>> GOOD AFTERNOON
I'M DANIEL REICH
IT'S MY HONOR TO INTRODUCE
TODAY'S WALS SPEAKER.
THIS TALK IS JOINTLY ORGANIZED
WITH THE INFLAMMATORY DISEASES
INTEREST GROUP SO IF YOU WILL
INDULGE ME FOR A MOMENT I WANT
TO TELL BUT THAT.
THIS GROUP WAS ESTABLISHED IN
2015 FOLLOWING THE INTRAMURAL
PROGRAM'S LONG TERM PLANNING
PROCESS TO TRY TO BRING TOGETHER
THE LARGE NUMBER OF LABOS CAMP
US THAT STUDY INFLAMMATION AS A
UNIFYING THEME IN DISEASE.
IT CURRENTLY HAS SUPPORT FROM
SEVEN ICs AS WELL AS THE
DEPUTY DIRECTOR FOR INTRAMURAL
RESEARCH.
MOSTLY IT'S A SPEAKER SERIES BUT
HAS A STEERING COMMITTEE FROM
MULTIPLE ICs AND THERE IS A
LIST SERVE.
SO IF ANY OF YOU WANT
INFORMATION ABOUT THE TALKS THAT
ARE BEING ORGANIZED, PLEASE SIGN
UP ON THE LIST.NIH.GOV WEBSITE.
THIS IS OUR LINE UP FOR THE REST
OF THE 2017-2018 SEASON.
WE HAVE A LOT OF GREAT SPEAKERS
AS YOU CAN SEE, BOTH FROM NIH
AND FROM AROUND THE COUNTRY AND
AS YOU'LL SEE TODAY, FROM AROUND
THE WORLD AS WELL AND WE HAVE
ALREADY STARTED PLANNING NEXT
YEAR'S SEASON AS WELL.
JUST A REMINDER THAT THIS IS THE
MIDDLE TALK OF THREE SOMEWHAT
RELATED FORETUE TUS TALKS TODAY.
THERE WILL BE AN IIG SEMINAR AT
4:15 IN LIPSETT.
DAN IS SPEAKING THERE.
AND AS WELL RIGHT AFTER THIS
TALK, THERE WILL BE A RECEPTION
IN THE LIBRARY.
SO, ON TO PROFESSOR SCHWARTZ WHO
STUDIED CHEMISTRY AT THE HEBREW
UNIVERSITY OF JERUSALEM AND WENT
ON TO DO HER GRADUATE STUDIES
UNDER MICHAEL SELAH AND MOSES AT
THE INSTITUTE.
AFTER A POSTDOC AT THE
UNIVERSITY OF MICHIGAN, SHE
RETURNED WHERE SHE HAS BEEN
SINCE 1987.
A PROFESSOR OF IN OR ABOUTO
IMMUNOLOGY.
OVER THE YEARS, SHE HAS WON
NUMEROUS AWARDS FOR HER WORK IN
OPTHALMOLOGY, SPINAL CORD
INJURY, NEUROSCIENCE,
NEUROIMMUNOLOGY, INCLUDING 2015
LUMBERING PRIZE FOR EXCELLENCE
IN MEDICAL RESEARCH IN THE 2017
RAPOPORT PRIZE FOR EXCELLENCE IN
BIOMEDICAL RESEARCH.
SHE IS IS THE PRESIDENT OF THE
INTERNATIONAL SOCIETY OF
NEUROIMMUNOLOGY AND HER OWN
SCIENTIFIC JOURNEY AND IDEAS ARE
SUMMARIZED IN HER 2016 BOOK,
NEUROIMMUNITY.
PROFESSOR SCHWARTZ IS ONE OF
THOSE PEOPLE WHO LOOKS AT THINGS
DIFFERENTLY FROM THE WAY OTHER
PEOPLE DO AND OF COURSE THAT IS
THE BEST WAY TO DO SCIENCE.
HER WORK HAS LONG BEEN FOCUSED
ON THE INTERFACE BETWEEN THE
BRAIN AND THE IMMUNE SYSTEM AS
WELL AS NORMAL AGING.
AND THAT WORK HAS REALLY SHIFTED
THE PARADIGM IN THIS SPACE.
IN A SERIES OF GROUNDBREAKING
STUDIES, SHE AND HER TEAM SHOWED
THAT BOTH THE ADAPTIVE AND THE
INNATE ARMS OF THE IMMUNE SYSTEM
CAN CONTRIBUTE NOT ONLY TO
DISEASE PATHOGENESIS, BUT ALSO
CRUCIALLY TO REPAIR PLASTICITY,
A CONCEPT SHE CALLED PROTECTIVE
AUTO IMMUNITY I.
AS PART OF THIS WORK, SHE
RECENTLY DEMONSTRATED THAT THE
GATEWAY FOR THE IMMUNE SYSTEM TO
INTERACT WITH THE BRAIN IS NOT
THE MEN IN GEES AS COMMONLY
THOUGHT BUT RATHER THE HIS PEE
PLEXUS DEEP WITHIN THE
VENTRICULAR SYSTEM OF THE BRAIN
AND THAT DYSFUNCTION OF THIS
GATEWAY PLAYS A MAJOR ROLE IN
ALZHEIMER'S AND IT'S THIS WORK
THAT IS THE TOPIC OF HER TALK
TODAY SISS STEMMATIC IMMUNITY
PROTECTS THE MIND.
SO WELCOME PROFESSOR SCHWARTZ.
[ APPLAUSE ]
>> THANK YOU FOR THE
INTRODUCTION.
--
[ LOW AUDIO ]
WHAT I'M GOING TO DOE FOR YOU IS
SUMMARIZE BRIEFLY 20 YEARS OF
WORKING WHICH WE CALL PARADIGM
SHIFT AND DEVOTE BIG PART OF MY
TALK TO ISSUE OF IMMUNE SYSTEM
BY IMMUNE CHECKPOINT BLOCKADE
CAN COMBAT ALZHEIMER'S DISEASE.
SO FOR THE LAST 20 YEARS HAD
RELATIONSHIP BETWEEN THE BRAIN
AND THE IMMUNE SYSTEM AND THIS
WAS SUMMARIZED -- WHERE IS THE
POINTER?
SO THIS WAS SUMMARIZED LATELY IN
AN ARTICLE, WHICH WE ASKED, CAN
IMMUNE THERAPY TREATMENT OR
DEGENERATIVE DISEASES SUPPORT
THE TRANSIENT BOOSTING ADAPTIVE
IMMUNITY CAN FIGHT ADVANCD
ALZHEIMER'S?
SO WE KNOW THAT ALMOST ALL
NEURODEGENERATED CONDITIONS,
WHETHER THERE IS ACUTE INJURY,
BRAIN OR SPINAL CORD OR MORE
DEGENERATED DISEASES,
ALZHEIMER'S, PARKINSON, ALS, ANY
DEPRESSION OR JUST AGING
DEMENTIA, THERE IS LOCAL
INFLAMMATION.
FOR DECADES IT WAS BELIEVED THAT
IT IS VERY MUCH SIMILAR TO THE
INFLAMMATION THAT WE SEE IN
MULTIPLE SCLEROSIS AND THEREFORE
ATTEMPTS HAVE BEEN MADE TO FIGHT
AGAINST THIS LOCAL NEW
INFLAMMATION WITH
ANTI-INFLAMMATORY DRUGS.
IN 20008 THERE WAS A HUGE
CLINICAL TRIAL USING NON
STEROIDAL ANTI-INFLAMMATORY DRUG
IN ALZHEIMER'S WHICH FAILED AND
THE QUESTION WAS, WHAT HAVE WE
MISSED?
ACCORDING TO OUR UNDERSTANDING,
THE BRAIN IS NOT --
[ LOW AUDIO ]
WE HAND IT NEURODEGENERATED
DISEASE INVOLVES NOT ONLY THE
BRAIN BUT ALSO DYSFUNCTION OF
SYSTEMIC IMMUNE SYSTEM AND WE
HAVE TO BE CAPER TO DISTINGUISH
BETWEEN THIS NEURODEGENERATED
DISEASE AND NEW INFLAMMATION
ASSOCIATED WITH AUTOIMMUNE
DISEASE.
SO WE KNOW THE --
[ INAUDIBLE ]
MAJOR ROLE IS TO RECOGNIZE AND
DESTROY MICROORGANISM AND
MALIGNANCY.
IT WAS BELIEVED FOR DECADES THAT
THEY KNEW THE BRAIN ESCAPE
IMMUNE SURVEILLANCE.
THIS WAS BASED MAINLY -- BLOOD
BRAIN BARRIER -- COVERED BY
BLOOD BRAIN BARRIER BASICALLY --
[ LOW AUDIO ]
DEFINITELY BLOOD BRAIN BARRIER
SHOULD BE SEEN UNDER ALL
CIRCUMSTANCES.
--
[ LOW AUDIO ]
NOW WE KNOW ALSO WITHIN THE
BRAIN THERE ARE RESIDENT CELLS,
THE MICROGLIA.
