Download - At the limits
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DEBATE
David Baker- For
Heinz Weindl-Against
The Key Pathogenic Cell in MS is a B cell
and is Independent of Antigen-Presentation to T cells
To B or Not T-B, that is the Question?
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AT THE LIMITS-MULTIPLE SCLEROSIS 2017
B CELLS ARE AN ACCOMPLICE
T CELLS ARE FACILITATORS
THE IMPORTANT PATHOGENIC CELL IN MS
VICTIM: OLIGODENTROCYTE HAS BEEN MURDERED
B CELL
MEMORY B CELLS ARE GUILTY
T CELLS ARE GUILTY
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INFLAMMATORY PENUMBRA IN MS
MYELIN = BROWN
DEMYELINATION
PERIVASCULAR
LESION
RELAPSING MS
BIOLOGY OF MULTIPLE SCLEROSIS
Myelin=brown stainOligodendrocytes do not express MHC class II in vivo
ANTIBODY
CYTOKINE
CELL
HYPOXIA
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MS is a T cell-mediatedProblem!
MS is a B cell-mediatedProblem!
Animal Models
Myelin-ReactiveT cells in MS
Dogma
Biology &Available Data
Response to TherapyTreatments
EAE is T cell Mediated!but, Animals Don’t Get MS
Healthy People Respond to the Same Antigens.
Myelin-immunotherapy = FAILED
All active treatmentstarget B cells
Cir
cum
stan
tial
Evid
en
ce
AT THE LIMITS-MULTIPLE SCLEROSIS 2017
To B or Not T-B, that is the Question?
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RESPONSE TO THERAPY
If MS is T Cell-Mediated, Why Does Ocrelizumab/Rituximab Work?
• Block B Cell Cytokines & Products
• Block Antigen-Presentation
Why evolve an extra APC Network?
• Block B Cell Follicles (& Pathogenic Antibodies)
Therapeutic Antibodies have very poor CNS penetration
Trophic Support-Cytotoxicity
DMT block peripheral Immune-Response to block Lesion formation
Minor 5-20% T cells Population Important
• Block Pathogenic CD20 T Cells
Is their critical B cell APC function In vivo?
CD4 T cell depletion = FAILEDMarked CD8 depletion (Dimethyl fumarate) = Modest
(DMF has modest depletion of B cells)
To B or Not T-B, that is the Question?
Inebilizumab (anti-CD19) inhibits MS lesionAgius et al. 2017 Mult Scler epub
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T CELL SPECIFIC IMMUNOTHERAPY IN MS = FAILED
• CD4 T CELL (~70%) DEPLETION WITH cM-T412 MARGINAL EFFECT- PERCEPTION = FAILED
• Th1 (IL-12/IL-23) T CELL INHIBITION WITH USTEKINUMAB-PERCEPTION = FAILED
• Th17 (IL-17) T CELL INHIBITION WITH SECUKINUMAB MARGINAL EFFECT-PERCEPTION = FAILED
B CELL-DEPENDENT EAE = RUBBISH EAEIT IS SUBOPTIMIZED…TO MAKE ANTIGEN PRESENTATION IMPORTANT
B CELL-DEPENDENT EAE = SUBOPTIMIZED EAE
• Disease Resistant Strain used• Weak Immunogen for Strain• Processing requiring antigen• Low severityTO MAKE ANTIGEN PRESENTATION BY B CELLS APPEAR IMPORTANT
UCL-INSTITUTE OF NEUROLOGYQueen SquareUCL-INSTITUTE OF NEUROLOGYQueen SquareUCL-INSTITUTE OF NEUROLOGYQueen Square
MULTIPLE SCLEROSIS: IS A CD4 Th17 T CELL-MEDIATED DISEASE?
RESPONSE TO THERAPY
B CELL SPECIFIC IMMUNOTHERAPY IN EAE = FAILED/MARGINAL
75% T cell Depletion
Sefia E et al. MSARDS 2017
B cell Knockout
wildtype
Kuerten S et al. J Neuroimmunol.
2006 177:99-111
B cell Depletion
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T CELL SPECIFIC IMMUNOTHERAPY IN MS = FAILED
• CD4 T CELL (~70%) DEPLETION WITH cM-T412 MARGINAL EFFECT- PERCEPTION = FAILED
• Th1 (IL-12/IL-23) T CELL INHIBITION WITH USTEKINUMAB-PERCEPTION = FAILED
• Th17 (IL-17) T CELL INHIBITION WITH SECUKINUMAB MARGINAL EFFECT-PERCEPTION = FAILED
UCL-INSTITUTE OF NEUROLOGYQueen SquareUCL-INSTITUTE OF NEUROLOGYQueen SquareUCL-INSTITUTE OF NEUROLOGYQueen Square
MULTIPLE SCLEROSIS: IS A CD4 Th17 T CELL-MEDIATED DISEASE?
