The Immunopathogenesis of Relapsing MS

Transcription

1 The Immunopathogenesis of Relapsing MS Olaf Stüve, M.D., Ph.D. Neurology Section VA North Texas Health Care System Dallas VA Medical Center Departments of Neurology and Neurotherapeutics University of Texas Southwestern Medical Center at Dallas

2 Disclosures Dr. Stüve has received speaker fees from Teva Neuroscience Dr. Stüve served as a consultant for Sanofi- Aventis, EMD Serono, Novartis, Pfizer, Teva Neuroscience, Roche, and Genzyme Dr. Stüve is supported by a Merit Award from the Department of Veterans Affairs, a research grant from the Dallas VA Research Corporation, and a career development grant from the Doris Duke Charitable Foundation

3 Learning objectives A. To understand the role of the adaptive immune system in the pathogenesis of relapsing-remitting MS B. To learn about the role of the innate immune system in relapsing-remitting MS C. To learn how FDA-approved therapies affect immune responses in relapsing-remitting MS

4 Multiple Sclerosis Stüve O, Zamvil SS. In: Lange: Medical Immunology (tenth edition)

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6 Circulation Central Nervous System T-cell extravasation B cell B-cell T-cell cross-activation Chemoattraction T-cell adhesion T-cell rolling CNS APC T-cell reactivation Inflammatory mediators Plasma cell Memory B cell Antibodies & Complement APC T-cell activation Inflammation Hypoxia, ischemia Energy depletion K + Na + Activation of Na + channels NA + Ca 2+ Na + Reverse Na + Ca 2+ exchange Oligodendrocyte

7 MHC II CD4 + APC

8 Experimental Autoimmune Encephalomyelitis (EAE) myelin Ag./CFA s/c +myelin Ag. CD4+ Th1 Nitin Karandikar, UTSW.

9 Baxter A. Nat.Rev.Immunol

10 Baxter. Nat.Rev.Immunol

11 Patterson. J.Exp.Med Baxter. Nat.Rev.Immunol

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13 Patterson. J.Exp.Med Waksman. J.Exp.Med Baxter. Nat.Rev.Immunol

14 Patterson. J.Exp.Med Waksman. J.Exp.Med Baxter. Nat.Rev.Immunol

15 Patterson. J.Exp.Med Zamvil. Nature T-cell clones specific for myelin basic protein induce EAE 1985 Waksman. J.Exp.Med Baxter. Nat.Rev.Immunol

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23 mg/dose

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25 41% p= % p=0.03

26 VLA-4 α 4 1 Natalizumab

27 Circulation Courtesy of Olaf Stüve, MD, PhD, UT Southwestern Medical Center at Dallas. Central Nervous System B cell adhesion Chemoattraction B cell cross-activation rolling CNS APC re-activation Inflammatory mediators Plasma cell Memory B cell Antibodies & Complement APC activation Inflammation Hypoxia, ischemia Energy depletion K + Na + Activation of Na + channels NA + Ca 2+ Na + Reverse Na + Ca 2+ exchange Oligodendendrocyte

28 Stüve et al. Ann Neurol

29 Stüve et al. Neurol

30 Fingolimod Presumed MOA/CNS impact Believed to modulate sphingosine 1-phosphate (S1P) receptors on lymphocytes and other tissues 1,2 S1P receptors are widely expressed, including in cardiac tissue, vascular endothelium, and pulmonary endothelium 2,3 Proinflammatory Th1 cells (MS-specific) Naïve s Anti-inflammatory Th2 cells (MS-specific) Prevents lymphocytes from leaving the lymph nodes and entering the bloodstream and CNS compartment 1,4,5 The mechanism by which fingolimod exerts therapeutic effects in MS is unknown 1 1. Gilenya (fingolimod) prescribing information. Novartis Pharmaceuticals Corporation. 2. Chun J, et al. Clin Neuropharm. 2010;33(2): Szczepaniak WS, et al. Am J Physiol Lung Cell Mol Physiol. 2010;299(1):L137-L Lopez-Diego RS, et al. Nat Rev Drug Discovery. 2008;7(11): Kappos L, et 30al. N Engl J Med. 2010;362(5):

31 Circulation Central Nervous System Fingolimod T-cell extravasation B cell B-cell T-cell cross-activation Chemoattraction T-cell adhesion T-cell rolling CNS APC T-cell reactivation Inflammatory mediators Plasma cell Memory B cell Antibodies & Complement APC Inflammation K + Na + Activation of Na + channels NA + Oligodendrocyte T-cell egress from lymphnode Hypoxia, ischemia Energy depletion Ca 2+ Na + Reverse Na + Ca 2+ exchange