FOR YEARS IF YOU OPEN ANY TEXT
BOOK OF ANY PAPER FOR 10 OR EVEN
5 YEARS AGO, YOU WOULD SEE THERE
IS INFLAMMATION MICROGLIAL FLESH
INFILTRATING MICROPHAGES.
WE KNOW THE MICROGLIA HAVE NOT
IDENTIFIED TO MACROPHAGES,
MICROGLIA, THE ONLY RESIDENT IS
IN THE BRAIN.
-- SLOW PROLIFERATION AND
MACROPHAGES DON'T REPLACE
MICROGLIA.
BUT IT IS VERY IMPORTANT TO NOTE
MICROGLIA, THE BRAIN CELLS
NEVERTHELESS THEY ARE UNDER
TIGHT CONTROL TO ENSURE THAT
THEY -- ACTIVITY WITHOUT
ENDANGERING ANY NEIGHBORING
CELLS AND THEREFORE THEY ARE
CONTROLLED BY THE MILIEU OF THE
CNS, WHICH IS ENRICHED WITH
TGF-BETA AND THERE IS ALSO VERY
TIGHT CELL SETTING INTRODUCTION,
THE MICROGLIAL EXPRESS RECEPTORS
AND WHICH VERY MUCH SUPPRESSED
BY THE LIGAND WHICH IS EXPRESSED
BY NEURON AND THERE IS ALSO --
SO OVER ALL MICROGLIA HAVE TIGHT
CONTROL WHICH ENSURE TIGHT
ACTIVITY BUT UNDER VERY STRICT
REGULATION.
SO SPECIFICALLY, WHAT WAS
BELIEVED FOR MANY YEARS THAT THE
BRAIN DOES NOT REQUIRE
CIRCULATING IMMUNE CELLS.
IT RELIES ONLY ON THE MYELOID
CELLS.
IT WAS BELIEVED THAT MICROGLIA
AND INFILTRATING CELLS ARE
REDUNDANT CELLS.
WE KNOW NOW THEY ARE NOT.
IMMUNE CELLS ENTRY THE CNS WAS
BELIEVED FOR DEC DECADES THAT IT
IS ONLY PATHOLOGY AND IT IS BAD.
WE WILL DISCUSS THAT'S NOT THE
SITUATION.
AND WE KNOW NOW THAT ENTRIFUL
IMMUNE CELLS FROM THE
CIRCULATION REQUIRE BREAKDOWN OF
THE BLOOD BRAIN BARRIER WHICH
WAS COMMONLY BELIEVED.
SO WHAT I'M GOING TO SHOW YOU
TODAY, VERY BRIEFLY THE PAST AND
MAINLY TO THE PRESENT.
SO IN 1998-1999, WE SHOWED FOR
THE FIRST TIME T-CELL AND
MACROPHAGES SUPPORT REPAIR.
WE FOUND THAT T-CELLS SUPPORT
NORMAL BRAIN PLASTICITY AND
EXCLUDED FROM THE BRAIN AND
SINCE 2017 WHERE WE DISCOVERED
THE PLEXUS SUPPORT ENTRY OF
IMMUNE CELLS TO CNS WITHOUT THE
NEED FOR BREACHING OF THE BLOOD
BRAIN BARRIER AND THEN WE FOUND
IN AGING AND IN ALL NEW
DEGENERATED CONDITION, THIS
BARRIER DYSFUNCTION AND WE CAN
OVERCOME DYSFUNCTION BY IMMUNE
CHECKPOINT BLOCKADE.
SO BRIEFLY, AS I SAID, WE FOUND
IN 1998 THAT MACROPHAGES SUPPORT
REPAIR.
THAT THE TIME IT WAS ACCEPTED
WITH A LOT OF SKEPTICISM AND IT
WAS CITED ONLY IN THE NEGATIVE
WAY.
HOW COME MACROPHAGES SUPPORT
REPAIR IF THE BRAIN IS FULL OF
RESIDENT MICROGLIA?
WE CLAIM THAT THEY ARE NOT
REDUNDANT CELLS.
SUBSEQUENTLY, MANY OTHER WORK
INCLUDING ALZHEIMER'S,
DEMONSTRATED RECRUITMENT OF
BLOOD-BORN MACROPHAGES OR
MONOCYTES DERIVED MACROPHAGES AS
WE CALL THEM, ARE NEEDED TO
FIGHT AGAINST MANY OTHER
PATHOLOGIES.
WE BELIEVE THAT BLOOD BORN
MACROPHAGES ARE NEEDED TO BE
RECORDED IN PATHOLOGICAL
CONDITIONS.
WE KNOW NOW THAT BLOOD BORN
MACROPHAGES CAN DISPLAY INSIDE
THE BRAIN MANY ACTIVITIES.
INFLAMMATORY TO INFLAMMATORY.
THEY CAN BE SOURCE OF DEGRADING
ENZYME.
THEY CAN BE ACTING INFLAMMATORY
TO DISPLAY ACTIVITY.
SUBSEQUENT TO THE MACROPHAGES,
WE DEMONSTRATED AN INDEPENDENT
PAPER THE T-CELL ALSO SUPPORT
BRAIN REPAIR AND SPECIFICALLY
T-CELLS THAT RECOGNIZE CNS
ANTIGEN AND WE COINED THE IDEA
OF PROTECTIVE AUTOIMMUNITY.
AT THAT TIME WE DIDN'T KNOW WHAT
THE RELATIONSHIP BETWEEN THE
T-CELL, THE MICROGLIA AND
MACROPHAGES.
THESE WERE TWO INDEPENDENT
OBSERVATIONS.
SUBSEQUENTLY, WE OBSERVED IN
MODEL OF SPINAL CORD AND I JUST
TOUCH IT VERY BRIEFLY.
WE FOUND T-CELLS SUPPORT
RECRUITMENT OF MONOCYTES DERIVED
MACROPHAGES STILL.
AND THE MAJOR ROLE OF MONOCYTES
DERIVED MACROPHAGES, AT SITE OF
THE INJURY IS TO SUPPRESS THE
MICROGLIAL RESPONSE AND
MONOCYTES DERIVED FROM IL10
DEFICIENT MICE FAIL TO SUPPORT
REPAIR.
SO OVER ALL WE HAD AN IDEA THAT
T-CELL CAN SUPPORT RECRUITMENT
OF MACROPHAGES AND THE LOCAL
MACROPHAGES ARE NEEDED TO
RESOLVE THE INFLAMMATION
SUBSEQUENTLY WE FOUND NEEDED TO
RESOLVE THIS TISSUE.
INDEPENDENT WORK AT THAT TIME,
GRADUATE STUDENTS WERE IN MY
LAB.
ONE IS A PROFESSOR NOW AND ONE
AT THE WEIZMANN INSTITUTE, THEY
WERE SPENDING WITH ME HOURS AND
ASKING ME IF T-CELL ARE NEEDED
TO SUPPORT REPAIR WHY WE NEVER
HAVE FULL REPAIR?
AND MAYBE T-CELL MUCH MORE
FUNDAMENTAL FLOW BRAIN
PLASTICITY.
AND WE THOUGHT IF THERE IS THE
CASE, IT IS VERY EASY TO CHECK.
WE TOOK ANIMAL AND PLACED THEM
IN RICH ENVIRONMENT, A CAGE THAT
WAS DEVELOPED BY ANOTHER LAB,
AND WE PLACED THE ANIMAL AND
UNDER THIS CONDITION YOU CAN SEE
INCREASING IN OR ABOUTOGENESIS.
WHEN PLACED IMMUNE COMPROMISED
ANIMAL IN THE SAME CAGE LIKE
SKID MICE OR MICE THAT ARE
DEFICIENT IN CNS T-CELL, WE
FOUND THERE IS DRAMATIC
REDUCTION IN NEUROGENESIS.
IN OTHER WORDS, WE FOUND THAT
ONE OF THE MECHANISM BY WHICH
NEUROGENESIS IS BOOSTED IN THE
RICH ENVIRONMENT INVOLVE T-CELL.
YOU CAN SEE VERY NICELY HERE ARE
NEWLY-FORMED IN THE HIPPOCAMPUS
OF THE WILDTYPE ANIMAL AND VERY
FEW IN IMMUNE COMPROMISED
ANIMAL.
WE CHECK COGNITION OF THESE MICE
AND FOUND THE SAME THAT
COGNITIVE ABILITY IS DOWN
REGULATED IN IMMUNE COMPROMISED
ANIMAL AND THIS WAS THE DEPLETED
BY NUMEROUS WORKS THEREAFTER.
SO WE SUGGESTED THAT T-CELLS
SUPPORT BRAIN PLASTICITY,
INCLUDING NEUROGENESIS.
HIPPOCAMPAL ACTIVITY AND LATELY
IT WAS SHOWN ALSO SOCIAL
BEHAVIOR.
SO OVER ALL WE ARE LEFT WITH KEY
ISSUE.
HOW CAN LEUCOCYTE ENTER TRAFFIC
TO CNS WITHOUT BREACHING THE
BLOOD-BRAIN BARRIER?