Time Post-Induction (Days)
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Fre
que
ncy o
f D
ise
ase
(%
)
0
10
20
30
40
50
60
70
80
90
100Vehicle
CD4d mAb
CD8d mAb
CD20d mAb
Anti-CD20 in EAE does not work or has a marginal effect, unless it depletes CD4 T cells.
RESPONSE TO THERAPY
B CELL SPECIFIC IMMUNOTHERAPY IN EAE = FAILED/MARGINAL
75% T cell Depletion
Sefia E et al. MSARDS 2017
Sefia E et al. MSARDS 2017
B cell Depletion
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Plasma cellCD19-, CD20-
CD27+,CD38+, CD138+
CD8 memory
CD19+ B CELLS ARE NOT A SINGLE SUBSET
CD4 naive CD4 memory
Th1/Th17
CD8 Naive
CD8 cytotoxicCD8 suppressor
CD4 T regulatory cell
Tr1 regulatory cell
CD19+B cell
T Cell Biologists World View of B Cell Biology
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BLOOD
Memory Cell(Guilty in MS)
CD19+, CD27+Unswitched
IgD+
CD19+, CD27+Class switched
IgD-
PlasmablastCD19+, CD20-
CD27+,CD38+
ImmatureCD19+, CD20+
CD27-,CD38+, CD10+
Pre-B CellsCD19+, CD20+
Plasma cellCD19-, CD20-
CD27+,CD38+, CD138+
BONE MARROW
Germinal Centre CellCD19+, CD20+
CD27+, CD269+
LYMPHOIDTISSUE
Primary Follicle Cortex (B cell Area)Secondary
Follicle
T cell Area
FollicularDendritic
Cell
Pro-B CellsCD19-/+, CD20+, CD34+
Naïve/MatureCD19+, CD20+
CD27-,CD38+, CD10-
Regulatory CellCD19+, CD20+CD5+, CD24+
CD19+ B CELLS ARE NOT A SINGLE SUBSET
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CD19+, CD27+Class-Switched
IgD-Germinal
Centre CellCD19+,CD20+
CD27+,CD269+
BLOOD
Memory Cell(Guilty in MS)
CD19+, CD27+Unswitched
IgD+
PlasmablastCD19+, CD20-
CD27+,CD38+
Naïve/MatureCD19+, CD20+
CD27-,CD38+, CD10-
ImmatureCD19+, CD20+
CD27-,CD38+, CD10+
Pre-B CellsCD19+, CD20+
BONE MARROW
CD34+ stem Cell
HUMAN B CELLS
Pro-B CellsCD19-/+, CD20-
CD34+
BLOOD
LYMPHOID TISSUE
Plasma cellCD19-, CD20-
CD27+,CD38+, CD138+
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Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
Mea
n P
erc
en
tag
e C
ha
ng
e f
rom
B
aselin
e
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
40
Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
Mea
n P
erc
en
tag
e C
ha
ng
e f
rom
B
aselin
e
0
20
40
60
80
100
120
140
160
180
200
Immatute B cellsCD19 B cells
Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
Mea
n P
erc
en
tag
e C
ha
ng
e f
rom
B
aselin
e
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
140
Mature
Naive B cells
Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
Mea
n P
erc
en
tag
e C
ha
ng
e f
rom
B
aselin
e
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
Memory B cells
Alemtuzumab Targets memory B cells
overshoot
overshoot
MEMORY B CELLS IN MS-THERAPY
Baker D et al. JAMA Neurol. 2017;74:961.
Environment for Secondary B cell Autoimmunities (about 50% at 5 Years)
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Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
Mea
n P
erc
en
tag
e C
ha
ng
e f
rom
B
aselin
e
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
40
Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
Mea
n P
erc
en
tag
e C
ha
ng
e f
rom
B
aselin
e
0
20
40
60
80
100
120
140
160
180
200
Immatute B cellsCD19 B cells
Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
Mea
n P
erc
en
tag
e C
ha
ng
e f
rom
B
aselin
e
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
140
Mature
Naive B cells
Time Post-Administration (Months)
0 3 6 9 12 15 18 21 24
Mea
n P
erc
en
tag
e C
ha
ng
e f
rom
B
aselin
e
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
Memory B cells
Alemtuzumab Targets memory B cells
overshoot
overshoot
MEMORY B CELLS IN MS-THERAPY
Baker D et al. JAMA Neurol. 2017;74:961.
