TO FETUS.
SO 25% OF US SITTING IN THIS
ROOM ARE MICROCHIMERIC FOR OUR
MATERNAL HEMATOPOIETIC CELLS,
FIRST DISCOVERED WHERE PEOPLE
WERE WAITING FOR A KIDNEY, IN
LIEDEN.
WHEN THEY HAD A LIVING DONOR,
THEY ALWAYS TEST THE IMMUNE
RESPONSE OF THE RECIPIENT
AGAINST THE DONOR BEFORE THEY DO
THE TRANSPLANT BECAUSE IF
THERE'S ALREADY A STRONG
RESPONSE THAT TRANSPLANT IS GONE
IN A WEEK.
SO MOTHERS ARE OFTEN DONORS.
IT TURNS OUT THAT 25% OF PEOPLE
WAITING ON THESE KIDNEY LISTS
WHEN TESTED DO NOT MAKE IMMUNE
RESPONSES AGAINST THEIR MOTHERS'
NON-INHERITED HLA ANTIGENS BUT
AGAINST THEIR FATHER BUT NOT
THEIR MOTHER.
ZHANG AND MILLER FOLLOWED UP IN
CANADA WITH MICE, MAKING
CROSSES, FOLLOW MATERNAL AND
FETAL CELLS AND SO ON AND
DISCOVERED 25% OF ADULT MICE ARE
MICROCHIMERIC FOR HUMAN CELLS.
50% OF PEOPLE WITH SKIDs HAVE
T CELLS FROM THEIR MOTHERS.
THERE WAS A BANDWAGON WILL
EXTRA-THYMIC T CELL PRODUCTION
BECAUSE PEOPLE COULD FIND T
CELLS IN NUDE MICE WHICH HAVE NO
THYMUS.
THEY FOUND T CELLS IN THE
OMENTUM.
THERE'S AN INTERESTING THING
ABOUT BREEDING NUDE MICE, NEW
THYMUS OR HAIR.
THEY ARE PRETTY INEFFICIENT AT
KEEPING UP BODY TEMPERATURE.
SO IF YOU WANT TO BREED NUDE
MICE WITH NUDE MOTHERS, YOU HAVE
TO KEEP YOUR ANIMAL COLONY AT
ABOUT 80 OR MORE DEGREES.
WHICH IS EXPENSIVE AND
UNCOMFORTABLE FOR PEOPLE WHO
WORK THERE.
PEOPLE TAKE HETEROZYGOUS MOTHERS
AND BREED THEM TO NUDE FATHERS.
AND NOW 50% OF YOUR PUPS ARE
NUDE.
SO THAT'S HOW THEY BREED.
WELL, TURNS OUT IF YOU BREED
NUDES
USING HETEROZYGOUS T CELL
SUFFICIENT MOTHERS YOU FIND T
CELLS IN THE BABY.
IF YOU BREED NUDES FROM NUDE
MOTHERS, IN YOUR 80-DEGREE
COLONY, YOU DON'T FIND T CELLS
IN THE BABIES.
THEY ARE MATERNAL.
THERE'S TRAFFIC FROM FETUS TO
MOTHER AND TRAFFIC FROM MOTHER
TO FETUS.
SO THAT IDEA WAS WRONG.
SO WHY DON'T MOTHERS REJECT
THEIR FETUSES?
ACCORDING TO THE DANGER MODEL,
IN ORDER TO INDUCE REJECTION
RESPONSE, YOU NEED ALARM SIGNALS
TO ACTIVATE APCs.
SO FETUSES THAT ARE DEVELOPING
NORMALLY HAVE A LOT OF CELL
DEATH, WE KNOW THAT.
YOU TURN THE PRIMITIVE INTO PAW
INTO A HAND, THEY GET SCAVENGED,
THEY DON'T RELEASE ALARM
SIGNALS.
AS LONG AS YOUR FETUS IS
DEVELOPING NORMALLY, AND
HEALTHILY, THERE'S NO IMMUNE
RESPONSE INITIATED.
>> HOW DO YOU RECONCILE THAT
(INAUDIBLE).
>> HOW DO I RECONCILE THAT WITH
THE GENERATION OF FETAL SPECIFIC
T REGS, SO IF YOU WANT ME TO
TALK ABOUT TREGS YOU'LL HAVE TO
ASK ME TO COME BACK.
[LAUGHTER]
BECAUSE THAT IS NOT A ONE-MINUTE
ANSWER.
HERE'S THE OTHER ONE PEOPLE
MIGHT BE THINKING ABOUT.
HOW DO I RECONCILE THAT WITH
ANTIBODIES TO RH?
RIGHT?
A MOTHER RH NEGATIVE WILL MAKE
ANTIBODIES TO HER FETUS WHO IS
RH POSITIVE.
WHAT'S INTERESTING, GOD IS IN
THE DETAILS, IT'S A PROBLEM IN
THE SECOND PREGNANCY, NOT THE
FIRST.
AND PEOPLE WHO -- THE MEDICAL
FIELD KNOWS THIS BECAUSE THEY
GIVE RHOGAM, GIVE ANTIBODIES
WHEN SHE'S HAVING HER FIRST
BIRTH.
BIRTH IS DANGEROUS.
RIPPING, BLEEDING, SURGEONS WITH
KNIVES.
IT'S DANGEROUS.
THAT'S WHEN THEY GET PRIMED.
NOT DURING THE PREGNANCY.
NOW, A GYNECOLOGIST IN MY LAB
FOR A WHILE, LIZ BONNIE, NOW AT
UNIVERSITY OF VERMONT SAID
THERE ARE A FEW WHO WILL MAKE
ANTIBODIES EARLIER THAN THAT
WITH A FRAGILE PLACENTA.
PIECES BREAK OFF, THAT'S NOT
PROGRAMMED CELL DEATH.
I DON'T THINK YOU NEED TREGS.
WE'LL TALK ABOUT WHAT THEY DO
SOME OTHER TIME.
OKAY.
SO, MOTHERS DON'T REJECT FETUSES
BECAUSE FETUSES DON'T LOOK
DANGEROUS.
BUT THERE IS ONE CONDITION WHERE
FETUSES CAN LOOK DANGEROUS AND
CAN ACTUALLY INDUCE A DISEASE IN
MOM.
SO, WE'RE MOVING TO
AUTOIMMUNITY.
THERE'S AN INTERESTING
PHENOMENON IN LUPUS, THE ONLY
AUTOIMMUNE DISEASE I'M GOING TO
TALK ABOUT TODAY.
I PUBLISHED A REVIEW IN
FRONTIERS IN IMMUNOLOGY ON
AUTOIMMUNITY, IF YOU WANT TO
KNOW WHAT I THINK ABOUT OTHER
AUTOIMMUNE DISEASES.
SO, IN LUPUS, OFTEN WOMEN WHO
HAVE LUPUS AND GET PREGNANT HAVE
VERY FEW OR NO FLARES WHILE
PREGNANT.
HOWEVER, THERE'S AN OPPOSITE
FINDING AS WELL.
WOMEN WHO DON'T HAVE LUPUS
SOMETIMES GET LUPUS WHEN THEY
ARE PREGNANT.
AND THEN IT GOES AWAY WHEN THEY
ARE NO LONGER PREGNANT.
THAT'S USUALLY A MISCARRIAGE, AN
IMPORTANT DETAIL.
SO, HOW DO DO YOU HAVE A MODEL
THAT CAN EXPLAIN THAT?
STAY TUNED.
SO, BEFORE WE GET INTO THAT, LET
ME TALK ABOUT WHAT I THINK ABOUT
TOLERANCE AND AUTOIMMUNITY.
VERY QUICKLY.
OKAY.
YOU HAVE A THYMUS.
AND YOU HAVE THREE KINDS OF T
CELLS THAT LEAVE, THAT ARE KIND
OF IMPORTANT HERE, NOT
NECESSARILY LEAVE.
THE FIRST ONE IS HIGH AFFINITY
ANTI-SELF.
THAT GETS DELETED.
WE WOULD ALL AGREE THAT GETS
DELETED.
ANYBODY WHO DOESN'T, RAISE THEIR
HAND.
>> I DARE YOU.
>> I DARE YOU, NO, RAISE YOUR
HAND.
THERE MIGHT BE SOME PEOPLE WHO
DON'T AGREE WITH THAT.
MOST OF US DO.