BASICALLY OUR MACROPHAGES
CONNECTED TO CNS AND MORE
IMPORTANTLY, HOW CAN T-CELL
SUPPORT BRAIN PLASTICITY IF THEY
ARE EXCLUDED?
WE KNOW THERE ARE NO T-CELL IN
BRAIN PARENCHYMA.
STRUGGLING WITH THIS QUESTION
FOR A WHILE, ONE OF MY GRADUATE
STUDENTS, OUTSTANDING GRADUATE
STUDENT, SHE WAS STRUGGLING WITH
IT FOR FOUR YEARS.
AND FINALLY, SHE DISCOVERED IN
THE MODEL OF SPINAL CORD INJURY
THAT MACROPHAGES SUPPORT REPAIR
AND CAN ENTER INTO THE LEFT --
BUT THE ONES DISPLAYING LOCALLY
AND INFLAMMATORY ROLE ARE COMING
BLOOD BARRIER WHICH IS IN THE
FRONT VENTRICLES.
THIS WAS A BIG SURPRISE BECAUSE
THE SPINAL CORD INJURIES
INFLICTED HERE, SHE FOUND THAT
MONOCYTES IS DERIVED MACROPHAGE
THAT IS LOCALLY DISPLAY
ANTI-INFLAMMATORY ROLE ARE
CRAWLING THROUGH THE BLOOD
BARRIER.
SO THE QUESTION WAS, WHAT
REVEALED ACTIVATION OF THE BLOOD
BARRIER?
WE WENT FURTHER AND ISOLATED THE
BLOOD BARRIER.
THIS IS THE COREY PLEXUS
EPITHELIUM AND WE FOUND THIS
TISSUE, EVEN IF WE EXPENSIVELY
PRO FUSED THE ANIMALS, WE FOUND
T-CELL OUTSIDE THE BLOOD VESSEL
IN STROMA.
WE TOOK THIS T-CELL AND WILL WE
DECIDED TO EXPLORE FURTHER HOW
IT WORKS.
WE ENVISIONED THAT MAYBE UNDER
INJURIOUS CONDITION, WE KNOW
THERE IS RELEASE OF IL6, TNF AND
IL1 BETA.
SO ENVISION THAT MAYBE THEVILLE
I OF THE EPITHELIUM CELLS SENSES
THE CYTOKINE MAYBE THERE ARE
T-CELLS SITTING IN THE STROMA.
WE ISOLATED THIS T-CELL FOUND
THAT ALMOST 97% OF THESE T-CELL
ARE CD4 POSITIVE T-CELL WHICH
MEANS THEY ARE ENGAGED WITH THE
COGNITIVE ANTIGEN AND WE FOUND
IN THE STROMA T-CELL ENGAGED
WITH ANTIGEN PRESENTING CELLS.
WE FOUND THAT THIS T-CELL CAN
LOCALLY REPRODUCE INTERFERON
GAMMA AND IL4 AND IL10.
WE DIDN'T FIND ANY T-CELL IN
THIS STROMA.
TO TEST OUR WORKING HYPOTHESIS,
WE TESTED WHAT ARE THE T-CELL
RECOGNIZING?
AND TOGETHER WITH THE WEIZMANN
INSTITUTE, WE DECIDED TO
SEQUENCE THE T-CELL RECEPTOR OF
THE T-CELLS WE ISOLATED FROM THE
EPITHELIAL AND PLEX US AND WE
FOUND T-CELLS, 70% OF THEM ARE
RECOGNIZING CNS ANTIGEN.
IN OTHER WORDS, THE GATEKEEPER
OF THE BRAIN, THE COREY PLEXUS
EPITHELIUM IS ENRICHED WITH
T-CELL THAT RECOGNIZES TNF
ANTIGEN.
WE CREATED A MONOLAYER AND
TESTED WHETHER INDEED THERE IS A
CYTOKINE EPITHELIAL CELLS ARE
SENSING SUCH AS TNF ALPHA UP
REGULATED INTO IT AFFECTING
EXPRESSION OF TRAFFICKING
MOLECULES BY THE CHROID PLEXUS
AND CHEMOKINE AND INTEGRIN.
SO WE EXPOSED THE CELLS EITHER
TO TNF ALPHA, OI6 OR IL1 BETA
AND ALSO TO THE CYTOKINE THAT WE
FOUND AT THE T-CELL ARE
PRODUCING SUCH AS INTERFERON
GAMMA, IL4 OR IL10.
TO MAKE A LONG STORY SHORT, WE
FOUND THAT THE ORANGEY CYTOKINE
THAT COMES FROM THE T-CELL THAT
ACTIVATES THE COREY PLEXUS IS
INTERFERON GAMMA.
CHROID PLEXUS.
NONE OF THEM ARE ACTIVATING THE
CHROID PLEXUS EPITHELIUM.
THEY DIDN'T ACTIVATE ONLY
INTERFERON GAMMA.
AND THERE WAS ENERGY BETWEEN THE
TNF ALPHA AND INTERFERON GAMMA
TO ACTIVATE THE CHROID PLEXUS
FOR TRAFFICKING MOLECULES, WHICH
WAS VERY SATISFACTORY FOR US
BECAUSE THAT IS WHAT WE
ENVISIONED.
THERE IS A SINGLE GENE BETWEEN
WHAT EPITHELIAL CELLS SENSE WHEN
IS THERE INFLAMMATION IN THE
BRAIN AND CYTOKINE THAT PRODUCE
T-CELL.
WE FOUND THAT INTERFERON GAMMA
KNOCK-OUT MICE OR INTERFERON
GAMMA RECEPTOR KNOCK-OUT MICE,
THERE IS A DRAMATIC REDUCTION IN
THE NUMBER OF T-CELLS THAT WE
FOUND IN THE CSF AND THERE IS
DRAMATIC REDUCTION IN
TRAFFICKING MOLECULES.
WE TESTED WHETHER TNF ALPHA IS
ACTIVATION OF THE CHROID PLEXUS
EPITHELIUM AND WE FOUND YES, IT
IS INDEED VERY MUCH DEPENDENT ON
NF-kB/P65.
SO WE FOUND INTERFERON GAMMA IS
THE KEY CYTOKINE THAT IS NEAR
THE ACTIVATED CHROID PLEXUS
EPITHELIUM FOR TRAFFICKING.
OUR KEY QUESTION CAME OUT, WHAT
DOES THE FATE OF THE COMPARTMENT
EFFECT THE BRAIN
NEURODEGENERATED DISEASE?
AND IF SO, CAN WE MANIPULATE THE
CHROID PLEX US AND AFFECT THE
DISEASE?
WE STARTED IN AGING AND THEN WE
MOVED TO ALZHEIMER'S.
SO WE FIRST TESTED TOOK THE
CHROID PLEXUS WITH AGING AND WE
FOUND THAT THERE IS DRAMATIC
REDUCTION IN THE AVAILABILITY OF
INTERFERON GAMMA WITH AGING OF
THE MOUSE AROUND 18 MONTHS THERE
IS DRAMATIC DROP.
WE TESTED WHETHER THE CHROID
PLEXUS IN AGED MICE EXPRESS ANY
OF THE COGNITIVE IMPAIRING
MOLECULE THAT WE FOUND BY THE
CREW.
AND WE FOUND THERE IS A DRAMATIC
INCREASE.
WE FURTHER DECIDED TO GET MORE
INSIGHT WHETHER AGING OF THE
BRAIN REFLECTS AGING OF THIS
CHROID PLEXUS EPITHELIUM OR
AGING OF THE BLOOD OR AGING OF
THE TISSUE.
TO THIS END, WE COLLECTED 11
TISSUE FROM YOUNG ANIMAL AND 11
TISSUE FROM AGED ANIMAL AND DID
OTHER SEQUENCING.
TO OUR SURPRISE, WE FOUND IN
AGING OF THE CHROID PLEXUS AS A
VERY UNIQUE SIGNATURE THAT IS
ELEVATION OF INTERFERON BETA
WHICH WE DIDN'T FIND IN ANY
OTHER AGED TISSUE AND WE DIDN'T
FIND IN YOUNG TISSUE.
SO THERE IS VAST ELEVATION OF
INTERFERON BETA, TYPE I.
AND DOWNREGULATION OF INTERFERON
GAMMA WHICH WE FOUND BEFORE.
INTERESTINGLY, SEVERAL MONTHS
BEFORE OUR SCIENCE PAPER THERE
WAS ANOTHER SCIENCE PAPER
SHOWING THIS RELATIONSHIP
BETWEEN INTERFERON BETA AND
INTERFERON GAMMA.
WE GOT HUMAN SECTION FROM UK AND
WE ASKED EXPLICITLY TO GET
TISSUE FROM AGED POPULATION,
NEUROLOGICAL DISEASE AND WE
FOUND IT IN AGED POPULATION THE
SAME SIGNATURE OF THE CHROID
PLEXUS AND ELEVATION OF
SIGNATURE INTERFERON BETA.
