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Developing Immunotherapy for Autoimmune Diseases

Developing Immunotherapy for Autoimmune Diseases. Premkumar Christadoss, M.B.B.S. Department of Microbiology and Immunology University of Texas Medical Branch 301 University Blvd. Galveston, Texas 77555-1070 pchrista@utmb.edu. Generalized Myasthenia Gravis. MG.

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Developing Immunotherapy for Autoimmune Diseases

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  1. Developing Immunotherapy for Autoimmune Diseases Premkumar Christadoss, M.B.B.S. Department of Microbiology and Immunology University of Texas Medical Branch 301 University Blvd. Galveston, Texas 77555-1070 pchrista@utmb.edu

  2. Generalized Myasthenia Gravis

  3. MG

  4. Neuromuscular Junction (NMJ) Conti-Fine, B.M. et al. J. Clin. Invest. (116) 2843-22854, 2006

  5. Normal MG NMJ in MG

  6. Electronmicroscopy Study of NMJ of an MG Patient Engel et al. Mayo clinic proc. 52:267, 1977

  7. AChR is a transmembrane glycoprotein formed by five homologous subunits in thestoichiometrya2bgdora2bed. The molecular weights of the subunits range between 45 and 55 kDa. Theasubunit is Considered to be the highly immunogenic region.

  8. EAMG induction AChR Source Primary immunization: 20 microgram AChR/CFA 28-30 days Boost: 20 microgram AChR/CFA 28-30 days Monitor for clinical EAMG Immunopathological evaluation

  9. MG in Mice Normal MG

  10. Molecular Mechanisms of EAMG AChR-Ab Plasma cells Complement activation Class II Peptide (a146-162) CD4 TCR IFN-g IL-18 NK B7 CD 28 Proliferation and Differentiation IL-10, TNF-a, IL-6, IL-12, IL-18 APC CD4 CD40L/CD40 AChR IL-1, IL-12 AChR-specific memory B cells AChR-specific memory T cell C’ C’ Damage to the neuromuscular junction B

  11. COMPLEMENT PATHWAYS CLASSICAL PATHWAY C1 C4b C2a MASP1 MASP2 MBL C3 C5 MAC (C5bC9) MBL PATHWAY C3b C3bBb Bb ALTERNATIVE PATHWAY

  12. AChR-immunized C3-/- and C4-/- mice are resistant to clinical EAMG Tuzun -Christadoss. J. Immunol. 171:3847, 2003

  13. Serum anti-AChR antibody levels of AChR-immunized mice Tuzun- Christadoss. J. Immunol. 171:3847, 2003

  14. IF Studies Reveal IgG Deposits But Not C3 or MAC Deposits at the NMJs of Mice with C3 or C4 Deficiency C4+/+ C4-/- C3-/- C3 MAC IgG Tuzun –Christadoss J. Immunol. 171:3847, 2003 RED -bungarotoxin binding (NMJ) GREEN C3, MAC or IgG deposits

  15. Antigen/organ specific Disease specific I. AChR T cell epitope tolerance II. AChR B cell epitope tolerance I. Anti-Proinflammatory Cytokine a. Soluble TNFR (etanercept) b. IL1-Ra c. Anti-IL-6 II. Blocking classical complement pathway a. Anti C1q/C2/C4 Immune Intervention

  16. Targeting Classical Complement Pathway

  17. Anti-C1q Administration Suppresses EAMG Tuzun-Christadoss, J.Neuroimmunol.174:157-167, 2006

  18. Dual Effect of Anti-C1q Tuzun-Christadoss, J.Neuroimmunol.174:157-167, 2006

  19. Anti-C1q Ab Treats EAMG B6 RIII Tuzun-Christadoss, J.Neuroimmunol, 182: 167-176, 2007

  20. Anti-C1q Ab Treatment Suppresses AChR and Dominant Peptide Specific IL-6 Production

  21. Effect of Cytokine Deficiencies in Clinical EAMG Normal IL-4 IL-10 Gene Depletion IFN-g Anti-AChR Ab Disease IL-12 IL-18 IL-6 TNF-a p55p75 0 20 40 60 80 100 120 % clinical disease and anti-AChR antibodies

  22. IL-6 and TNF in EAMG TNF TNF AChR specific IL6 IL-6 Th Th GC formation Activation of B cells and generation of effector B cells. Potentiates production of IgG anti-AChR antibodies (pathogenic) B B Activates C3 Promotes EAMG pathology

  23. Targeting ProinflammatorCytokines A. Soluble Recombinant HumanTNFR (Etanercept)

  24. Soluble TNFR (Etanercept) Treats EAMG Christadoss and Goluszko J. Neuroimmunol, 122:186, 2002

  25. Etanercept Treatment Fails to Suppress Serum Anti-AChR Ab Christadoss and Goluszko, J. Neuro. Immunol. 122:186, 2002.

