Investigating IL-6 Experimental Myasthenia Gravis

University Of Texas Medical Br Galveston, Galveston TX

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Abstract

DESCRIPTION (provided by applicant): Studies suggest a pivotal role for IL-6, TNF, and IL- 18 in development of experimental autoimmune myasthenia gravis (EAMG), because a dramatic suppression of clinical EAMG was observed in IL-6, TNF receptor p55 p75, or IL-18 gene KO mice in the B6 background. The precise cellular and molecular mechanisms by which IL-6, TNF, and IL- 18 contribute to EAMG pathogenesis are not known. The central hypothesis is that IL-6 contributes to EAMG pathogenesis by activating acetylcholine receptor (AChR)-specific T and B cells and germinal center (GC) formation, promoting secondary anti-AChR IgG antibodies and activation of the C3 component of complement. The immunopathological and clinical effects will be evaluated by in-vivo IL-6 administration in B6 and IL-6 KO mice during primary and/or secondary immunizations with AChR. Clinical and immunopathological signs of EAMG will be induced in B6 mice by in vivo administration of IL-6 after priming with AChR. AChR-primed LNC will be exposed to IL-6 and its effect on anti-AChR IgM and IgG isotypes will be evaluated. Also, we will examine whether IL-6 and TNF act in concert or regulate one another in mediating EAMG. B7-1 gene-deficient or B7-1 molecule-blocked mice, and B6 mice will be immunized with AChR, and the effect evaluated of B7-1 deficiency or blocking in EAMG development and production of IL-6 and TNF. To prevent EAMG, antibody to IL-6 will be administered with primary and/or secondary immunizations with AChR. To ameliorate established clinical EAMG, antibody to IL-6 will be administered after clinical signs are established. Finally, combination immunotherapy will be performed with high-dose AChR T cell epitope tolerance and IL-6 neutralization in B6 mice. If IL-6 is involved in activating pathogenic AChR-specific B cells, forming GC, and upregulating and activating C3 and if in vivo blocking of IL-6 function induces remission of established clinical EAMG, then IL-6 antagonist could be used in MG therapy. To avoid non-specific immunosuppression by IL-6 antagonists, high-dose AChR T cell epitope tolerance could be given as maintenance therapy after the first course of combination immunotherapy.