Alemtuzumab hCD52 Tgmice kills by ADCC-needs both antibody & natural killer cells/ PMN to kill. (Hu et al. 2009)
Bone marrowNot purged
Environment for Secondary B cell Autoimmunities (about 50% at 5 Years)
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MS Treatment Memory B cells in the
Blood
Availability of B cells to
enter CNS
Relapse Rate/
MRI Lesions
Glatiramer acetate
Beta Interferon
Dimethyl fumarate
Mitoxantrone
Fingolimod
Natalizumab
Alemtuzumab
Daclizumab*
Rituximab
Atacicept*
Infliximab*
HSCT
Cladribine
Reduced
Reduced
Reduced
Reduced
Reduced
Increased
Reduced
Reduced*
Reduced
Increased*
Increased*
Reduced
Reduced
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased*
Decreased
Increased*
Increased*
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Decreased
Increased
Increased
Decreased
Decreased
* Non-MS data
Loss of B memory Cell function in Efficacious Treatments
MEMORY B CELLS IN MS-THERAPY
Baker D et al. EBioMedicine 2017; 16:41.
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Mitoxantrone
FingolimodBeta Interferon Hierarchy of Responsiveness
Loss of B memory Cell function in Efficacious Treatments
Dooley J et al. Neurology N2 2016 3 (e240).Baker D et al. EBioMedicine 2017; 16:41.
MEMORY B CELLS IN MS-THERAPY
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NatalizumabLoss of B memory Cell function in Efficacious Treatments
MEMORY B CELLS IN MS-THERAPY
CD19+, CD27+ B Memory
Anti-CD20
Ocrelizumab Phase II extension (Baker et al EbioMedicine 2017; 16:41)
Palanichamy A et al. J Immunol. 2014; 193:580
6 months
1 year
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Loss of B memory Cell function in Efficacious Treatments
MEMORY B CELLS IN MS-THERAPY
Anti-CD20
Ocrelizumab Phase II extension (Baker et al EbioMedicine 2017; 16:41)
Palanichamy A et al. J Immunol. 2014; 193:580
6 months
1 year
Induction therapy potential
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Developmental Repopulation of B cells is Slow
in Western Europe
Cla
ss s
wit
ched
MEMORY B CELLS IN MS-AETIOLOGY
Duchamap et al. Immun Inflamm 2014:2:131
Absolute NumbersPercentages
Induction therapy using CD20-B cell depletion in non-MS autoimmune
________________________________________________________________________________Total Memory B cells Class switched memory B cells
________________________________________________________________________________Healthy Control 30.5 ± 6.9%; P = 0.001 18.3 ± 5.8% P = 0.001Responder 6.3 ± 0.9% 3.6 ± 0.5% (5 year)Non-Responder 51.1 ± 23.2% P = 0.009 42.8 ± 18.1% P = 0.036; (3-5 year)________________________________________________________________________________Amolik JH et al. Athritis rheum 2007; 56:3044Myasthenia gravis (Lebrun et al. 2016), NMO (Kim et al. 2015), Lupus (Vital et al. 2011), Arthritis (Trouvin et al. 2015)
Audia S et al. Blood. 2011; 118:4394
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Childhood(1-13year)
Perc
enta
ge o
f M
em
ory
B c
ells
+ S
D
0
10
20
30
40
50
60Healthy
multiple sclerosis
Adolescent(14-17year)
Adult(25-55 year)
AdultOnset
Paediatric Onset
Memory B cells appear in paediatric MS more rapidly than during aging
Schwartz A et al. 2017. Neurol Neuroimmunol Neuroinflamm 4:e309
MEMORY B CELLS IN MS-PATHOLOGY
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________________________________________CD19+, CD27+ Memory B cells
Blood CSF MS Type Remission Relapse Remission________________________________________Paediatric MS 30.1% 20.9% 66.4%
Adult MS 32.2% 26.7% 75.9%________________________________________
MEMORY B CELLS IN MS-PATHOLOGY
Schwartz A et al. 2017. Neurol Neuroimmunol Neuroinflamm 4:e309
Memory B cells drop in Blood during relapse and accumulate in CNS
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T CELLS OUTNUMBER MEMORY B CELLS
MYELIN = BROWN
DEMYELINATION
PERIVASCULAR
LESION
RELAPSING MS
BIOLOGY OF MULTIPLE SCLEROSIS
DISPRUPTIVE INFLUENCE
ANMS LESION
T CELLS = 7-24% OF LEUCOCYTES MEMORY B CELLS = 0.2-1.7% OF LEUCOCYTES
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Genetic Association with B Cell Activating Factor (BAFF) in Sardinian MSCD24+, CD27+ = Unswitched and Class-Switched memory B cells are increased
Northern European MS may use a different Genetic Pathway
MEMORY B CELLS IN MS-AETIOLOGY
HLA-DRB1*1501: Expressed by B cellsIL2RA (CD25) Expressed by memory B IL7RA (CD127) Expressed by pre-B cells
Many MS Susceptibility Genes withpresumed T cell function are present in oracts of B cell lineagesHLA-DRB1*1501: Expressed by B cellsIL2RA (CD25) Expressed by memory B IL7RA (CD127) Expressed by pre-B cellsTNFRSF1A Expressed by pre B cellsSTAT4 Expressed by pre B cellsIL12A Expressed by Immature B cellsBCL10 Expressed by Immature B cellsCXCR5 Expressed by Memory B cells
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HSCT
MEMORY B CELLS IN MS-AETIOLOGY
Antibody Secretion
Cytokine Secretion
APCFunction
B cell
CD22M
HC
Y
EBV
Burns DM et al.Blood. 2015;126:
Memory
MEMORY B CELLS HAVE KILLING POTENTIALTHEY MAY BE T CELL CO-STIMULATION INDEPENDENT
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EBV Drives Memory B Cell FormationEBV PROMOTES HUMAN IMMUNITY
van den Heuvel D et al.