  26. A pilot Trial of Etanercept in the Treatment of Steroid-Dependent MG *+ • Mean change in QMG score from basline at 6 months was - 2.9 (p=0.041). • Mean change in MMT at 6 months was - 8.4 (p=0.020). • Mean decrease in prednisone dose from baseline to end of study was 17.5 mg/48 hr dose (p=0.0084). • Etanercept was well tolerated, and no severe adverse reaction observed • + 11 patients enrolled; 8 completed, and 2 patients withdrawn due to disease worsening.

  27. Immunological Effect of Etanercept • No reduction in plasma anti-AChR antibody. • Peripheral blood CD4 and B cell (CD19+) counts rose steadily during the 24 week study. • Patients who had higher increases in their cytokine levels had a worse outcome.

  28. Targeting ProinflammatorCytokines b. Recombinant Human IL1-Ra

  29. Activation of the Adaptive Immune System with IL-1

  30. IL-1Ra treatment stopped IL-1Ra treatment stopped IL-1Ra Treatment Prevents Clinical EAMG Yang –Christadoss, J. Immunol. 175:2018, 2005

  31. IL-1Ra Treats EAMG Yang –Christadoss, J. Immunol. 175:2018, 2005 P<0.05 P<0.05 P<0.05

  32. Possible Consequence of Down Regulating IL-1 by IL-1Ra in Mice with Clinical EAMG IL-1 IL-1Ra CD40L, OX40 Expression on T cells Anti-AChR IgG , IgG1 and C3 Inflammatory cytokines IFN-g, IL-2, IL-1, IL-6, TNF-a Anti-AChR antibodies and complement mediated NMJ pathology

  33. IL-6 in MG: Multiple Hit AChR Specific NMJ CD4 IL-6 B IgG2b -C1q C4-C3- C5-9 C3

  34. IL-6–ADanger Molecule in EAMG ! 1. IL-6 deficient mice are resistant to EAMG and produce less C3 2. C3 and FCγRIII deficient mice are resistant to EAMG and produce less IL-6 3. Amelioration of EAMG following anti-C1q treatment is associated with reduced IL-6

  35. Anti-IL-6 Ab Treatment Reduces the Incidence of EAMG Days after second immunization

  36. Anti-IL-6 Ab Treatment Suppresses Serum Anti-AChR IgG and IgG2b Ab

  37. Anti-IL-6 Ab Treatment Suppresses AChR Specific Cytokine Production

  38. Classical Complement Pathway and IL-6 in EAMG Pathogenesis anti-AChR antibody production T helper B cell Antigen presenting cell AChR IL-6 C3 Immune complex formation AChR C1q C1r C1s C1q FcγRIII activation Classical complement pathway activation Stimulation of IL-6, C1q and C3 production Membrane attack complex formation

  39. Balancing the Immune System to Treat Autoimmune Disease (MG) Disease IL-6, TNF C3-C5b-C9 Anti-AChR IgG IL-6, TNF-normal level Healthy Suppress anti-AChR and C5b-C9

  40. Targeting IL-6 and Classical Complement Pathway Suppressed anti-AChR antibody production T helper B cell Antigen presenting cell AChR IL-6 C3 Immune complex formation AChR C1q C1r C1s C1q Classical complement pathway activation FcγRIII activation Stimulation of IL-6, C1q and C3 production Membrane attack complex formation

  41. MG lab in Galveston

  42. MG Lab - Galveston Erdem Tuzun1,2 Shamsher Saini Andrey Bednov Ben Scott 3 Jing Li1 Iris Wingrow3 Huibin Qi Xiarong Wu Collaborators Huan Yang Bo Wu Stephen Higgs Tian Lin Xio Galen Kaufmann Mat Merigioli Juli Rowin 1MG foundation Osserman/Sosin/McClure Post doctoral Fellows 1,2MDA Research Career Award Recipients 3 MG Foundation Henry Viets Fellow Supported by NIH,MDA, AFM,and MG Foundation

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