THE SECOND IS AN ANTI-PERIPHERAL
ANTIGEN THAT IS ON SOME KIND OF
LARGE ORGAN LIKE SKIN OR LIVER.
THIS IS NUMBER TWO.
AND THEN THE THIRD ONE IS AN
ANTI-PERIPHERAL ANTIGEN,
SPECIFIC FOR SOMETHING THAT'S
BARRICADED OR SMALL.
LIKE BRAIN.
OR LET'S SAY ISLETS.
FORGETTING TREGS FOR THE MOMENT.
WHAT HAPPENS TO THESE CELLS?
THAT ONE GETS DELETED.
THAT ONE LEAVES.
BECAUSE LIVER ANTIGENS, NOT ALL
ARE PRESENTED IN THE THYMUS, AND
IT CIRCULATES.
THE LIVER IS BIG, NOT
BARRICADED, SOON IT WILL GO
THROUGH THE LIVER.
IT'S GOING TO SEE LIVER ANTIGENS
ON LIVER APCs IN THE ABSENCE
OF ALARM SIGNALS, ABSENCE OF
CO-STIMULATION, AND IT DIES.
BECAUSE THE LIVER IS BIG AND NOT
VERY BARRICADED THAT T CELL
DOESN'T LAST VERY LONG.
LET'S LOOK AT T CELL NUMBER
THREE AGAINST BRAIN OR ISLET.
THERE'S NOT A LOT OF TRAFFIC
THROUGH THE BRAIN.
THERE IS TRAFFIC BUT NOT A LOT.
AND THERE ISN'T A LOT OF TRAFFIC
THROUGH HIGH LET'S OF LANGERHANS
EITHER, THEY ARE GOING TO
CIRCULATE A WHILE BEFORE THEY
SEE THEIR ANTIGEN.
IF BOTH CASES, SHOULD THE T CELL
GET ACTIVATED BEFORE IT GETS
TOLERIZED?
WHAT HAPPENS?
LET'S LOOK AT THE LIVER T CELL
AND SAY IT'S OUT THERE, IT'S
COME OUT OF THE THYMUS
YESTERDAY, HASN'T GONE THROUGH
THE LIVER YET, AND YOU GET AN
INFECTION, EITHER IN THE LIVER
OR CROSS-REACTS WITH THE LIVER.
THAT T CELL GETS ACTIVATED.
IT EXPANDS ITS POPULATION, LET'S
SAY IT'S A CD8, GOES OUT AND
AMONG OTHER THINGS WIPES OUT
PART OF THE LIVER.
EACH CD8 IS ESTIMATED TO KILL
BETWEEN THREE AND 30 OR A
HUNDRED TARGETS AND NEEDS TO BE
RESTIMULATED.
WE'LL COME BACK IF I HAVE TIME
FOR TUMORS.
REMEMBER THAT, THREE TO A
HUNDRED TARGETS.
WHEN IT KILLS THREE OR A HUNDRED
LIVER CELLS, IT RESTS.
IF THE INFECTION IS OVER, IT NOW
CIRCULATES AND WILL AGAIN
CIRCULATE THROUGH THE LIVER IN
THE ABSENCE OF ALARM SIGNALS AND
GET TOLERIZED.
PEOPLE FORGET MEMORY CELLS CAN
ALSO BE DELETED BY LACK OF
CO-STIMULATION.
THIS WAS FIRST DISCOVERED WITH T
CELL CLONES.
WHICH ARE MEMORY CELLS.
NOT ONLY THE NAIVE CELL THAT CAN
GET DELETED IN THE PERIPHERY,
ABSENCE OF CO-STIMULATION, IT'S
ALSO THE MEMORY CELL.
YOU ALWAYS HAVE THIS CHANCE TO
KEEP DELETING YOUR AUTOREACTIVE
CELLS IN THE PERIPHERY, IF IT'S
A HEALTHY PERIPHERY.
WHAT ABOUT THE BRAIN T CELL?
SO, IT LASTS A BIT LONGER.
IT MIGHT LAST A LOT LONGER.
AND SO IT HAS A HIGHER
PROBABILITY OF GETTING ACTIVATED
BEFORE IT BECOMES TOLERIZED.
SO, I'M NO LONGER SURPRISED THAT
MUCH AUTOIMMUNITY,
TISSUE-SPECIFIC AUTOIMMUNITY, IS
TO SMALL OR BARRICADED ORGANS.
BRAIN, ISLETS, EYE, WE'LL COME
BACK TO THE EYE.
GO AHEAD.
SHOUT.
LOUDER.
>> (INAUDIBLE).
>> THE QUESTION IS, DO I THINK
THAT ORGANS THAT HAVE MORE DEATH
LIKE THE LIVER AS OPPOSED TO THE
BRAIN, DEPENDS ON HOW MUCH
ALCOHOL YOU DRINK, RIGHT?
THAT I WOULD HAVE A HIGHER
PROBABILITY OF HAVING AN
AUTOIMMUNE RESPONSE.
SHORT ANSWER, I DON'T KNOW.
SLIGHTLY LONGER ANSWER, I THINK
NOT.
BECAUSE IN ORGANS WHERE YOU HAVE
A LOT OF DEATH, LIKE GERMINAL
CENTERS, WE'LL GET TO THAT, YOU
ALSO HAVE SPECIAL SCAVENGERS AND
GOOD SCAVENGING TO PICK UP DYING
CELLS.
IF THEY ARE DYING BY PROGRAMMED
CELL DEATH, THEN NO.
IF YOU'RE DOING DAMAGE, IF I
BEAT YOU OVER THE HEAD WITH A
BASEBALL BAT EVERY DAY FROM THE
DAY YOU WERE BORN, YOU WOULD
PROBABLY NOT ONLY BE KIND OF
GAGA, BUT YOU MIGHT HAVE AN
AUTOIMMUNE DISEASE AGAINST
SOMETHING IN YOUR HEAD.
WHEN DEATH IS NORMAL PROCESS YOU
HAVE SPECIAL SCAVENGERS.
THANK YOU FOR ASKING THE
QUESTION.
LET'S USE THAT.
SO MANY MANY YEARS AGO, I WAS IN
GERMANY TALKING TO MEDICAL
STUDENTS.
I GAVE THEM A TOTAL FAIRY TALE
ABOUT ONE WAY OF GETTING LUPUS.
IT TURNED OUT ONE OF THOSE
MEDICAL STUDENTS GREW UP TO
BECOME A RHEUMATOLOGIST AND
TESTED THAT FAIRY TALE AND IT
TURNED OUT TO BE TRUE.
HERE IS THE FAIRY TALE.
IN GERMINAL CENTERS, SO A
GERMINAL CENTER, WHAT IS A
GERMINAL CENTER?
IT'S PART OF A LYMPH NODE OR
SPLEEN WHERE B CELLS PLUS T,
FHs, WORK TOGETHER TO MAKE AN
ANTIBODY RESPONSE.
THEY B CELLS PROLIFERATE.
IN THE PROLIFERATION THEY NOT
ONLY PROLIFERATE THEY
HYPERMUTATE, GETTING B CELLS
WITH HIGHER AFFINITY BUT IN THAT
PROCESS OF RANDOM HYPERMUTATION
A LOT OF B CELLS GET LOWER
AFFINITY, SOME MAKE NO ANTIBODY
AT ALL, THEY DIE BY PROGRAMMED
CELL DEATH.
THERE'S SO MUCH DEATH IN
GERMINAL CENTERS THAT THERE ARE
SPECIAL SCAVENGERS TO PICK THEM
UP, MACROPHAGES.
HERE WAS MY FAIRY TALE.
SUPPOSE YOU HAD A TINGIBLE BODY
MACROPHAGE, SO IT NO LONGER
SAWING THE DYING B CELLS, B
CELLS WOULD STILL DIE BY NORMAL
PROGRAMMED CELL DEATH BUT
WOULDN'T GET SCAVENGED, WOULD
FALL APART.
AND WHAT HAPPENS WHEN YOU FALL
APART?
YOU RELEASE ALARM SIGNALS.
THIS IS A PERSON WHO WOULD HAVE
A LUPUS FLARE EVERY TIME THEY
GOT AN INFECTION THAT GAVE THEM
GERMINAL CENTERS.
MOST OF THE ANTIBODIES, NOT ALL,
MOST ARE AGAINST INTRACELLULAR
COMPONENTS, DNA, RNA, TUBULIN,
SO ON, CELLS ARE FALLING APART.