TOGETHER WITH OTHERS, WE DECIDED
TO EXPLORE WHETHER THE ELEVATION
OF INTERFERON BETA AND THE
DOWNREGULATION OF INTERFERON
GAMMA IS CAUSED BY SIGNALING
FROM THE BRAIN OR FROM THE
CIRCULATION.
SO WE CREATED THESE MICE AND WE
FOUND THAT CONNECTING YOUNG
ANIMAL TO AGED ANIMAL, AGE TO
AGE, YOUNG TO YOUNG, IS
CONTROLLED.
TO MAKE A LONG STORY SHORT, WE
FOUND THAT THE DOWNREGULATION OF
INTERFERON GAMMA IS CONTROLLED
BY THE CIRCULATION WHEREAS THE
UP REGULATION OF INTERFERON BETA
IS CONTROLLED BY SIGNALING
COMING THROUGH THE CSF.
THE NEXT QUESTION WE ASKED
OURSELVES, CAN WE REJUVENATE THE
CHROID PLEXUS AND RESTORE
ABILITY?
TO REJUVENATE THE CHROID PLEXUS,
WE INJECTED INTO THE CS IS F
ANTIBODY DIRECTED TO TYPE I
INTERFERON BETA RECEPTOR.
WE ENVISIONED INTERFERON BETA
WHICH IS PRODUCED BY THE
EPITHELIAL CELLS CAN DO
REGULATION AND EFFECT EPITHELIAL
CELLS AND CAN EFFECT THE BRAIN.
SO TO NEUTRALIZE BOTH ACTIVITY,
WE INJECTED ANTIBODY DIRECTLY
INTO INTERFERON BETA RECEPTOR.
WE FOUND THAT WE HAVE STORED ALL
ACTIVITY OF THE CHROID PLEXUS BY
NEUTRALIZING INTERFERON BETA
RECEPTOR RELATIVE TO ISOTYPE IGG
CONTROL AND WE REDUCED GLIOSIS
IN THE AGED BRAIN.
TO FURTHER TEST WHETHER IT HAS
ANY EFFECT ON COGNITION, WE TOOK
AGED MICE AND SCORED THE MICE
FIRST TO FIND OUT THOSE AGED
MICE THAT HAVE IMPAIRED
COGNITION AS WAS REPORTED AND
THE SAME IN HUMAN, 30% OF THE
AGED MICE ARE STILL INTACT
MEMORY.
WE TOOK 70%, SPLIT INTO TWO
GROUP, ONE RECEIVED IGG CONTROL
AND THE OTHER RECEIVED THE
ANTIBODY TO INTERFERON BETA
RECEPTOR AND WE FOUND THAT THIS
GROUP SHOWED IMPROVED COGNITION
ALMOST TO THE LEVEL OF THE THOSE
WITH INTACT MEMORY.
SINCE WE PUBLISHED THIS PAPER,
WE DECIDED TOO CHECK WHETHER THE
SIGNALS OF THE INTERFERON BETA
WHICH IS PRODUCED BY THE CHROID
PLEXUS EFFECT THE MICROGLIA.
WE SAW THE MICROGLIA FROM AGED
BRAIN AND FROM YOUNG BRAIN AND
THEN WE FOUND THE MAJORITY OF
THE SIGNATURE OF THE MICROGLIA
AGED MICE IS TYPE I INTERFERON.
AND AMONG THE MOLECULE EXPRESSED
BY THE AGED MICROGLIA IN WHICH
EFFECTED THE NEUTRALIZING
INTERFERON BETA RECEPTOR WHICH
WAS PUBLISHED AS COGNITIVE
IMPAIRING.
AND ANOTHER PUBLISHED BY BETH
STEVENS AND OTHERS, IMPAIRING
COGNITION.
SO OVERALL, WHAT WE FOUND IS
THAT TYPE I IS A VERY PROMINENT
SIGNATURE OF THE MICROGLIA.
AND NEUTRALIZING TYPE I
SIGNATURE CAN ALLEVIATE SOME OF
THE SYMPTOMS OF AGING AND
RESTORE MICROGLIA ACTIVITY.
BASED ON THIS, WE DECIDED TO GO
TO ALZHEIMER'S WITH THE IDEA
THAT WE ALREADY KNEW IN
ALZHEIMER'S WE NEED MACROPHAGES
TO FIGHT AGAINST ALZHEIMER'S.
WE ALREADY KNEW ENTRY OF
MACROPHAGES TO THE CNS DEPEND ON
THE CHROID PLEXUS EPITHELIUM AND
WE ALREADY KNEW THAT WE NEEDED
INTERFERON GAMMA IN ORDER TO
SUBJECTIVATE THE CHROID PLEXUS
AND INTERFERON GAMMA IS GOING
DOWN WITH AGING.
WE DECIDED TO SEE WHAT IS THE
FATE OF THE CHROID PLEXUS IN
AGING AND WHETHER WE CAN REVERSE
IT.
SO, AS YOU'RE FAMILIAR, THERE
IDENTIFIED IN ALZHEIMER'S
INCLUDING AMYLOID PLAQUES AND
NEUROFIBERI LARRYITAGE ELSE AND
THERE ARE ALREADY SEVERAL ANIMAL
MODELS THAT MIMICS THE
NEUROFIBRILLARY TANGLES.
THERE IS A LOCAL
NEUROINFLAMMATION AS I SAID AT
THE BEGINNING OF MY TALK, TO
TREAT THE NEW INFLAMMATION WITH
SYSTEMIC ANTI-INFLAMMATORY DRUG.
NEEDLESS TO SAY THAT ANY THERAPY
THAT WAS DIRECTED TO A BETA PLUS
WASN'T TURNED OUT TO BE DISEASE
MODIFYING.
IT'S NOT BECAUSE A BETA PLUS ARE
NOT DESTRUCTIVE BUT BY THE TIME
THAT THEY ARE PROMINENT AND
THERE IS COGNITIVE DECLINE, IT
MAY BE EFFICIENT BUT
INSUFFICIENT.
SO WE DECIDED TO FOCUS ON THIS
IS JUST TO SUMMARIZE THE WORK
THAT WAS PUBLISHED ALTHOUGH THE
USE IS DEMONSTRATING THE
RECRUITMENT OF MACROPHAGES TO
THE SITE OF PATHOLOGY CAN
BENEFIT THE DISEASE NOT ONLY
FACILITATING REMOVAL OF BLOOD
BUT ALSO CHANGING THE MILL YOU
YOO OF THE CNS FROM ONE
INFLAMMATORY TO LES
INFLAMMATORY.
SO WE DECIDED TO FOCUS ON TWO
ANIMAL MODEL OF ALZHEIMER'S.
ONE WHICH IS A ASSOCIATED WITH A
BETA PATHOLOGY AND ONE IS
ASSOCIATED WITH TAU PATHOLOGY.
THE A BETA PATHOLOGY, THERE ARE
SEVERAL MODELS.
WE DECIDED TO FOCUS ON THE ONE
WHICH WE CALL THE FIVE X5.
THERE ARE FIVE HUMAN MUTATION
AND THIS WAS DEVELOPED IN
CHICAGO 2006.
THIS IS THE ONLY MODEL THAT
STIMULATE ALMOST ALL THE
SYMPTOMS THAT ARE IN HUMAN WITH
THE SENSE THERE IS A COGNITIVE
LOSS, THERE IS A BAIT PATHOLOGY
AND THERE IS ALSO NEURONAL LOSS
AND LOCAL INFLAMMATION.
SO WE STARTED WITH THIS MODEL
AND THE FIRST THING THAT WE
TESTED WHETHER THE CHROID PLEXUS
EPITHELIUM EXPRESSED TRAFFICKING
MOLECULES.
AND WE TESTED ALL OF THE
TRAFFICKING MOLECULES THAT WE
KNEW ALREADY THAT ARE NEEDED FOR
RECRUTMENT EVER MACROPHAGES.
WE TESTED BY -- AND THESE LINES
SHOW YOU THE EXPRESSION OF
TRAFFICKING MOLECULES BY AGED
CONTROL, YOU CAN SEE FROM TWO
MICE ONWARD, NOT ONLY THERE IS
NO ELEVATION THAT YOU NEED TO
FACILITATE MACROPHAGES BUT IT IS
GOING DOWN.
AND THE MOST STRIKING
DOWNREGULATION CYCLE WAS
INTERFERON GAMMA DEPENDENT.
BASED ON THIS, WE WENT TO SEE IS
WHETHER IN THIS MOUSE MODEL
THERE IS REDUCTION IN THE
AVAILABILITY OF INTERFERON
GAMMA.
AND WE FOUND BY FLOW CYTOMETRY
AND INTERCELLULAR STEMMING
INTERFERON GAMMA AND THERE IS A
STRIKING DROP IN INTERFERON
GAMMA IN THIS MOUSE MODEL.
