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Developing Immunotherapy for Autoimmune Diseases Premkumar Christadoss, M.B.B.S. Department of Microbiology and Immunology University of Texas Medical.

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Presentation on theme: "Developing Immunotherapy for Autoimmune Diseases Premkumar Christadoss, M.B.B.S. Department of Microbiology and Immunology University of Texas Medical."— Presentation transcript:

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2 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

3 Generalized Myasthenia Gravis

4 MG

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

6 NMJ in MG NormalMG

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

8 AChR is a transmembrane glycoprotein formed by five homologous subunits in the stoichiometry    or   . The molecular weights of the subunits range between 45 and 55 kDa. The  subunit is Considered to be the highly immunogenic region.

9 Primary immunization: 20 microgram AChR/CFA Boost: 20 microgram AChR/CFA days Immunopathological evaluation AChR Source Monitor for clinical EAMG EAMG induction EAMG induction

10 MG in Mice Normal MG

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

12 C1C4bC2a C3C5MAC CLASSICAL PATHWAY MBL PATHWAY ALTERNATIVE PATHWAY (C5bC9) C3b Bb C3bBb MBL MASP1 MASP2 COMPLEMENT PATHWAYS

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

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

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

16 Immune Intervention Antigen/organ specific I. AChR T cell epitope tolerance II. AChR B cell epitope tolerance Disease specific 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

17 Targeting Classical Complement Pathway

18 Anti-C1q Administration Suppresses EAMG Tuzun-Christadoss, J.Neuroimmunol.174: , 2006

19 Dual Effect of Anti-C1q Tuzun-Christadoss, J.Neuroimmunol.174: , 2006

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

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

22 TNF-  p55p75 IL-6 IL-18 IL-12 IFN-  IL-10 IL-4 Normal % clinical disease and anti-AChR antibodies Anti-AChR Ab Disease Effect of Cytokine Deficiencies in Clinical EAMG Gene Depletion

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

24 Targeting ProinflammatorCytokines A. Soluble Recombinant HumanTNFR (Etanercept)

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

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

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28 A pilot Trial of Etanercept in the Treatment of Steroid-Dependent MG *+  Mean change in QMG score from basline at 6 months was (p=0.041).  Mean change in MMT at 6 months was (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.

29 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.

30 Targeting ProinflammatorCytokines b. Recombinant Human IL1-Ra

31 Activation of the Adaptive Immune System with IL-1

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

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

34 IL-1 IL-1Ra CD40L, OX40 Expression on T cells Possible Consequence of Down Regulating IL-1 by IL-1Ra in Mice with Clinical EAMG Inflammatory cytokines IFN-  IL-2, IL-1, IL-6, TNF-  Anti-AChR IgG, IgG 1 and C3 Anti-AChR antibodies and complement mediated NMJ pathology

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

36 IL-6 – A Danger 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

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

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

39 Anti-IL-6 Ab Treatment Suppresses AChR Specific Cytokine Production

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

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

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

43 MG lab in Galveston

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


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