YOU DON'T GET ANTIBODIES TO M
HC LUPUS BUT INTRACELLULAR
COMPONENTS.
MARTIN HERMAN, I'LL WRITE HIS
NAME DOWN, HERRMAN, LOOK HIM UP,
THERE.
I'M NOT GOOD AT THIS.
WHEN HE LOOKED AT HIS LUPUS
PATIENTS HE FOUND ABOUT 5% OF
THEM HAD INDEED MUTATIONS IN THE
SCAVENGE RECEPTOR OF TINGIBLE
BODY MACROPHAGES.
HOW ABOUT THAT?
OKAY.
YOU'LL SAY, YEAH, BUT LUPUS IS
PREDOMINANTLY A FEMALE DISEASE.
WELL, TRUE.
AND NOT.
SO, POST PUBERTY ONSET LUPUS IS
PREDOMINANTLY FEMALE.
PRE-PUBERTY ONSET LUPUS, WHICH
IS RARE, HAS NO SEX BIAS.
SO WHY IS IT THAT POST PUBERTY
ONSET LUPUS IS MOSTLY FEMALE?
I THINK IT'S BECAUSE THERE IS
DEATH THAT GOES ON IN FEMALE
BODIES THAT DOESN'T GO ON IN
MALE BODIES, WE POP AN OVARY
EVERY MONTH, KILL OFF, CLEAN UP,
REGENERATE AN ENTIRE UTERINE
LINING EVERY MONTH.
THAT'S A LOT OF DEATH.
IT'S A LOT OF SCAVENGING, IT'S A
LOT OF WOUND HEALING AND SO ON.
IT'S A LOT OF GENES INVOLVED, A
LOT OF POTENTIAL FOR MUTATIONS.
AND A LOT OF POTENTIAL FOR
ENVIRONMENTAL INSULT.
SO, I TELL RHEUMATOLOGISTS WHO
GET YOUNG LUPUS PATIENTS THEY
USUALLY ARE DIAGNOSED IN THEIR
TEENS AND EARLY 20s, TO PUT
THEM ON THE PILL AND DON'T LET
THEM CYCLE.
AND SEE WHAT HAPPENS.
IT'S CALLED DIAGNOSIS BY
TREATMENT.
I WOULD BET THAT A GOOD
PROPORTION OF THOSE PEOPLE WILL
STOP HAVING THEIR LUPUS
SYMPTOMS.
I GAVE THIS TALK MANY YEARS AGO
AND A VERY OLD LADY, OLDER THAN
I AM, CERTAINLY OLDER THAN I WAS
THEN, CAME UP TO ME LATER AND
SAID SHE GOT LUPUS WHEN SHE WAS
14, AND HER FAMILY PHYSICIAN, A
LONG TIME AGO, FAMILY PHYSICIAN
TOLD HER IF SHE MADE IT TO
MENOPAUSE IT MIGHT GO AWAY.
SHE MADE IT TO MENOPAUSE, IT
WENT AWAY.
AND THIS ACTUALLY HAPPENS TO
SOME PROPORTION OF PEOPLE WHO
HAVE LUPUS.
IT'S A REPRODUCTIVE-AGE PROBLEM.
SO WHEN I TELL RHEUMATOLOGISTS
PUT THEM ON THE PILL AND DON'T
LET THEM CYCLE THEY SAY THAT'S
NOT NORMAL, WE'RE NOT DOING
THAT.
YOU KNOW WHAT?
CYCLING EVERY MONTH ISN'T NORMAL
EITHER.
WE WERE NOT MEANT TO CYCLE EVERY
MONTH.
UNTIL THE PILL WE TENDED TO BE
PREGNANT OR LACTATING.
CYCLING EVERY MONTH IS NOT
NORMAL.
NO WONDER, MAYBE, LUPUS
INCIDENCE HAS RISEN SINCE THE
1960 IT'S WHEN THE PILL WAS
FIRST MADE.
SO, OKAY, I TOLD YOU THAT I
WOULD TELL YOU ABOUT THESE TWO
PREGNANCY THINGS.
THE WOMAN WHO HAS LUPUS, GETS
PREGNANT, NO LONGER CYCLING.
WHATEVER IS GOING WRONG WITH
CYCLES IS GIVING HER THIS ALARM
SIGNAL AND RESPONSES, IS NO
LONGER HAPPENING.
SHE DOESN'T FLARE.
AND VERY OFTEN THEY FLARE WITH A
VENGEANCE AFTER BIRTH.
THAT'S A DANGER MODEL
EXPLANATION FOR WHY THEY DON'T
FLARE.
HERE'S THE DANGER MODEL
EXPLANATION FOR THOSE WOMEN WHO
DON'T HAVE LUPUS, WHO NOW
SOMETIMES GET IT WHILE THEY ARE
PREGNANT.
THAT IS THERE'S SOMETHING WRONG
WITH THE FETUS.
THERE'S A LOT OF DEATH IN THE
FETUS.
A LOT OF PROGRAMMED CELL DEATH,
A LOT OF GENES.
A LOT OF SCAVENGING.
MORE GENES.
IMAGINE YOU HAVE A FETUS THAT
HAS SOMETHING GOING WRONG WITH
ITS DEATH PROCESS.
SO IT'S RELEASING ALARM SIGNALS.
CELLS ARE FALLING APART.
THE MOTHER, BECAUSE WE KNOW
THERE'S TRAFFIC IN BOTH
DIRECTIONS, THE MOTHER RESPONDS
TO THAT.
AND WHILE SHE'S PREGNANT WITH
THIS SLIGHTLY DAMAGED WHATEVER,
FETUS, SHE WILL HAVE LUPUS.
THESE FETUSES, MOSTLY MISCARRY,
WHAT YOU'D EXPECT FROM A FETUS
WHO HAS A PROBLEM WITH DEATH
PROCESSES.
ONCE THEY LEAVE, THE MOTHER'S
LUPUS GOES AWAY.
THAT'S HOW THE DANGER MODEL CAN
EXPLAIN.
OKAY.
THAT'S AUTOIMMUNITY IN A VERY
SMALL NUTSHELL.
TUMORS.
SO, IMMUNOTHERAPY OF TUMORS IS
AT LEAST FOR SOME PEOPLE THE
BANDWAGON OF THE DAY.
WAS IT 2018, 17, CAR-T CELLS,
CAR T CELL RECEPTOR WAS THE
MOLECULE OF THE YEAR?
IT'S WONDERFUL.
PEOPLE ARE MAKING NEW VACCINES.
USING CAR-T CELLS, USING
CHECKPOINT INHIBITORS.
AND THEY ARE GETTING A LOT OF
RESULTS.
IN 30 TO 40% OF TUMOR-BEARING
PEOPLE.
WHAT'S GOING ON IN THE OTHER 60
TO 70%?
HERE'S A DANGER MODEL POINT OF
VIEW ON THIS.
WHAT'S WRONG WITH THE TUMOR?
SOMEBODY, WHAT'S WRONG WITH A
TUMOR?
WHAT MAKES A TUMOR A TUMOR?
LOSS OF GROWTH INHIBITION,
UNCONTROLLED GROWTH.
WHEN A CELL STARTS UNCONTROLLED
GROWING IT DOES LOTS OF OTHER
THINGS.
BUT IT'S THAT LOSS OF GROWTH
CONTROL WHICH IS REALLY THE
UNIVERSAL ASPECT OF TUMORS.
THE IMMUNE SYSTEM CANNOT
DISCRIMINATE BETWEEN RAPID CELL
DIVISION IN THE BONE MARROW, IN
THE GUT, RAPID CELL DIVISION IN
THYMUS, RAPID CELL DIVISION IN
SKIN, AND RAPID CELL DIVISION IN
A TUMOR.
THAT'S NOT SENDING ALARM
SIGNALS.
SO, AT LEAST IN THE EARLY STAGES
OF TUMORS, YOU KNOW, THEY ARE
GROWING, DIVIDING.
OR MULTIPLYING.
BECAUSE DIVISION AND
MULTIPLICATION IN BIOLOGY ARE
THE SAME.
WHILE THEY ARE GROWING, YOU
KNOW, THEY ARE NOT SENDING ALARM
SIGNALS.
SO, WHAT HAPPENS TO A T CELL
THAT IS CIRCULATING THAT CAN SEE
A TUMOR ANTIGEN IN A C MOLECULE?