WE TESTED EXPRESSION OF -- AND
FOUND IN AC YOUNG PEOPLE, THE
CHROID PLEXUS EXPRESS LEVEL OF
ICON GOING DOWN WITH AGING AND
FURTHER IN
[ INAUDIBLE ]
SO IN THIS MOUSE MODEL WE FOUND
THERE IS REDUCTION OF
TRAFFICKING MOLECULE AND
REDUCTION INTERFERON GAMMA.
SUBSEQUENT TO OUR WORK, THERE
WAS ANOTHER WORK USING ANOTHER
MOUSE MODEL OF ALD ALZHEIMER'S,
THE J20, AND THEY FOUND EXACTLY
THE SAME PHENOMENA THAT
INTERFERON GAMMA IS GOING DOWN
AND ICON IS GOING DOWN WITH THE
DISEASE PROGRESSION.
NOW IN PRINCIPLE, WE TESTED TO
SEE WHETHER THERE IS ANY
RELATIONSHIP BETWEEN EXPRESSION
OF TRAFFICKING MOLECULES AND
ENTRY OF IMMUNE CELLS TO THE CSF
AND IN THE MODEL OF STRESS WHICH
LEADS TO POST-TRAUMATIC STRESS
DISORDER SYMPTOMS, WE FOUND A
GREAT CORRELATION BETWEEN
EXPRESSION OF TRAFFICKING
MOLECULES AND OUR ABILITY TO
DETECT IMMUNE CELLS MAINLY
T-CELL INTO CSF.
SO IN PRINCIPLE THERE ARE
SEVERAL WAYS TO AUGMENT LEVEL OF
AVAILABILITY OF INTERFERON
GAMMA, WHICH I CALL THEM EITHER
PRESS THE GAS OR LOOSEN THE
BRAKES.
SO EITHER YOU CAN ACTIVATE THE
IMMUNE SYSTEM OR -- TO ACTIVATE
YOU NEED MOLECULES OR
ANTI-VACCINATION.
SO WE DECIDED TO TESTED WHETHER
AUGMENTING AVAILABILITY FOR
INTERFERON GAMMA COULD BE
ACHIEVED BY BLOCKING SUPPRESSIVE
MECHANISM.
NOW SUPPRESSIVE MECHANISM CAN BE
MYELOID SUPPRESSIVE CELLS OR
IMMUNE CHECKPOINT INHIBITORY
IMMUNE CHECKPOINT.
WE DECIDED BECAUSE WE KNOW THAT
WITH AGING THERE IS ELEVATION OF
REGULATORY --
[ INAUDIBLE ]
WE KNOW WITH EXHAUSTION OF THE
IMMUNE SYSTEM THERE IS ELEVATION
OF INHIBITORY IMMUNE CHECKPOINT.
22 DECIDED TO FOCUS ON APPROACH
OF LOOSENING THE BREAKS.
SO WHAT WE DID THE FIRST THING
WE DID IS BRED THE ALZHEIMER'S
MICE WITH FOX P3R WHICH WE GOT
FROM -- AND WE CAN DEPLETE
REGULATORY T-CELL.
WE DEPLETED THEM AFTER TWO WEEKS
THE LEVEL OF REGULATORY CELLS
REBOUND.
AND WE TESTED WHETHER A SINGLE
SESSION OF REDUCING REGULATORY
T-CELL WILL BE SUFFICIENT TO
ACTIVATE THE CHROID PLEXUS AS A
GATEWAY AND TO OVERCOME THE
DISEASE PATHEDDOLOGY.
SO WE FOUND THAT A WEEK AFTER
THE DEPLETION OF REGULATORY
T-CELL AT THE CHROID PLEXUS
EPITHELIUM WAS ACTIVATED BOTH MY
IMMUNOHISTOCHEMISTRY.
WE FURTHER FOUND THAT MONTHS
AFTER THE DEPLETION OF
REGULATORY T-CELL WE SEE MYELOID
CELLS AND REGULATORY T-CELL IN
THE BRAIN PARENCHYMA AROUND THE
PLEXUS.
WHEN WE CHECK COGNITIVE ABILITY
AND PATHOLOGY, WE WERE AMAZED TO
SEE, THIS IS THE PATHOLOGY IN
THIS MOUSE MODEL THE BETTER
PLAQUES ARE HUMAN PLAQUES.
SO VERY EASY TO DISTINGUISH.
WE USE ANTIBODY DIRECTED TO
HUMAN A BETA AND I'M NOT SURE
THAT YOU CAN SEE WITH THIS SLIDE
BUT YOU CAN SEE THE HIPPOCAMPUS
OF THE MICE WITHOUT DEPLETION
AND THIS IS THE DEPLETION ASSIST
STEMMATIC OF REGULATORY T-CELL.
THERE WAS A DRAMATIC REDUCTION
BOTH IN THE CORTEX AND THE
HIPPOCAMPUS.
YOU CAN SEE QUANTIFICATION HERE.
WE TESTED COGNITIVE ABILITY BY
MOUSE MAZE WHICH MEASURE MAINLY
SPECIAL LEARNING AND MEMORY.
SO THIS MAZE INVOLVES THREE
PHASES.
A PHASE OF LEARNING ACQUISITION
AND THE -- TWO PHASES OF MEMORY.
SO DURING FOUR DAYS OF MEMORY
LEARNING ACQUISITION, THE
ALZHEIMER'S MICE THAT WERE NOT
DEPLETED OF REGULATORY T-CELL,
DIDN'T LEARN THIS.
THE BLACK SHOW YOU WILDTYPE AND
BLUE SHOW MICE WITH DEPLETED
REGULATORY T-CELLS.
SO ALMOST BEHAVE AS NORMAL MICE.
WHEN WE REMOVED THE PLATFORM FOR
THE MAZE SO IN THE WATER POOL,
THERE IS A PLATFORM WHICH IS
VERY CLOSE TO THE SURFACE OF THE
WATER.
THE ANIMAL DON'T SEE THE
PLATFORM BUT THERE ARE PICTURE
AROUND THE WATER POOL.
SO THEY CAN REMEMBER TO NAVIGATE
THEMSELVES TO THE PLATFORM BASED
ON THE PICTURE AROUND THE POOL.
SO WHEN YOU REMOVE THE PLATFORM
WE MEASUREED THE TIME THAT
ANIMAL SPENT AROUND THE PLACE
THAT THEY REMEMBERED THE
PLATFORM.
SO THE ANIMAL DEPLETED THE
REGULATORY T-CELL REMEMBERED
VERY SIMILAR TO THE WILDTYPE
ANIMAL WHEREAS ANIMALS THAT WERE
NOT DEPLETED OF REGULATORY
T-CELL DIDN'T REMEMBER AND FOUND
ALSO DRAMATIC REDUCTION IN THE
GLIOSIS.
BASED ON THIS IDEA WE REALIZED
THAT WE NEED TO RECORD TOTALS
ALZHEIMER'S BRAIN REGULATORY
T-CELL AND IN ORDER TO ACHIEVE
THESE, WE INDIVIDUAL TO REDUCE
THE REGULATORY T-CELL TO ALLOW
AVAILABILITY OF INTERFERON GAMMA
PRODUCING CELLS AT THE CHROID
PLEXUS.
THIS WAS FOR US VERY MUCH
REMINISCENT OF WHAT WE KNOW IN
CANCER AND WE DECIDED TO CHECK
WHETHER BLOCKING THE IMMUNE
CHECKPOINT WE CAN ACHIEVE THE
SAME.
NOW WE DECIDED TO FOCUS ON
PD-1/PD-L1 FOR A REASON.
WE KNEW THE MEMORY WAS CD4 AND
CD8 EXPRESSING PERMANENT D1 AND
MORE IMPORTANTLY, THE LIGAND,
THE PD-L1 CAN BE EXPRESSED BY
EPITHELIAL CELLS REGULATORY
T-CELLS AND ANTIGEN PRESENTING
CELLS, ALL OF WHICH WE HAVE AT
THE CHROID PLEXUS EPITHELIUM.
SO WE ENVISION THAT SUPPRESSIVE
T-CELL CAN OUT SUPPRESS EITHER
BY REGULATORY T-CELL ANTIGEN
PRESENTING CELLS AND ALSO
DECIDES THE CHROID PLEXUS.
SO WE DECIDED TO GIVE THE ANIMAL
EITHER ANTI-PD-1 OR ANTI-PD-L1
AND THEREBY UNLEASH CD4 POSITIVE
T-CELL IN ADDITION TO THE CD8
WHICH WILL UNLEASH FOR CANCER
THERAPY.
WE STARTED WITH ANTI-PD-1 BUT
I'LL SHOW YOU UNPUBLISHED DATA
WITH ANTI-PD-L1.
SO, THE FIRST THING THAT WE DID,
WE GAVE THEM -- THIS WAS
PUBLISHED A YEAR AGO IN NATURE
MEDICINE.
SO WE GAVE THE ANIMAL ANTI-PD-1
AND CHECK WHETHER THE CHROID
PLEXUS WAS ACTIVATED INSIDE THE
INTERFERON GAMMA-TYPE SIGNALING
AND THIS WAS THE CASE.