32 Kowarik et al. Neurology

33 Circulation Central Nervous System T-cell extravasation B cell B-cell T-cell cross-activation Chemoattraction T-cell adhesion T-cell rolling CNS APC T-cell reactivation Inflammatory mediators Plasma cell Memory B cell Antibodies & Complement APC T-cell activation Inflammation Hypoxia, ischemia Energy depletion K + Na + Activation of Na + channels NA + Ca 2+ Na + Reverse Na + Ca 2+ exchange Oligodendrocyte

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35 VLA-4 α 4 1 Natalizumab

36 Stüve et al. Ann Neurol

37 Stüve et al. Ann Neurol

38 CD20 Rituximab

39 Expression of CD20 on the B-Cell Lineage Roitt I et al. Immunology. 6th ed. Chapter 8. Mosby; Sell S et al. Immunology, Immunopathology, and Immunity. 6th ed. Chapter 4. ASM Press; Tedder TF et al. J Immunol. 1985;135:

40 Circulation Courtesy of Olaf Stüve, MD, PhD, UT Southwestern Medical Center at Dallas. Central Nervous System extravasation B cell B cell cross-activation Chemoattraction adhesion rolling CNS APC re-activation Inflammatory mediators Plasma cell Memory B cell Antibodies & Complement B cell activation Inflammation Hypoxia, ischemia Energy depletion K + Na + Activation of Na + channels NA + Ca 2+ Na + Reverse Na + Ca 2+ exchange Oligodendendrocyte

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42 Cross et al. JNI

43 Circulation Courtesy of Olaf Stüve, MD, PhD, UT Southwestern Medical Center at Dallas. Central Nervous System extravasation B cell B cell cross-activation Chemoattraction adhesion rolling B cell re-activation Inflammatory mediators Plasma cell Memory B cell Antibodies & Complement APC activation Inflammation Hypoxia, ischemia Energy depletion K + Na + Activation of Na + channels NA + Ca 2+ Na + Reverse Na + Ca 2+ exchange Oligodendendrocyte

44 MHC II CD4 + B cell

45 Martin et al. Arch Neurol

46 Cell/uL Cell/uL Cladribine: The Clarity Study Phase III Trial: Hematological Effects CD19 B-cell Count CD4 T-cell Count Placebo (n=434) Cladribine 3.5 mg/kg (n=428) Cladribine 5.25 mg/kg (n=451) Adapted from Rieckmann P, et al. Presented at: 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 9-12, 2009; Düsseldorf, Germany.

47 Are all lymphocytes bad for patients with relapsingremitting MS?

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49 CD4 + s CD8 + s CD19 + B cells Cox et al. EJI

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55 Circulation Central Nervous System T-cell extravasation B cell B-cell T-cell cross-activation Chemoattraction T-cell adhesion T-cell rolling CNS APC T-cell reactivation Inflammatory mediators Plasma cell Memory B cell Antibodies & Complement APC T-cell activation Inflammation Hypoxia, ischemia Energy depletion K + Na + Activation of Na + channels NA + Ca 2+ Na + Reverse Na + Ca 2+ exchange Oligodendrocyte

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58 Conclusion During relapsing-remitting MS, clinical attacks are likely caused by lymphocytes

59 Conclusion During relapsing-remitting MS, clinical attacks are likely caused by lymphocytes Much of our knowledge on the immunology in relapsing-remitting MS stems from observations made with specific pharmacotherapies

60 Conclusion During relapsing-remitting MS, clinical attacks are likely caused by lymphocytes Much of our knowledge on the immunology in relapsing-remitting MS stems from observations made with specific pharmacotherapies There is an intricate interplay between many cellular subsets

61 Conclusion CD4 + s and B cells are thought to be key players in MS pathogenesis

62 Conclusion CD4 + s and B cells are thought to be key players in MS pathogenesis Some s and B cells also have regulatory function

63 Conclusion CD4 + s and B cells are thought to be key players in MS pathogenesis Some s and B cells also have regulatory function Regulatory cells may be used therapeutically

64 Conclusion More recently, data have been generated on cell subsets of the innate immune system, including: Myeloid cells Granulocytes

65 Conclusion More recently, data have been generated on cell subsets of the innate immune system, including: Myeloid cells Granulocytes These cells can be modulated with pharmacotherapies

66 Obtaining CME Credit If you would like to receive CME credit for this activity, please visit: This information can also be found in the Summit 2011 Program on page 8

67 The End