IT WILL GET SIGNALED.
IT WON'T GET CO-STIMULATED.
AND SO IT DIES.
SO, WHILE THIS TUMOR IS GROWING,
IT'S INDUCING TOLERANCE OF
ITSELF.
NOW WHEN IT GETS -- IF IT'S A
SOLID TUMOR AND GETS BIG ENOUGH,
AND IF IT'S POORLY VASCULARIZED
IT WILL START TO STARVE IN THE
MIDDLE.
AND TUMOR PATHOLOGISTS TELL ME,
THEY CALL THIS STERILE NECROSIS,
BECAUSE STARVATION IS PROGRAMMED
CELL DEATH.
AND SO THESE CELLS ARE GOING TO
GET SCAVENGED.
SO YOU STILL DON'T GET
ACTIVATION OF T CELLS.
AND THEY CONTINUE TO BE
TOLERIZED.
WHEN THE DEATH GETS SO BIG THAT
THE SCAVENGING CAPACITY IS
OVERLOADED, NOW YOU WILL GET
SOME ALARM SIGNALS, SOME CELLS
DIE AND DON'T GET SCAVENGED,
TUMOR INFILTRATING LYMPHOCYTES,
TILs, TAKE THEM OUT, GROW THEM
IN BATHTUBS FULL OF IL-2, AND
STICK THEM BACK IN.
IF YOU'D HEARD STEVE GIVE A
TALK, I DON'T KNOW, 15 YEARS AGO
OR SO, HE ALWAYS HAD THREE
SLIDES HE GAVE.
ONE, FIRST ONE, A GUY WHO HAD A
MELANOMA METASTASIS IN HIS LUNG
THE SIZE OF A SOFTBALL.
HE ISOLATED TILs, PUT THEM
BACK IN, IT WENT DOWN TO THE
SIZE OF A BASEBALL.
HE DID IT AGAIN.
IT WENT DOWN TO THE SIZE OF A
GOLF BALL.
THEN IT GREW OUT AND KILLED THE
PATIENT.
WHAT IS WRONG WITH THIS PROCESS?
ANYBODY?
WHAT'S WRONG, HE STOPPED.
HE STOPPED.
AND PEOPLE WHO DO TUMOR VACCINES
ALSO STOP.
THEY GIVE A VACCINE ONCE, TWICE,
THREE TIMES, FIVE TIMES, THEY
STOP.
WHAT HAPPENS IS YOU'VE GOT A
TUMOR, AND IT'S GROWING.
YOU DO SOMETHING.
YOU VACCINATE, YOU PUT IN
TILs, YOU DO SOMETHING, IT
GETS SMALLER.
IF YOU GOT THE LAST TUMOR CELL,
GREAT.
IF YOU HAVEN'T, WHAT'S GOING ON
WITH THE IMMUNE RESPONSE, LET'S
SAY CD8, IS IT'S GOING UP, PEAKS
AT DAY 8 OR SO AND COMES DOWN.
RIGHT?
TUMOR STARTS TO GROW OUT AGAIN.
YOU DO IT AGAIN.
TUMOR GETS SMALLER.
YOU'RE IMMUNE RESPONSE GOES UP
AND COMES DOWN.
THEY STOP.
GIVING ONE OR TWO SHOTS OF A
VACCINE AGAINST A VIRUS OR
BACTERIUM OR WHATEVER, PATHOGEN,
WORKS, BECAUSE YOU GIVE THE
VACCINE, EXPAND YOUR T CELLS
THAT CAN SEE IT, BOOST, THAT'S
AS GOOD AS IT'S GOING TO GET
BECAUSE THERE ARE LIMITS TO HOW
MUCH YOU CAN EXPAND THEM.
THEY REST.
THEY GO INTO RESTING MEMORY
STATE.
WHEN THE PATHOGEN COMES, IT DOES
THE DAMAGE THAT REINITIATES THE
RESPONSE.
BUT KILLING OF TUMORS BY A
KILLER IS PROGRAMMED CELL DEATH.
IMMUNE SYSTEM DOES NOT THROW
FUEL ON THE FIRE.
KILLERS DON'T INDUCE A KIND OF
DEATH THAT'S IMMUNOGENIC.
MANY TUMOR PEOPLE TALK ABOUT
THIS, IMMUNOGENIC CELL DEATH AND
NON-IMMUNOGENIC CELL DEATH.
BUT THEY DON'T PUT IT TO WORK.
SO, STEVE ROSENBERG GAVE A TALK,
BEFORE COVID, SO SAY THREE YEARS
AGO, WHERE HE HAPPENED TO LET
SLIP THAT HE HAD GIVEN TWO
PATIENTS TILs, THREE TIMES.
BOTH OF THEM WENT INTO LONG-TERM
REMISSION.
SO I ASKED HIM WHY HE DOESN'T DO
THAT MORE OFTEN.
HIS ANSWER WAS INTERESTING.
HE SAID, I ONLY HAVE SO MUCH
MONEY.
I ONLY HAVE SO MANY CLINICAL
FELLOWS.
I ONLY HAVE SO MANY PATIENTS
THAT ARE WILLING TO GIVE THEIR
BODIES TO SCIENCE.
I WANT SOMETHING THAT'S GOING TO
WORK IN TWO SHOTS.
I SAID, AIN'T GONNA HAPPEN.
IF YOU'RE REALLY LUCKY, AND IT
WAS SMALL OR YOU GOT A REALLY
GREAT IMMUNE RESPONSE OR IT
HADN'T TOLERIZED COMPLETELY AND
YOU HAD A HIGHER FREQUENCY OF
CELLS TO START WITH, YEAH.
MOST OF THE TIME, NO.
KEEP BOOSTING.
IT'S A REALLY SIMPLE ANSWER.
IF YOU HAVE A VACCINE THAT MAKES
A TUMOR GET SMALLER, DON'T STOP.
NOW, WE PUT IN CAR-T CELLS, THEY
KILL, 30 TO 100 TARGETS, AND
THEN THEY REST.
YOU NEED TO RESTIMULATE THEM.
I'VE HAD FELLOWS TELL ME NO, NO,
NO, THEY ARE THERE, THEY ARE
ACTIVE, I CAN PULL THEM OUT OF
THE ARM, PUT THEM IN CULTURE,
TURN THEM INTO KILLERS.
THAT TAKES FIVE-DAY CULTURE,
ACTIVATED APCs.
PULLING THEM OUT OF THE ARM,
THEY ARE RESTING CD8s.
YES, THEY ARE THERE.
BUT YOU NEED TO BOOST THEM.
SO, MAYBE THEY COULD DO THAT
MORE OFTEN.
WHAT ABOUT CHECKPOINT
INHIBITORS?
SO TOM WALDEMANN ASKED ME SOME
TIME AGO DID I HAVE ANY THOUGHTS
ABOUT MAKING CHECKPOINT
INHIBITOR THERAPY A LITTLE MORE
UNIVERSAL.
A LITTLE MORE EFFECTIVE.
I ASKED HIM, IF HE KNEW IN THE
TUMORS WHERE HE WAS GIVING THIS
TO PEOPLE, DID HE KNOW IF THIS
WAS AN IMMUNOLOGICALLY COLD OR
IMMUNOLOGICALLY HOT TUMOR?
HIS ANSWER WAS NO.
SOMETIMES YOU CAN'T KNOW.
BECAUSE YOU CAN'T GET TO IT.
YOU CAN'T BIOPSY AND ASK IF
THERE ARE ACTIVATED FEW TILs
IN THERE.
GIVE YOUR CHECKPOINT INHIBITORS
TO PEOPLE WHO DON'T HAVE AN
IMMUNE RESPONSE GOING.
WELL, IT DOESN'T HELP.
YOU NEED TO GET THAT IMMUNE
RESPONSE GOING FIRST.
AND THEN GIVE YOUR CHECKPOINT
INHIBITOR.
SO HOW DO YOU DO THAT?
WELL, IF YOU KNOW WHAT THE
ANTIGEN IS YOU CAN VACCINATE.
IF THE TUMOR IS SURFACE OR CLOSE
TO THE SURFACE, YOU CAN DO
DAMAGE IN IT.
YOU KNOW, STICK A PIN IN IT.
INJECT IT, ALUM DOES AMAZING
AMAZING DAMAGE.