AS CONTROL WE USE IGG CONTROL.
ANTIBODIESED TO -- WE CHECKED TO
SEE WHETHER THE CHROID PLEXUS
WAS ACTIVATED TO EXPRESS
TRAFFICKING MOLECULES AND SAW IT
ACTIVATED.
AND INTERESTINGLY, WHEN WE GAVE
THE ANIMAL PRIOR TO THE
ANTI-PERMANENT D1 A DAY BEFORE
THE ANTI-PD-1 INTERFERON GAMMA,
WE BLOCKED THE INDUCED ACTIVITY
OF THE ANTI-PD-1 WHICH WAS VERY
FINE FOR US BUT INDEED IT WAS
INTERFERON GAMMA DEPENDENT.
WE NEXT TESTED WHETHER AS A
RESULTED OF THE TREATMENT THERE
IS INCREASED RECRUITMENT OF
MONOCYTES DERIVED MACROPHAGES,
AND WE FOUNDED THAT TWO WEEKS
AFTER THE TREATMENT THERE WAS
ABOUT TWO FOLD INCREASE IN THE
NUMBER OF MONOCYTES DIVIDE
MACROPHAGES AND AGAIN, WHEN WE
GAVE THE ANIMAL ANTI-INTERFERON
GAMMA PRIOR TO THE ANTI-PD-1, WE
BLOCKED THIS ELEVATION.
BESIDES THIS, WE DECIDED TO MOVE
TO TEST COGNITIVE ABILITY AND IN
THIS CASE, WE INTENTIONALLY USED
VERY ADVANCED STAGE OF THE
DISEASE.
IN THIS ANIMAL, THERE IS A
COMPLETE LOSS OF COGNITION BASED
ON THE PEOPLE THAT DEVELOPED
THIS MODEL AND BASED ON OUR
EXPERIENCE AT SIX MONTHS OR
MORE.
SO WE STARTED AT 10 MONTHS OLD
AND TREATED THE ANIMAL 10 MONTHS
OLD WITH ANTI-PD-1 AND TESTED
THEM EIGHT MONTHS LATER.
THIS IS SAY SINGLE INJECTION IN
OUR RECORDINAL PAPER WE GAVE TWO
DOSAGE --
[ INAUDIBLE ]
SUBSEQUENTLY WE REPEATED AND
INJECTION WAS SUFFICIENT AND
MICE LATER TO SEE COGNITIVE
ABILITY.
NOW IT WAS RECOMMENDED IN THIS
MICE TO HUES THE TOOL MAZE SO
AGAIN WATER POOL BUT THEY ARE 6
ARM IN THE WATER POOL AND IN ONE
ARM THERE IS A PLATFORM AND WHAT
YOU MEASURE THE LEARNING CURVE,
THE ANIMAL BY THE NUMBER OF AIR
ERRORS THEY MADE BEFORE THEY
NAVIGATE THEMSELVES STRAIGHT TO
THE ARM WITH THE PLATFORM.
SO TO ADD SOME MICE SHOWN IN
THEY REMEMBERED.
THE BLACK SHOWS YOU WILDTYPE
ANIMAL.
GRAY SHOW YOU THE ONE SYSTEM
TREATED WITH THE IGG WHICH WE
CALL PLACEBO AND THE GREEN SHOW
YOU ANIMALS THAT WERE TREATED
WITH ANTI-PD-1 SO THERE WAS
REVERSE OF COGNITIVE LOSS IN
THIS MICE.
WE TESTED THE PLAQUE BURDEN AND
YOU CAN SEE HERE THIS ANIMAL
RECEIVED TWO SESSION OF
INJECTION AND ANALYZE TWO MONTHS
AFTER WE STARTED TREATMENT.
SO ANIMALS THAT RECEIVED 3
INJECTIONS WE TESTED TWO MICE
AFTER WE STARTED, THERE WAS A
VERY NICE PLAQUE REMOVAL AND THE
GREEN SHOW YOU GLIOSIS AND THE
RED SHOW YOU THE PLAQUE.
WHEREAS ANIMALS THAT WERE
TREATED WITH IGG YOU STILL SEE A
VERY HIGH BURDEN OF PLAQUE AND
GLIOSIS.
SO THE EFFECT ON HIS STOL GEE
WAS DRAMATIC.
SINCE WE PUBLISHED THIS PAPER,
WE DECIDED TO SEE WHETHER EVERY
TREATMENT IN THIS MICE MODEL
WILL PREVENT LOSS OF COGNITION
OR DELAY LOSS OF KIG NITION.
SO WE STARTED TO TREAT THE
ANIMAL AT THREE MONTHS, FOUR
MONTHS, AND FIVE MONTHS AND
TESTED THEM AT FIVE AND SIX
MONTHS.
AND WHAT CAN YOU SEE AT FIVE
MONTHS, THE ONES THAT -- THE
CONTROL MICE ARE STILL SHOWING
SOME COGNITIVE ABILITY AT THE
LAST TRIAL, THE LAST DAY.
AT SIX MONTHS THEY ALREADY -- SO
IN THE CAUSE OF THIS EXPERIMENT,
THE CONTROL ARM BECOMING WORSE
WHEREAS THE ONES THAT TREATED
WITH ANTI-PD-1 MAINTAINED 80 TO
LEARN AND REMEMBER.
SUBSEQUENTLY, WE TESTED TO SEE
WHETHER THE TREATMENT IS
ASSOCIATED WITH RESCUE OF
NEURONS WHICH WE MEASURE BECAUSE
THAT IS THE PLACE THAT WAS
RECOMMENDED IN THIS MOUSE MODEL
TO SEE NEURONAL SURVIVAL AND
CASPASE 3 IS A MEASURE OF
APOPTOSIS.
YOU CAN SEE HERE THAT THE
TREATMENT IS A VERY NICE NEW
PROTECTION AND THERE IS DRAMATIC
REDUCTION IN CASPASE 3 EXPRESSED
BY THE NEURONS.
WE DECIDED TO TEST WHETHER
ANTI-PD-L1 WILL HAVE SIMILAR
EFFECT AND YOU CAN SEE DOSE
DEPENDENT RESPONSE.
THE . 1 MILLIGRAM.
NO EFFECT .5 AND 1.5.
SO THE ANTI-PD-1 HAS SIMILAR
EFFECT AND SHOW VERY NICE DOSE
DEPENDENCY AND WE SHOW VERY NICE
EFFECT ON THE INFLAMMATORY
MILIEU IN FAVOR OF THE ELEVATION
OF IL10 AND REDUCTION OF IL20.
NOW IMPORTANTLY, BECAUSE THE
TREATMENT IS GIVEN SYSTEMIC AND
NOT TO THE BRAIN, WE ENVISIONED
THAT IT IS NOT DEPENDENT ON THE
TYPE OF PATHOLOGY OF THE BRAIN
BUT WE ARE ACTIVATING A CASCADE
OF IMMUNE EVENTS THAT STARTS AND
CULMINATES IN THE BRAIN.
SO WE DECIDED TO CHECK ANOTHER
MOUSE MODEL OF ALZHEIMER'S WHICH
IS NOT A BETA DRIVEN AND IT'S
TAU PATHOLOGY.
IN THIS MODEL, THE HUMAN
MUTATION OF MICROTUBULAR
REPORTING IS PHOSPHORYLATED.
IN THIS MOUSE MODEL YOU TEST --
RECOMMENDED TO TEST SHORT-TERM
MEMORY.
SO BASICALLY IT IS A ANIMALS
FIRST LEARN TWO YAM ONE ARM IS
CLOSED.
AND AFTER THAT THEY ARE
HABITUATED TO THE TWO ARM YOU
OPEN THE THIRD ARM AND MEASURE
THE TIME THE ANIMAL SPENT IN THE
NOVEL ARM.
IF THEY DON'T REMEMBER, YOU
SPEND EQUALLY TIME IN THE SHORT
ARM.
IF REMEMBER, THEY WILL SPEND
MORE TIME IN THE NOVEL THAN IN
THE TWO OTHER ARM.
SO, YOU CAN SEE IT VERY NICELY
HERE.
SO THE TAU PATHOLOGY TREATED
WITH IGG AND THESE ARE TREATED
WITH ANTI-PD-1 AND ANTI-PD-L1.
SO THE WILDTYPE SPENT 60% OF THE
TIME IN THE NOVEL ARM AND
SIMILARLY THE TREATED ONE, AND
WAS FOUND IN THIS MOUSE MODEL
AGAIN, THE TREATMENT IS
ASSOCIATED WITH RECRUITMENT OF
MONOCYTES DERIVED MACROPHAGE
SYSTEM INTO THE PARENCHYMA AND
THERE IS REDUCTION OF
PHOSPHORYLATION OF TAU.
SO THE EFFECT OF THE DISEASE IS
NOT DEPENDENT ON THE TYPE OF
ETIOLOGY BUT OF THE IMMUNE
SYSTEM AND THIS IS JUST TO SHOW
YOU THAT IT WILL CAUSE A
DRAMATIC REDUCTION IN THE
PHOSPHORYLATION OF TAU MUTATION.