J Leukoc Biol. 2017; 101:
949-956
Evolutionary Advantage• Life-long B cell Immunity to help prevent infections
EBV drives proliferation & differentiation of memory B cells and blocks plasma cell differentiation.
Latent EBV virus reservoir in circulating memory B cells
Viral reactivation & shedding in saliva for transmissionImmune mechanisms can limit viral activity
Evolutionary Price
• B cell Lymphomas (Burkitts & Hodgkins) Lymphoma• Glandular Fever (B cell proliferation & CD8 T cell killing)• Autoimmunity (Historically post-reproductive age)
MEMORY B CELLS IN MS-BIOLOGY
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CONCLUSIONS
B Cells appear to be the Major Target for Activity in MS
• Limited evidence that T cells control MS (Trial failures).
(CD4 depletion, Th1, Th17 cytokine therapy)
• Efficacy across with a range of different agents via a common B cell mechanism
Treatment Hierachy based on Memory B Cell Depletion Potential
• Memory B cell depletion is a major, common, mediator for relapse control in MS
• Memory B cell function, cytokine activity and EBV activity are interlinked
• There is pathogenic autoantibody in MS (May be secondary to damage)
Unifying mechanism consistent with (a) Aetiology (b) Pathology (c) Therapy
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VAGAL NERVE STIMULATION?
MONOCLONAL ANTIBODIES
SMALL MOLECULE INJECTABLES
REMOVAL OF SURVIVAL FACTORS
MOLECULESVIA THE MOUTH
GUILTY-VERDICT
GIVE THE MEMORY B CELL
THE “DEATH PENALTY”
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SUMATION
B IS FOR BIOLOGY = RESPONSE TO THERAPY
Unifying mechanism incorporating: (a) Aetiology (b) Pathology (c) Therapy
• Rodents have complicated B cell biology/ do not get infected with EBV
Experimental Autoimmune Encephalomyelitis is Not MS
• Treatment Hierachy based on: Memory B Cell Depletion Potential
Memory T cell Depletion Potential
• Response to Therapy. Fingolimod enhances CCR7-, CD45RO+ cells
(This would contain the pathogenic population…. if MS was T cell-mediated)
Song ZY et al. PoS One. 2015;10(4):e0124923.
CD45RO’sIncrease
CD45RO’s increase in the CNS of MS
• Prevention of Rebound after Natalizumab withdrawal = CD20 B cell depletion
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WEINDL ARGUMENTS
NO COMPELLING EVIDENCE PRESENTEDTO CAST DOUBT ON THE CENTRAL ROLE OFMEMORY B CELLS IN MULTIPLE SCLEROSIS
THERE IS REASONABLE DOUBTAGAINTS IT BEING THE T CELL
(Response to therapy)
JUST BECAUSE A CELL IS PRESENT DOES NOT MEAN IT IS IMPORTANT (GUILTY)
MOST IMMUNE CELLS IN LESIONS ARE IRRELEVANT THEY ACCUMULATE BECAUSE OF INFLAMMATORY SIGNALS
The Chewbacca defence: the aim to deliberately confuse the jury rather
than to factually refute the case of the other side.
The concept of disguising a flaw in one's argument by presenting large amounts of irrelevant information
T Cells Control MS….It does not make Sense! Vote for the B’s…B cells = Biology of MS
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THANKS FOR LISTENING WITH AN OPEN MIND
Do not acquit the B cell
The Memory B cell is GuiltyGive the T cell a suspended sentence for facilitation
GIVE THE MEMORY B CELL
THE “DEATH PENALTY”
Injectable Oral Antibody
magic bullet
The Chewbacca defence: the aim to deliberately confuse the jury rather
than to factually refute the case of the other side.
The concept of disguising a flaw in one's argument by presenting large amounts of irrelevant information
T Cells Control MS….It does not make Sense! Vote for the B’s…B cells = Biology of MS