DO WHAT RON GERMAIN'S LAB DOES,
USE TWO TUNED LASERS, NEITHER
LASER ALONE IS ENOUGH TO DAMAGE
TISSUE SO YOU DON'T DAMAGE THE
TISSUE IN BETWEEN.
WHERE YOU PUT THE TWO LASERS,
YOU DAMAGE.
THAT'S A WAY, ONE WAY AT LEAST,
TO TURN A COLD TUMOR INTO A HOT
TUMOR.
LET THE T CELLS EXPAND.
THEN GIVE YOUR CHECKPOINT
INHIBITORS.
SO I THINK WHAT'S WRONG WITH A
LOT OF TUMOR IMMUNOTHERAPY IS
NOT IT'S BAD THERAPY.
IT'S JUST BEING USED INCORRECTLY
BECAUSE PEOPLE BASE USE ON AN
OLD MODEL, AND THAT IS -- SAYS
THAT ONCE YOU GET AN IMMUNE
RESPONSE GOING, THE MERE
PRESENCE OF THE ANTIGEN IS
ENOUGH TO MAINTAIN IT.
THE MERE PRESENCE OF THAT
ANTIGEN IS NOT ENOUGH TO
MAINTAIN IT.
THOSE CELLS GO INTO RESTING
STATE, YOU NEED TO REACTIVATE
AND REACTIVATE APCs IN ORDER
TO REACTIVATE IT.
WE NEED TO STOP THINKING IN THE
OLD WAY AND USE THESE QUITE
AMAZING THERAPIES IN THE WAY
THEY SHOULD BE USED.
MAYBE IF WE DID THAT, STOPPED
THINKING THE OLD WAY, WE COULD
ACTUALLY CURE MORE PEOPLE.
THANK YOU FOR LISTENING.
[APPLAUSE]
QUESTIONS?
ARGUMENTS?
CRITICISMS?
>> (INAUDIBLE).
>> CAN I TELL YOU WHAT I THINK
IS DIFFERENT BETWEEN 20% WHO
RESPOND AND 70 WHO DON'T?
>> WHAT IS THE DIFFERENCE?
I JUST TOLD YOU.
OKAY.
SO, ACTUALLY I FORGOT ONE
CATEGORY.
SO, IN A TUMOR THAT HAS NO ALARM
SIGNALS, YOU CAN GIVE YOUR
CHECKPOINT INHIBITORS, IT
DOESN'T HELP BECAUSE YOU DON'T
HAVE IMMUNE RESPONSE TO CHECK.
YOU NEED TO GET THAT IMMUNE
RESPONSE GOING FIRST.
SO THAT WOULD BE A DIFFERENCE
BETWEEN ONE KIND OF COLD
TUMOR -- WAIT, I'M NOT DONE.
THERE'S ALSO THE POSSIBILITY AND
PROBABILITY OF TUMORS THAT HAVE
ALREADY TOLERIZED.
ESPECIALLY IN -- I'M ALMOST 77,
MY THYMUS ISN'T PUTTING OUT A
LOT.
T CELL ANYMORE.
IF I GET A TUMOR AND IT'S GOING
TOLERANCE, I HAVEN'T GOT A LOT
OF NEW REPLACEMENTS.
SO THEN YOU CAN DO SOMETHING
LIKE WHAT EPHRAIM FUCHS DOES,
YOU SHOULD HAVE SOME T CELLS
THAT CAN SEE THAT TUMOR.
THAT PLUS CHECKPOINT INHIBITORS
COULD BE REALLY FUN.
YOU DON'T LIKE IT?
IT'S OKAY.
>> (INAUDIBLE).
>> 30% RESPOND, 70% THAT DON'T,
COLDER, HOTTER?
>> ARE THE 20% THAT RESPOND
SMALLER?
YES, SOME OF THEM.
>> OLDER OR NOT TOLERIZED.
>> NOT TOLERIZED OR THEY ARE
BIGGER, REMEMBER I SAID YOU GET
REALLY BIG IN SOLID TUMOR YOU
GET ENOUGH DEATH IN THE MIDDLE
YOU START ACTIVATING -- YOUR
SCAVENGERS CAN'T KEEP UP AND
YOU'LL BE EXPANDING T CELLS.
EACH ONE OF THE T CELLS CAN KILL
THREE TO A HUNDRED TARGETS AND
THEY HAVE TO GO BACK TO THE
LYMPH NODE AND GET RESTIMULATED,
THAT TAKES TWO DAYS, EVEN FOR A
SECONDARY, WHAT'S THE TUMOR
DOING?
THE MEANTIME?
MAKING MILLIONS MORE.
YOU LOST THE RACE.
THAT WOULD BE A GOOD ONE TO
TREAT.
GO AHEAD.
>> SO HOW DO YOU ALSO RECONCILE
THIS WITH THE CONCEPT OF
IMMUNOSURVEILLANCE, CD8 T CELLS
THAT ARE ELIMINATING --
>> OKAY, HOW DO I RECOGNIZE WITH
THE CONCEPT OF IMFLOW KNOW OF
OF -- IMMUNOSURVEILLANCE.
WE USED TO THINK WE GOT A TUMOR
MIGHT HAVE FINISHES AND THE ONES
THAT GREW YOU THE THE IMMUNE
SYSTEM COULDN'T DEAL WITH.
NOW WE KNOW BECAUSE OF P53 AND
CHECKPOINTS, DIFFERENT
CHECKPOINTS, WE DON'T GET TUMORS
THAT OFTEN.
SO I THINK THAT WHAT'S GOING ON
HERE IS WE DON'T GET TUMORS VERY
OFTEN.
THEY ARE JUST ALSO SENDING ALARM
SIGNALS WHEN WE GET THEM.
NOW, THERE WAS BILL CULLY, LONG
TIME AGO, WHO NOTICED THAT ONE
OF THE SARCOMAS ON A PATIENT GOT
A BACTERIAL INFECTION AND
DISAPPEARED.
SO, TUMORS DO SPONTANEOUSLY
SOMETIMES GO AWAY.
IF I HAD A MEDICAL NO, MA'AM --
MELANOMA ON THE HAND I WOULD BE
STICKING PINS IN IT OR BANGING
IT ON THE PIANO, RIGHT?
JAY.
>> I HAD A QUESTION.
THERE'S BEEN DEBATE FOR MANY
YEARS WHETHER IMMUNOSURVEILLANCE
WAS REAL OR NOT.
BOB SHRIVER HAD EXPERIMENTS THAT
MADE IT CLEAR THAT IF YOU INDUCE
A SARCOMA WITH CARCINOGEN IN AN
IMMUNODEFICIENT MOUSE, YOU GET
TUMORS THAT HAVE REJECTION
ANTIGENS THAT WILL BE REJECTED
IN AN IMMUNOCOMPETENT MOUSE,
WHEREAS THE ONES THAT ARISE, IF
YOU GIVE THE METHCOLANTHERE IN
YOU IMMUNOCOMPETENT MOUSE THEY
DON'T HAVE REJECTION ANTIGENS
PRESUMABLY BECAUSE TUMORS THAT
HAD THEM GOT ELIMINATED BEFORE
THEY EVER BECAME CLINICALLY
EVIDENT.
>> IT'S A REALLY BAD MODEL,
METHCOLANTHERE.
IT CAUSES DAMAGE.
TRANSPLANTING TUMORS ALSO CAUSES
DAMAGE.
THERE WERE THOSE DATA AND DATA
SAYING NUDE MICE DON'T GET MORE
TUMORS THAN OTHER MICE.
RAG KNOCKOUT MICE DON'T GET MORE
TUMORS THAN OTHER MICE.
T CELL KNOCKOUT MICE DON'T GET
MORE TUMORS THAN OTHER MICE.
I THINK THE SHRIVER DATA WITH
METHCOLANTHERE-INDUCED TUMOR IS
ONE WE NEED TO IGNORE.
[LAUGHTER]
SOMETIMES YOUR MODEL TELLS YOU
WHAT DATA TO IGNORE.
>> OKAY.
>> YOU COULD BE WRONG.
>> ANOTHER QUESTION.