NOW, WE REPEATED THIS EXPERIMENT
IN A DOSE DEPENDENT MANNER AND
THIS SHOWS YOU VERY NICELY THIS
IS WILDTYPE ANIMAL.
THE TIME INDIVIDUALS SPENT IN
THE NOVEL ARM.
THIS IS IGG CONTROL IN ALL ARM
AT THE SAME TIME.
THIS IS LOW DOSE IN ALL ARM THE
SAME TIME AND IF YOU GO IL, YOU
SEE ANIMALS SPENT MORE IN THE
NOVEL ARM BOTH IN.5 AND 1.5.
SO BASED ON ALL OF THIS, WE
ASKED OURSELVES WHY DO WE NEED
TO RECRUIT MACROPHAGES?
WHY MICROGLIA CANNOT DO THE JOB?
SO I FINISH WITH A VERY BRIEF
STORY ABOUT THE MICROGLIA.
WE DECIDED TO CHECK WHAT IS THE
FATE OF THE MICROGLIA IN THIS
DISEASE?
THEY WILL SUPPORT ON MICROGLIA
ALZHEIMER'S CLAIMING THEY ARE
NOT EFFECTIVE, SOME CLAIMS THEY
ARE INFLAMMATORY.
SO A LOT OF -- AND WE FOUND THAT
LACK OF CONSENSUS IS REFLECTION
OF NOT HAVING GOOD MARKERS FOR
MICROGLIA.
SO TOGETHER WITH THE WEIZMANN
INSTITUTE, WE DECIDED TO GO FOR
SINGLE-CELL RNA-SEQ OF THE
MICROGLIA.
I KNOW SOME OF YOU --
[ INAUDIBLE ]
MICROGLIA WE DID COLLABORATION
AND WE DECIDED TO COLLECT
SINGLE-CELL RNA AND SINGLE CELL
MICROGLIA INTO THE SEQUENCE.
WHAT WE FOUND IS THAT IN THE
ALZHEIMER'S THERE IS SAY SMALL
SUB POPULATION OF MICROGLIA THAT
BEHAVE DISTINCTIVELY FROM THE
REST, ABOUT 5-10%.
WE COULDN'T DETECT THEM IF YOU
DO YOUR BEST RNA SEQUENCING OF
MICROGLIA ONLY BY SINGLE CELL
COULD WE DETECT THEM.
WE FOUND THAT BASED ON THE
MARKERS THEY EXPRESSED, THEY ARE
LOSING SOME OF THE STRAINING
ACTIVITY OF MICROGLIA SUCH AS
CXCL1 AND THEY ARE UP REGULATED
MANY GENES THAT HAVE ALREADY
REPORTED BY GWAS THAT ARE
ASSOCIATED WITH THE DISEASE
PATHOLOGY SUCH AS
[ INAUDIBLE ]
SO BASED ON THE PROFILE, WE FELT
CONFIDENT THIS MICROGLIA
ASSOCIATED WITH ACTIVITY WHEN WE
FOUND THEY ARE ADJACENT TO THE
PLUS IN MICE AND IN HUMAN.
WE FOLLOWED THE DEVELOPMENT OF
THIS MICROGLIA AND WE FOUND THAT
THEY ARE DEVELOPING WITH THE
DISEASE PROGRESSION.
AND THEN WE COLLABORATED WITH
MARCO BECAUSE WE FOUND THAT THEY
ARE ELEVATEING TRENCHING 2 AND
IT'S -- TREMENDOUS 2.
WE FIRST SAW DOWNREGULATION OF
THE MANY GENES THAT ARE
ASSOCIATED WITH HOME STAYSIS AND
THEN WE FOUND FRESHMEN 2 AND
THEN FOUND MANY OTHER.
SO WE WANTED TO SEE WHETHER
TREM2 IS KEY REGULATED IN
DEVELOPMENT.
SO WE HAVE SINGLE CELL MICROGLIA
FOR WILDTYPE ANIMAL, 22 POSITIVE -- TREM2 POSITIVE AND
NEGATIVE MOUSE.
TO MAKE A LONG STORY SHORT, WHAT
WE FOUND THAT THE FIRST STAGE OF
MICROGLIA ACTIVATION IN THIS
MOUSE MODEL IS TREM2 INDEPENDENT
AND THE LAST STAGE IS TREM2
DEPENDENT.
THE DISEASE IS WORSE IN T.
RM2 KNOCK-OUT MICE AND WHAT WE
ARE SEEING IN TREM2 KNOCK OUT
ALZHEIMER'S MICE WE DON'T SEE
THE MICROGLIA.
ALL OF THEM ARE STUCK IN THE
INTERRING PHASE.
SO IT MEANS THEY ARE TREM2
NEGATIVE AND ELEVATION WITH
MICROGLIA ORCHESTRATE THE
DEVELOPMENT OF THIS DISEASE
ASSOCIATE MICROGLIA AND WE ARE
CURRENTLY FOCUSING TO SEE TO
WHAT EXTENT THEY ARE BENEFICIAL
AND WHETHER THE TREATMENT IS BY
RECRUITING MACROPHAGES OR CHANGE
PROFILE.
BUT WE HAVE ONLY PRELIMINARY
DATA.
SO OVERALL, IED LIKE TO
SUMMARIZE MY TAKE HOME MESSAGE
TODAY.
SO WHAT WE ARE SHOWING THIS WELL
CONTROLLED IMMUNE ACTIVATION
OUTSIDE OF THE CNS RATHER THAN
SUPPRESSION IS NEEDED TO COMBAT
NEURODEGENERATED DISEASE
REGARDLESS OF THE DISEASE
ETIOLOGY.
WE FOUND IN A BETA AND FOUND IT
IN THE TAU.
SINCE IMMUNE ACTIVATION IS NOT
DISEASE SPECIFIC, IT CAN
POTENTIALLY BE APPLICABLE TO A
WIDE SPECTRUM OF DISEASE.
THE CHOICES OF ACTIVATION MODE,
WHETHER STEPPING ON THE GAS
PEDAL OR RELEASING THE BREAKS IS
VERY MUCH DEPEND ENT ON THE
DISEASE STAGE AND THE TYPE OF
DEFICIENCY.
WE HAVE OTHER DISEASE MODELS
SUCH AS ALS WHEN WE FOUND THIS
CHROID PLEXUS DYSFUNCTION
NEVERTHELESS THE CHECKPOINT
INHIBITORY CHECK POINT ARE NOT
SUFFICIENT.
WE SEEING THAT ACTIVATION OF THE
SYSTEMIC IMMUNE SYSTEM
FACILITATES RECRUITMENT OF
MACROPHAGES TO PARENCHYMA BUT WE
DON'T KNOW WHETHER ACTIVITY SAID
TOTALLY DEPENDENT ON MACROPHAGES
OR THE MACROPHAGES INDUCE OTHER
CELLS TO BE MORE BENEFICIAL.
THE TREATMENT IS
MECHANISM-DRIVEN AND MICROGLIA
ARE POTENTIALLY BENEFICIAL BUT
THEIR ACTIVATION REQUIRES
RELEASE SOME OF THE MICROGLEIAL
OFF SIGNALING WE ARE FURTHERING
STUDY.
THIS IS A CARTOON PRODUCED FOR
ME --
>> WHEN YOUR ENTERTAIN UNDER
THREAT, IT SENDS A DISTRESS
SIGNAL TO THE IMMUNE SYSTEM TO
COME TO THE RESCUE.
BUT IMMUNE CELLS ARE TOO BIG TO
GET INTO THE BRAIN THE NORMAL
WAY.
SO THEY HAVE TO USE A BACKDOOR.
AS WE AGE, THAT BACKDOOR ENTRY
GETS HARDER.
BUT WHAT IF WE JUST GIVE THE
IMMUNE CELLS A BIT OF HELP?
A BOOSTER?
WELL, RESEARCHERS ARE FINDING
THAT CAN HAVE A POSITIVE EFFECT
ON ALZHEIMER'S MEMORY LOSS.
AT LEAST TO MICE ANYWAY.
COULD IT WORK IN HUMANS TOO?
>> SO I GOT THIS CARTOON FROM
THE EU FOR GETTING THE
ADVANCED -- ERC FOR THE SECOND
TIME AND I THOUGHT IS NICE
ILLUSTRATION.
SO BEFORE I FINALIZE BECAUSE I
TALKED A LOT ABOUT IMMUNE
CHECKPOINT BLOCKADE AND YOU KNOW
A LOTTED IN COUNSELING
CHECKPOINT, I WOULD LIKE TO
EMPHASIZE THAT BASED ON THE
MECHANISMS OF ACTION, WE DON'T
NEED TO KEEP EXPOSED ANIMAL OF
THE PATIENT FOR CONTINUOUSLY FOR
THE IMMUNE CHECKPOINT.
IT SHOULD BE TREATMENT.
WE FOUND THAT THE SINGLE
TREATMENT WE STILL SEE EFFECT.
