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- 1. DEBATE David Baker- For HeinzWeindl-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?
- 2. AT THE LIMITS-MULTIPLESCLEROSIS 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
- 3. INFLAMMATORY PENUMBRA INMS 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
- 4. MS is aT cell-mediated Problem! MS is a B cell-mediated Problem! Animal Models Myelin-Reactive T 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 treatments target B cells Circumstantial Evidence AT THE LIMITS-MULTIPLE SCLEROSIS 2017 To B or Not T-B, that is the Question?
- 5. RESPONSE TO THERAPY IfMS 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 = FAILED Marked 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 lesion Agius et al. 2017 Mult Scler epub
- 6. T CELL SPECIFICIMMUNOTHERAPY 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 EAE IT 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 severity TO MAKE ANTIGEN PRESENTATION BY B CELLS APPEAR IMPORTANT UCL-INSTITUTE OF NEUROLOGY Queen Square UCL-INSTITUTE OF NEUROLOGY Queen Square UCL-INSTITUTE OF NEUROLOGY Queen 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
- 7. T CELL SPECIFICIMMUNOTHERAPY 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 NEUROLOGY Queen Square UCL-INSTITUTE OF NEUROLOGY Queen Square UCL-INSTITUTE OF NEUROLOGY Queen 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 FrequencyofDisease(%) 0 10 20 30 40 50 60 70 80 90 100 Vehicle 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
- 8. Plasma cell CD19-, CD20- CD27+, CD38+,CD138+ CD8 memory CD19+ B CELLS ARE NOT A SINGLE SUBSET CD4 naive CD4 memory Th1/Th17 CD8 Naive CD8 cytotoxic CD8 suppressor CD4 T regulatory cell Tr1 regulatory cell CD19+ B cell T Cell Biologists World View of B Cell Biology
- 9. BLOOD Memory Cell (Guilty inMS) CD19+, CD27+ Unswitched IgD+ CD19+, CD27+ Class switched IgD- Plasmablast CD19+, CD20- CD27+, CD38+ Immature CD19+, CD20+ CD27-, CD38+, CD10+ Pre-B Cells CD19+, CD20+ Plasma cell CD19-, CD20- CD27+, CD38+, CD138+ BONE MARROW Germinal Centre Cell CD19+, CD20+ CD27+, CD269+ LYMPHOID TISSUE Primary Follicle Cortex (B cell Area)Secondary Follicle T cell Area Follicular Dendritic Cell Pro-B Cells CD19-/+, CD20+, CD34+ Naïve/Mature CD19+, CD20+ CD27-, CD38+, CD10- Regulatory Cell CD19+, CD20+ CD5+, CD24+ CD19+ B CELLS ARE NOT A SINGLE SUBSET
- 10. CD19+, CD27+ Class-Switched IgD- Germinal Centre Cell CD19+,CD20+ CD27+, CD269+ BLOOD MemoryCell (Guilty in MS) CD19+, CD27+ Unswitched IgD+ Plasmablast CD19+, CD20- CD27+, CD38+ Naïve/Mature CD19+, CD20+ CD27-, CD38+, CD10- Immature CD19+, CD20+ CD27-, CD38+, CD10+ Pre-B Cells CD19+, CD20+ BONE MARROW CD34+ stem Cell HUMAN B CELLS Pro-B Cells CD19-/+, CD20- CD34+ BLOOD LYMPHOID TISSUE Plasma cell CD19-, CD20- CD27+, CD38+, CD138+
- 11. Time Post-Administration (Months) 03 6 9 12 15 18 21 24 MeanPercentageChangefromBaseline -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 MeanPercentageChangefromBaseline 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 MeanPercentageChangefromBaseline -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 MeanPercentageChangefromBaseline -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)
- 12. Time Post-Administration (Months) 03 6 9 12 15 18 21 24 MeanPercentageChangefromBaseline -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 MeanPercentageChangefromBaseline 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 MeanPercentageChangefromBaseline -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 MeanPercentageChangefromBaseline -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 Tg mice kills by ADCC-needs both antibody & natural killer cells/ PMN to kill. (Hu et al. 2009) Bone marrow Not purged Environment for Secondary B cell Autoimmunities (about 50% at 5 Years)
- 13. MS Treatment MemoryB 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.
- 14. Mitoxantrone Fingolimod Beta Interferon Hierarchyof 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
- 15. Natalizumab Loss of Bmemory 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
- 16. Loss of Bmemory 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
- 17. Developmental Repopulation ofB cells is Slow in Western Europe Classswitched 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 = 0.001 Responder 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; 56:3044 Myasthenia 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
- 18. Childhood (1-13year) PercentageofMemoryBcells+SD 0 10 20 30 40 50 60 Healthy multiple sclerosis Adolescent (14-17year) Adult (25-55 year) Adult Onset Paediatric Onset MemoryB 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
- 19. ________________________________________ CD19+, CD27+ MemoryB 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
- 20. T CELLS OUTNUMBERMEMORY B CELLS MYELIN = BROWN DEMYELINATION PERIVASCULAR LESION RELAPSING MS BIOLOGY OF MULTIPLE SCLEROSIS DISPRUPTIVE INFLUENCE AN MS LESION T CELLS = 7-24% OF LEUCOCYTES MEMORY B CELLS = 0.2-1.7% OF LEUCOCYTES
- 21. Genetic Association withB Cell Activating Factor (BAFF) in Sardinian MS CD24+, 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 cells IL2RA (CD25) Expressed by memory B IL7RA (CD127) Expressed by pre-B cells Many MS Susceptibility Genes with presumed T cell function are present in or acts of B cell lineages HLA-DRB1*1501: Expressed by B cells IL2RA (CD25) Expressed by memory B IL7RA (CD127) Expressed by pre-B cells TNFRSF1A Expressed by pre B cells STAT4 Expressed by pre B cells IL12A Expressed by Immature B cells BCL10 Expressed by Immature B cells CXCR5 Expressed by Memory B cells
- 22. HSCT MEMORY B CELLSIN MS-AETIOLOGY Antibody Secretion Cytokine Secretion APC Function B cell CD22MHC Y EBV Burns DM et al.Blood. 2015;126: Memory MEMORY B CELLS HAVE KILLING POTENTIAL THEY MAY BE T CELL CO-STIMULATION INDEPENDENT
- 23. EBV Drives MemoryB 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 transmission Immune 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
- 24. CONCLUSIONS B Cells appearto 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
- 25. VAGAL NERVE STIMULATION? MONOCLONAL ANTIBODIES SMALLMOLECULE INJECTABLES REMOVAL OF SURVIVAL FACTORS MOLECULES VIA THE MOUTH GUILTY-VERDICT GIVE THE MEMORY B CELL THE “DEATH PENALTY”
- 26. SUMATION B IS FORBIOLOGY = 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’s Increase CD45RO’s increase in the CNS of MS • Prevention of Rebound after Natalizumab withdrawal = CD20 B cell depletion
- 27. WEINDL ARGUMENTS NO COMPELLINGEVIDENCE PRESENTED TO CAST DOUBT ON THE CENTRAL ROLE OF MEMORY B CELLS IN MULTIPLE SCLEROSIS THERE IS REASONABLE DOUBT AGAINTS 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
- 28. THANKS FOR LISTENINGWITH AN OPEN MIND Do not acquit the B cell The Memory B cell is Guilty Give 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