>> MY OTHER QUESTION THOUGH THAT
I CAME UP HERE TO ASK IS, I
THINK IN 2022, WHATEVER, A
COUPLE YEARS AGO, SAMIR KALAF
PUBLISHED A PAPER IN WHICH THEY
LOOKED AT THE TIMING OF GIVING A
CANCER VACCINE AND CHECKPOINT
INHIBITORS, I THINK IT WAS
ANTI-PD-1 AND FOUND SURPRISINGLY
THAT IF THEY GIVE THE CHECKPOINT
INHIBITOR FIRST AND GAVE THE
VACCINE LATER, THE VACCINE
DIDN'T WORK NEARLY AS WELL AS IF
THEY GAVE THE VACCINE AND
CHECKPOINT INHIBITOR AT THE SAME
TIME OR THE -- OR GAVE THE
CHECKPOINT INHIBITOR LATER.
AND WE -- OUR LAB, WILL BECKER
IN OUR LAB COULD REPRODUCE THOSE
FINDINGS.
>> I DON'T FIND THAT SURPRISING.
>> SO, IT'S IMPORTANT BECAUSE
WITH A LOT OF THESE CUSTOM
CANCER VACCINES THAT PEOPLE ARE
TRYING TO MAKE TO NEOEPITOPES
AND SO FORTH IT TAKES TIME TO
MAKE THE CUSTOM VACCINE, AND
THERE'S A TENDENCY TO SAY, WELL,
WE DON'T WANT TO LEAVE THE
PATIENT UNTREATED WHILE DOING
THAT SO WE'LL START CHECKPOINT
INHIBITORS FIRST AND THEN WHEN
THE VACCINE IS READY WE'LL GIVE
THE VACCINE.
IF SAMIR'S DATA ARE CORRECT --
>> THAT'S A BAD IDEA.
>> THAT'S THE WRONG THING TO DO.
SO BUT I WANT TO KNOW WHETHER
YOU HAVE A HYPOTHESIS TO EXPLAIN
THAT FINDING.
>> WELL, WHEN T CELLS GET
ACTIVATED, THEY UPREGULATE
THINGS.
OKAY?
>> TRUE.
>> THAT WHOLE PD-1, PD-L1 AXIS
NOW BECOMES MORE SENSITIVE.
THERE'S MORE OF IT.
SO I WOULD THINK WHEN YOU'VE GOT
RESTING T CELLS GIVING
CHECKPOINT INHIBITORS IS
USELESS.
DEPENDING ON HALF-LIFE OF THE
ANTIBODY, I DON'T KNOW WHAT THE
HALF-LIFE IS, DEPENDING HOW LATE
YOU WAIT TO GIVE THE VACCINE,
YOU MAY STILL HAVE IT.
OR YOU MAY NOT.
I WOULD GIVE THE VACCINE, I
WOULDN'T DO IT AT THE SAME TIME.
GIVE THE VACCINE, WAIT A COUPLE
DAYS AND THEN GIVE THE
CHECKPOINT INHIBITOR.
>> THAT'S WHAT SAMIR FOUND WAS
BETTER EMPIRICALLY.
>> GREAT.
>> AND HE FOUND THAT THE T CELLS
THAT WERE ACTIVATED, IF YOU GAVE
CHECKPOINT INHIBITOR FIRST WERE
CD38 POSITIVE, HE CALLED THEM
SUBPRIMED OR SOMETHING LIKE
THAT, POORLY PRIMED, NOT CLEAR
WHAT THE MECHANISM IS AND I
THOUGHT YOU MIGHT HAVE IDEAS.
>> WELL, THAT WAS THE IDEA.
ANYBODY ELSE?
>> FURTHER QUESTION --
(INAUDIBLE).
>> SO THIS IS A LOT TO REPEAT.
SO, THIS MAN IS HAVING A
PROBLEM.
WITH THE IDEA TUMORS DON'T SEND
ALARM SIGNALS.
SMOKERS GET MORE LUNG CANCER
THAN NONSMOKERS, WE THINK SMOKE
IS DAMAGING TO THE LUNG.
LARGE TUMORS KILL PEOPLE.
THAT'S PRETTY DAMAGING.
LET'S DO THE LARGE TUMOR FIRST.
IT'S HAD A LONG TIME TO TOLERIZE
FOR ITSELF.
BEFORE IT ACTUALLY STARTS DOING
DAMAGE.
AND THEN ONE CAN ASK WHAT KIND
OF DAMAGE IS IT DOING?
IS THAT A KIND OF DAMAGE THAT
GIVES YOU ALARM SIGNALS?
THERE'S ALL KINDS OF DEATHS THAT
DON'T.
PYROPTOSIS DOES.
APOPTOSIS DOESN'T.
SO I THINK THE LARGE TUMOR, THE
VERY LARGE TUMOR, HAS ALREADY
TOLERIZED ENOUGH FOR ITSELF THAT
EVEN WHEN IT DOES A LITTLE
DAMAGE, YOU GET THE TILs, A
LITTLE BIT OF DAMAGE, THREE T
CELLS, THEY EXPAND, KILL 300
TARGETS, HAVE TO BE
RESTIMULATED, THE TUMOR IS
GETTING THAT MUCH BIGGER.
YOU'VE LOST THE RACE.
NOW, UV-INDUCED DEATH IN THE
SKIN, UV-INDUCED DEATH IS
PROGRAMMED CELL DEATH.
IRRADIATION DEATH OF A TUMOR IS
PROGRAMMED CELL DEATH.
WE'VE GOT TO THINK ABOUT WHAT
KIND OF DEATH WE'RE DOING HERE.
LUNG, I DON'T THINK I KNOW
ENOUGH ABOUT WHAT CIGARETTE
SMOKE DOES AND HOW IT DAMAGES TO
BE ABLE TO ANSWER THAT PART OF
IT.
I THINK ONE OF THE THINGS I TELL
MY POSTDOCS IS THAT ONE OF THE
REALLY NICE THINGS ABOUT BEING A
SCIENTIST IS THAT IT'S REALLY
OKAY TO SAY YOU DON'T KNOW.
AND ABOUT THAT, I DON'T KNOW
ENOUGH ABOUT CIGARETTE SMOKE.
>> (INAUDIBLE).
>> I CAN'T HEAR YOU.
>> (INAUDIBLE).
>> MIGHT CAUSE AUTOIMMUNITY.
>> NO, THE IDEA OF THE TUMOR, IT
COMES -- (INAUDIBLE) --
>> OKAY.
YEAH, YEAH.
>> INDUCING MORE RESISTANT TUMOR
CELLS.
>> LET'S DEAL WITH THAT.
THE IDEA IS IF YOU VACCINATE,
AND YOU GET YOUR TUMORS TO GO
DOWN, YOU GET A FEW CELLS LEFT,
GROW OUT, DO IT AGAIN, SOME MAY
NO LONGER HAVE THE ANTIGEN
YOU'RE VACCINATING TO, THEY
BECOME RESISTANT.
YES, ABSOLUTELY, AND THAT'S BEEN
SHOWN IMMUNOLOGIC ESCAPE, TUMOR
ESCAPE.
THE VACCINE SHOULD NOT BE
AGAINST ONE ANTIGEN UNLESS IT'S
AGAINST THE MUTATION THAT IS
MAKING THAT TUMOR A TUMOR.
IF YOU CAN GET THAT ONE, RIGHT,
WHEN THE TUMORS NO LONGER HAVE
THAT THEY ARE NO LONGER TUMOR
CELLS, NO LONGER NON-GROWTH
CONTROLLED.
YOU'RE RIGHT.
VACCINE SHOULD BE AGAINST MORE
THAN ONE ANTIGEN.
I COULD DO AT LEAST THREE.
THE CHANCES OF GETTING IMMUNE TO
ALL THREE ARE PRETTY LOW.
I KNOW THIS.
I HAVE A BUNCH OF SHEEP.
THEY GET WORMS.
THEY DIE FROM WORMS ACTUALLY.
I USE THREE WORMERS THAT WORK BY
THREE DIFFERENT WAYS.
WITH THE IDEA THAT, YOU KNOW,
ONE IN 100,000 TO A MILLION
MIGHT HAVE A MUTANT AGAINST ONE,
ONE IN A MILLION AGAINST
ANOTHER, ONE IN A MILLION
AGAINST A THIRD.
CHANCE OF ONE WORM HAVING ALL
THREE IS 1 IN 10 TO THE 18th.
I DON'T KNOW THERE'S THAT MANY
WORMS ON THE PLANET.
SO IT'S THE SAME.
GIVE THREE.
WE KNOW THIS FROM AIDS.