AND THE INTERVAL IS NEEDED IN
ORDER TO ALLOW THE ENTIRE
ACTIVITY TO GET.
SO THE TREATMENT WILL BE
DISTINCTIVE FOR THE TREATMENT
FOR CANCER AND THAT IS WHY I
COMPETITIVE GRANTS BY THE EU,
WHICH IS CALLED THE -- ERC AND
MANY OTHER EU AND MANY OTHER
FOUNDATION, COMPETITIVE
FOUNDATION IN ISRAEL AND OUTSIDE
OF ISRAEL.
THIS GRADUATE STUDENT DID
CURRENTLY IN MY LAB THAT DID THE
WORK, QUITE INTERNATIONAL.
ALL THE SINGLE CELL WAS DONE IN
COLLABORATION WITH OUTSTANDING
YOUNG SCIENTISTS AT THE WEIZMANN
INSTITUTE AND SOME OF THE WORK
WAS DONE IN COLLABORATION WITH
STANFORD AND OTHERS FROM ISRAEL
AND FROM ITALY AND FROM SWEDEN.
AND THESE ARE FORMER GRADUATE
STUDENT MANY OF WHICH OR WHOM
ARE NOW INDEPENDENT PROFESSOR
EITHER IN THE STATES OR ISRAEL
OR EUROPE AND WITHOUT THEM I
COULDN'T BE ABLE TO DO THIS
WORK.
THANK YOU.
[ APPLAUSE ]
I AM HAPPY TO TAKE QUESTIONS.
>> HI.
SO, I'M USED TO SEEING LIKE A
TYPE I INTERFERON SIGNATURE
LEADING TO SOME SORT OF DAMAGE
OF SOME KIND.
I WAS WONDERING HOW YOU THINK
THIS CHROID PLEXUS IS PREVENTING
ANY SORT OF DAMAGE WHILE
MAINTAINING.
>> I THINK THERE IS MORE AND
MORE DATA ACCUMULATING THAT EVEN
IN MS AND TYPE I INTERFERON BY
ITSELF IS NOT DAMAGING.
IT MAY BE THAT OVERDOSEING CAN
BE BAD EVEN IN ANIMAL MODEL.
INTERFERON GAMMA BY ITSELF IS
NOT SUFFICIENT TO DRIVE THE
DISEASE.
>> THAT WAS TOUR DE FORCE.
THIS MIGHT BE A NAIVE QUESTION.
BUT PD-1 PATHWAY BLOCKADE HAS
NOW BEEN PERFORMED ON CANCER
PATIENTS.
IS THERE ANY EVIDENCE THAT THEY
EXPERIENCE COGNITIVE CHANGES?
>> YOU'RE ASKING A VERY GOOD
QUESTION.
WE CONTACT MANY CENTERS IN
ISRAEL AND IN EUROPE AND IN THE
STATES TREATING PATIENTS WITH
ANTI-PD-1.
OR ANTI-PD-L1.
FIRST OF ALL THEY ARE TREATING
IN A DIFFERENT REGIMEN.
SECONDLY IT WAS NEVER
RECOMMENDED BY THE FDA OF ANY
CLINICAL DRIVE TO TEST
COGNITIVE.
SO THERE IS NO REPORT ON THESE.
SO THE ANSWER IS ZERO.
THE ONLY THING THEY TOLD ME THAT
ELDERLY POPULATION RESPOND VERY
WELL TO ANTI-PD-1 AND ANTI-PD-L1
FOR CANCER.
SO IT MEANS A POTENTIAL.
BUT COGNITIVE ABILITY, NO
FURTHER.
>> SO THE QUESTION IS, IS THIS
SYSTEM OF IMMUNE PROTECTION
EFFECTING THE FETAL STAGE?
BECAUSE IT WAS SUGGESTED THAT
INFECTION OF THE MOTHER MIGHT
CAUSE -- SO I WAS THINKING IN
TERMS OF THE IMPLICATIONS OF
YOUR OBSERVATIONS IN THE MICE.
>> WE ARE CURRENTLY TESTING IT.
THAT IS A VERY GOOD POINT.
EXCELLENT POINT.
I DON'T HAVE AN ANSWER.
THE ONLY THING I HAVE CLEAR
ANSWER, WE TESTED MENTAL
DISABILITY AND WE FOUND THAT IN
ANIMAL MODEL, THE CONES ARE
DEPRESSION OR POST-TRAUMATIC
STRESS DISORDER.
THE GATE COMPLETELY SHUT OFF AND
IF WE -- SUPPRESSION, WE CAN
REDUCE SOME OF THE SYMPTOMS OF
DEPRESSION.
BUT WITH RESPECT TO PREGNANCY,
WE HAVE VERY PRELIMIARY DATA.
IT'S THE COMMUNITY HAS MODEL OF
BABIES DURING PREGNANCY -- WE
COULD NOT DETECT ANY EFFECT OF
THE CHROID PLEXUS.
>> THE CLINICAL TRIALS SOON?
>> IT IS BEYOND MY CONTROL.
BUT A START-UP COMPANY SIGNED
AGREEMENT WITH A COMPANY FOR
TRANSLATING INTO PATIENT.
>> SO DO YOU HAVE AN IDEA OF HOW
THIS IS GOING TO MOVE TO THE
CLINICAL TRIALS?
DO YOU THINK IT WILL STAY
SYSTEMIC OR DO YOU HAVE ANY
PLANS OF MAKING IT MORE SPECIFIC
TO THE CHROID PLEX US?
>> NO, WE CANNOT -- YOU CAN NOT
MONITOR INPATIENT, IN LIVING
INDIVIDUAL THE CHROID PLEXUS.
SO WE ARE USING BLOOD MARKERS TO
MONITOR THE ACTIVITY AS MEASURE
OF THE EFFECT ON THE CHROID.
THERE IS NO WAY TO DETECT THE
CHROID.
YOU CAN SEE THE SIGNATURE BUT
THE RESPONSE -- NO WAY TO
MEASURE CHEMOKINE.
>> HI.
FANTASTIC TALK.
>> THANK YOU.
>> I WAS WONDERING IF THE
T-CELLS THAT AFFORDED
PROTECTION, DID THEY GET TURNED
INTO TISSUE RESIDENT T-CELLS ORD
DID THEY STAY IN THE PERIPHERY?
>> THAT'S A GOOD POINT BUT I
DON'T HAVE ANSWER.
WE HAVE T-CELL THAT SIT ALL THE
TIME IN THE CHROID PLEXUS
WE KNOW THAT THEY ARE NATIVE FOR
ACTIVATION.
WE SEE IN SEVERAL PARADIGMS
ENTRY OF T-CELL INTO THE
PARENCHYMA.
BUT THERE IS NO WAY TO TELL YOU
THE -- IS THE ONE THAT IS IN THE
PARENCHYMA.
ALSO WE SEE WITH ALL THE
PATHOLOGY WE SEE FACTOR CELLS
AND THEN T-CELL AND WE DON'T
KNOW WHETHER IT IS LOCAL
CONVERSION OR SEPARATE
RECRUITMENT.
SO THERE ARE MANY THINGS THAT IS
WE STILL DON'T KNOW AND WE DON'T
HAVE THE TOOLS TO FOLLOW THE
SOURCE.
>> AND THEN JUST ONE MORE
FOLLOW-UP ISSUE.
I WAS GOING TO ASK IF THIS
PROTECTION IS TRANSPLANTABLE?
CAN YOU TAKE THE T-CELLS FROM A
PROTECTED MOUSE AND TRANSFER
THEM?
>> WE DID IT LONG AGO.
YOU CAN TAKE T-CELL AND TAKE ANY
EFFECT OF T-CELL -- THERE IS
NOTHING.
THEY SHOULD BE MEMORY T-CELL
THAT COGNITIVE ANTIGEN IS BEING
PRESENTED IN THE CHROID PLEXUS.
WE STILL DON'T KNOW WHETHER THE
T-CELL WE SEE IN THE PARENCHYMA
THE SAME.
THERE IS NO -- WE DON'T KNOW.
>> WHAT DO YOU THINK IS THE
MECHANISM BY WHICH CELLULAR
ENTRY IS RESTRICTED TO THE
CHROID PLEXUS AS DISTINGUISHED
FROM ALL THE OTHER TYPE
JUNCTIONS IN THE NERVOUS SYSTEM?
AND ASKED A FINNESTRA PLAY ANY
ROLE IN THIS PROCESS?
>> SO, THE DIFFERENCE BETWEEN
THE CHROID PLEXUS IS BECAUSE THE
ONLY PLACE WHERE IT IS NOT
ENDOTHELIAL
[ INAUDIBLE ]
IT'S EPITHELIAL CELLS CONNECTED.
WHERE IT IS NOT CONNECTED OF THE
CHROID PLEXUS WHERE MADE BY
EPITHELIAL CELLS AND EPITHELIAL
CELLS SAYS ONCE IT IS ACTIVATED,
CAN PASS THROUGH.
>> THANK YOU.
[ APPLAUSE ]
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