At the limits
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Transcript of At the limits
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?
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
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
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?
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
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
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
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
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
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+
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)
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)
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.
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
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
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
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
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
________________________________________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
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
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
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
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
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
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”
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
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
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