PEOPLE USED TO GIVE ONE DRUG
UNTIL THE VIRUS MUTATION, GIVE
ANOTHER ONE.
NOW THEY GIVE FOUR.
ALL AT ONCE.
AND IT WORKS.
SO I WOULD USE AT LEAST THREE.
AND THEN YOUR CHANCE OF TUMOR
ESCAPE IS MUCH, MUCH LOWER.
WE'RE GOING TO HAVE A HALF HOUR
TOGETHER.
>> YES, I KNOW.
>> SHORT.
>> ANSWER THIS PART OF THE
QUESTION ABOUT CIGARETTE SMOKE.
>> OKAY.
GO TO THE MICROPHONE.
HERE.
NO, NO, HERE, IT'S QUICKER.
>> YEAH, SO FIRST OF ALL, THERE
ARE CARCINOGENS IN CIGARETTE
SMOKE, I CAN'T NAME ALL OF THEM,
BUT IT'S KNOWN THAT LUNG CANCER
IS ONE OF THE CANCERS THAT HAS
GENERALLY HAS A HIGH TUMOR
MUTATIONAL BURDEN, MEANING THERE
ARE LOTS OF MUTATIONS THAT COULD
BE TARGETS FOR IMMUNOTHERAPY.
SO, AT LEAST THAT'S BECAUSE OF
THE CARCINOGENS IN THE CIGARETTE
SMOKE.
BUT THE OTHER THING I WANT TO
POINT OUT IS THAT STUDIES HAVE
BEEN DONE TO SHOW NICOTINE
ITSELF IS CARCINOGENIC.
>> THE QUESTION WAS ABOUT CELL
DEATH.
>> YEAH.
>> ARE THEY CARCINOGENIC BECAUSE
THEY CAUSE DEATH?
>> I'M SORRY, THE COMPONENTS IN
CIGARETTE SMOKE THAT ARE
CARCINOGENIC ARE MUTAGENS, IF
THEY HIT THE WRONG GENE YOU CAN
GET A MALIGNANCY.
>> RIGHT.
>> WHAT I WANTED TO MAKE --
>> THAT'S THE ANSWER TO THAT
ONE, RIGHT?
>> YEAH.
>> CELL-CAUSING DEATH.
>> WHAT I WANTED TO MAKE PEOPLE
AWARE OF, THAT MANY PEOPLE ARE
NOT AWARE OF, IS THAT NICOTINE
ITSELF CAN CAUSE TUMORS IN MICE,
FOR EXAMPLE.
AND THAT THEREFORE THE IDEA THAT
VAPING, INHALING NICOTINE
WITHOUT ALL OF THOSE CARCINOGENS
FROM TOBACCO SMOKE DOESN'T
COMPLETELY PROTECT YOU BECAUSE
THE NICOTINE ITSELF, BESIDES
BEING ADDICTIVE, IS ALSO
CARCINOGEN.
>> AN ADVERTISEMENT TO STOP
VAPING; THERE YOU GO.
>> YOU'VE BEEN IGNORING ME
THERE.
>> I'M SO SORRY.
I'M BLIND.
>> ANYWAY, VERY INTERESTING
TALK.
>> BUT.
[LAUGHTER]
>> WELL, SO THEN WHAT IS
AUTOIMMUNITY, WHAT IS SOMETHING
LIKE M.S., RIGHT?
IF I'M HEARING YOU CORRECTLY,
YOU CONSTANTLY HAVE TO HAVE THIS
IMMUNOGENIC CELL DEATH
HAPPENING, IN ORDER TO SUSTAIN
THESE BOUNDS COMING BACK AGAIN
AND AGAIN.
>> YES, VERY IMPORTANT POINT.
BECAUSE MANY PEOPLE -- HANG ON.
MANY PEOPLE SUGGESTED, MY
CATEGORY TWO, AUTOIMMUNITY, LIKE
WITH RHEUMATIC FEVER, RIGHT, YOU
CAN INITIATE AND AUTOIMMUNE
RESPONSE WITH CROSS-REACTION TO
SOME PATHOGEN.
BUT THE NICE THING ABOUT
RHEUMATIC FEVER, IT TELLS YOU
THAT YOU NEED TO KEEP DOING THAT
BECAUSE WHEN THEY PUT KIDS ON
PENICILLIN FOR 20 YEARS, AND
THEY DON'T HAVE THAT, IT GOES
AWAY.
YES, YOU HAVE TO KEEP DOING IT.
>> YEAH, SO WE HAVE, YOU KNOW,
TODAY I SAW IN THE CLINIC,
RIGHT, WE HAVE PEOPLE WHO HAVE
THIS TRANSVERSE MYELITIS,
ONE-TIME ATTACK, IMMUNE
MEDIATED, WE CAN'T FIND
PATHOGENS, THEORETICALLY IT'S
AUTOIMMUNE.
IT NEVER HAPPENS AGAIN.
RIGHT?
>> UH-HUH.
>> SO, THEN BASED ON DANGER
MODEL, IN ORDER TO HAVE CHRONIC
AUTOIMMUNE DISEASE,
ORGAN-SPECIFIC AUTOIMMUNE
DISEASE, THAT ORGAN MUST HAVE
PERIODS OF THIS IMMUNOGENIC CELL
DEATH BECAUSE OTHERWISE EVEN THE
CELLS THAT HAVE BEEN AUTOIMMUNE,
RIGHT, EVENTUALLY THEY WOULD
BECOME ALLERGIC, WOULD BE
DELETED.
>> THEY WOULD BE MEMORY CELLS.
>> SEEMS LIKE A CANCER -- RIGHT,
A A COUNTERPART TO YOUR CANCER
STORY.
>> YES AND NO.
QUICKLY, YES AND NO.
YOU WON'T BE DISAPPOINTED.
I PROMISE YOU.
>> OKAY.
[LAUGHTER]
>> YOU GUYS ARE STILL HERE?
SO, THERE'S FOUR CATEGORIES OF
AUTOIMMUNE DISEASE, VERY
QUICKLY.
ONE, BORING, YOU HAVE AN
INFECTION AND DON'T KNOW IT AND
MY FAVORITE POSTER CHILD HERE IS
LYME, FIRST DIAGNOSED AS
JUVENILE RHEUMATOID ARTHRITIS.
HOW MANY OTHER ARTHRITIES ARE
INFECTION WITH SOMETHING WE
DON'T KNOW.
YOU'RE DESTROYING THE ORGAN AS
TRYING TO GET RID OF THE
PATHOGEN.
TWO --
>> M.S. CAN BE THAT.
>> HANG ON.
I THINK M.S. COULD BE ANY ONE OF
THESE CATEGORIES, PROBABLY IS
MORE THAN ONE DISEASE.
SOME PEOPLE RESPOND TO
INTERFERON BETA, SOME DON'T,
SOME TO PAXLOVID, SOME DON'T,
IT'S DIFFERENT DISEASES.
SECOND IS ALSO AN INFECTION,
KNOWN AS MOLECULAR MIMICRY FOR
VERY LONG TIME.
YOU HAVE AN INFECTION, WITH
SOMETHING NOT NECESSARILY IN THE
TARGET ORGAN.
HERE'S RHEUMATIC FEVER.
YOU GET STREP.
YOU RESPOND TO STREP.
>> THAT CANNOT BE SUSTAINED
AUTOIMMUNITY, RIGHT?
>> IT CAN BE IF YOU DON'T GIVE
PENICILLIN.
THEY GIVE IT BECAUSE THE FIRST
RESPONSE STARTS DESTROYING THE
HEART VALVE AND THEY KNOW IF
THEY NOW DO A SECONDARY
RESPONSE, IT'S GOING TO BE EVEN
WORSE.
SO THEY KEEP THE STREP OUT.
SO, IMAGINE YOU'VE GOT AN
INFECTION IN THE GUT.
AND IT'S GOT A CROSS-REACTIVE
PEPTIDE WITH SOMETHING IN THE
BRAIN, AND IT'S A CHRONIC
INFECTION.
YOU NOW HAVE LONG-LASTING M.S.
>> NO, NO, NO, NO, NO.
YOU HAVE ATTACK OF M.S., FIND
THESE LESIONS IN THE BRAIN.
YOU DON'T HAVE TO DO ANYTHING.
>> NO, YOU DON'T HAVE TO --
>> NO, NO, NO, YOU DON'T DO
ANYTHING AND LESIONS WILL HEAL.
>> IT'S THAT THE OTHER KIND OF
M.S., RELAPSING REMITTING AND
PROGRESSIVE, RIGHT?
SO, RELAPSING REMITTING, TO ME
--
>> NO, WE THINK IT'S ONE M.S.
>> WELL, MAYBE.
IT'S THE DIFFERENT STAGE OF THE
DISEASE.
[LAUGHTER]
>> CAN I SPEAK?
>> YEAH.
>> THANK YOU.
YOU'VE GOT AN ENVIRONMENTAL
PATHOGEN.
IT COMES EVERY SPRING, MAYBE.
IT'S OUT THERE AND YOU RUN INTO
IT WHEN YOU GO RUNNING, MAYBE.
YOU GET IT, YOU CLEAR IT.
BUT IT'S OUT THERE.
YOU GET IT AGAIN.
YOU CLEAR IT.
AND IT HAPPENS TO CROSS-REACT
WITH SOMETHING IN THE BRAIN.
EVERY SINGLE TIME YOU CLEAR IT
YOU'LL GET A FLARE.
ONE OF THE QUESTIONS THAT AT
LEAST SOME M.S. PEOPLE HAVE
GIVEN ME IS HOW CAN I EXPLAIN
WHY THE LESIONS -- IT'S HARD TO
PREDICT WHERE THEY ARE GOING TO
BE.
I HAVE AN ANSWER FOR THAT.
IT'S HAND WAVING.
PEOPLE ASK IF MY WRISTS GET
TIRED OF HAND WAVING.
[LAUGHTER]
HERE'S THE SUGGESTION.
BECAUSE WE SEE THAT.
YOU GET A LESION, A LESION HERE,
A LESION THERE, ANOTHER ONE
HERE.
WE KNOW THAT IF YOU CUT -- CAN'T
REMEMBER WHAT IT'S CALLED, A
NERVE HERE, IF YOU CUT IT, THE
MICROGLIA AT THE OTHER END OF
THE NERVE GET ACTIVATED, IN A
WAY THAT ANY DENDRITIC CELL OR
MACROPHAGE TRYING TO PRESENT TO
A T CELL WOULD GET UPREGULATED,
CLASS 1, CLASS 2, CD40 AND SO
ON, AND THEN THEY REST.
IF YOU'VE DONE DAMAGE TO A
NERVE, NO MATTER HOW FAR AWAY,
AS LONG AS IT'S CONNECTED TO THE
BRAIN, YOU COULD GET TEMPORARY
MICROGLIA ACTIVATION.
THERE IS T CELL TRAFFIC THROUGH
THE BRAIN.
NOW LET'S SAY YOU ARE IN THE
PROCESS OF CLEARING THIS
CROSS-REACTIVE INFECTION, AND
YOU GOT A LITTLE DRUNK AND
YOU'RE DRIVING HOME AND YOU WEAR
CONTACTS, AND YOU RUN INTO THIS
TRUCK WITH HUGE HEADLIGHTS,
WHICH DOES DAMAGE TO YOUR
RETINA.
NOW YOU'VE GOT AN AREA OF THE
BRAIN, A LITTLE BIT DAMAGED,
ACTIVATED MICROGLIA AND
CROSS-REACTIVE PEPTIDE AND T
CELLS WILL GO THERE AND THAT'S
WHERE YOUR LESION IS GOING TO
BE.
WELL, WE DON'T HAVE A GOOD MODEL
IN MICE.
IF WE HAD -- THERE'S SOME KIND
OF MONKEY YOU CAN DO A MODEL FOR
M.S.
GIVE IT EAE.
PUT A PAPER CLIP ON ITS TAIL.
SEE WHERE THE LESION GOES.
WE CAN'T DO IT IN MICE BECAUSE
IT'S NOT A CEREBELLAR DISEASE IN
MICE.
YOU COULD DO IT IN THIS MONKEY.
I THINK RELAPSING REMITTING CAN
BE A CROSS-REACTION WITH
ENVIRONMENTAL ANTIGEN.
THAT'S THE SECOND CATEGORY HERE.
IT'S STILL INFECTION BUT DOESN'T
HAVE TO BE THE TARGET ORGAN
BECAUSE YOU HAVE AN AUTOIMMUNE
COMPONENT.
THANK YOU FOR STAYING SO LONG.
THREE MORE MINUTES AND I'M DONE.
THIRD CATEGORY IS DEATH, THAT'S
LUPUS.
I'VE ALREADY TALKED ABOUT THAT.
THAT'S DEATH.
I THINK IN ALL THESE THREE
CATEGORIES THERE'S NOTHING WRONG
WITH THE IMMUNE SYSTEM.
THERE IS ONE FOURTH, ALSO GIVES
YOU LUPUS.
BAD DEATH AND BED SCAVENGING.
BAD, MMM, RECOGNITION OF DEATH,
IF YOU LIKE, OR BAD RECOGNITION
IN GENERAL.
THERE'S A FORM OF LUPUS IN MICE,
WHERE THERE'S BEEN A
DUPLICATION, AND YOU HAVE A HIGH
LEVEL OF AN RNA RECOGNIZER.
AND IT RESPONDS TO THE NORMAL
LEVELS OF SYSTEMIC RNA.
SO NOW YOU GET ACTIVATION SIG
SIGNALS AND LUPUS.
I THINK M.S. IS EITHER GOING TO
BE HERE, WITH INFECTION IN THE
BRAIN, OR HERE, WITH MOLECULAR
MIMICRY, WHERE YOU HAVE AN
INFECTION SOMEWHERE ELSE.
AND IF IT'S CHRONIC, YOU'LL GET
PROGRESSIVE.
IF IT'S RELAPSING REMITTING,
THEN I WOULD SAY IT'S NOT
CHRONIC INFECTION.
THAT'S THE BEST I CAN DO.
DOESN'T LIKE IT.
IT'S OKAY.
I TOLD YOU I'M NOT AN EXPERT IN
ANY OF THESE FIELDS, AND THE
EXPERTS WILL GET UP AND SAY UGH.
>> I'M THINKING YOUR FINGER
SHOWING LIKE THE TUMOR GROWTH
AND TUMOR DEATH, THE THIRD TUMOR
GROW, GROW, BUT T CELL RESTS,
I'M THINKING LIKE THE THIRD TIME
TUMOR GROWTH IS ALSO ORIGINAL
ONE, ALSO THE FIRST ONE, TWO
MORE, THE THIRD ONE TUMOR GROWTH
THEY CHANGE, THEY LIKE TO BECOME
THE --
>> RIGHT.
SO THAT WAS ALSO SUGGESTED.
AND I THINK THERE WILL BE TIMES
LIKE THAT.
IF YOU VACCINATE AGAINST ONLY
ONE ANTIGEN ON THE TUMOR, THEN
IT CAN MUTATE, SO THE T CELLS
CAN'T FEED ANYMORE.
BUT YOU STILL NEED TO KEEP THAT
IMMUNE RESPONSE GOING.
>> YES, BUT LIKE MAYBE NOT THE
RIGHT EXAMPLE, LIKE THE
MELANOMA, DOING THE PD-L1
THERAPY, AND SOME PATIENT MAYBE
THEY HAVE MORE, MORE T CELL,
AFTER LIKE THREE MONTHS OR SIX
MONTHS THERAPY, THOSE TYPES,
THEY ARE RESPONSE, BUT AFTER
MAYBE SEVERAL MONTHS MAYBE THE
TUMOR --
>> THE TUMOR MUTATED.
THEY WILL DO THAT.
>> YEAH.
YEAH.
>> THEY WILL DO THAT.
I THINK THAT'S A SMALL SUBSET.
>> OKAY.
>> ESPECIALLY IF YOU HAVE A
POLYCLONAL RESPONSE.
AND THAT MOST OF THEM, I'M NOT
SAYING IT'S ALL, I TELL MY
POSTDOCS EVERY TIME YOU SAY
"ALL" OR "NEVER" IN BIOLOGY IT'S
A LIE.
>> OKAY.
THANK YOU.
>> THERE ARE EXCEPTIONS.
BUT THERE WILL BE THOSE, YES,
ABSOLUTELY, AND THOSE WILL BE
HARD TO DEAL WITH.
>> THANK YOU.
YOU'RE WELCOME.
I THINK I'M DONE.
[APPLAUSE]