IMMUNOTHERAPY OF EXPERIMENTAL AUTOIMMUNE MYASTHENIA-GRAVIS - SELECTIVE EFFECTS OF CTLA4IG AND SYNERGISTIC COMBINATION WITH AN IL2-DIPHTHERIA TOXIN FUSION PROTEIN

We examined the effects of CTLA4Ig treatment in an experimental model of myasthenia gravis (EAMG) induced by immunizing Lewis rats with puri fied Torpedo acetylcholine receptor (AChR). During a primary response, CTLA4Ig treatment inhibited AChR antibody production profoundly, and induced a shift of AChR antibody isotypes from the normally predominan t IEG2 isotype pattern toward an IgG1 response. Challenge of rats prev iously treated with CTLA4Ig produced markedly lower AChR antibody resp onses compared to untreated controls, persistent inhibition of the IgG 2b isotype, and no development of EAMG. Treatment of a secondary AChR response with CTLA4Ig or with DAB(389)IL2 (which kills lymphocytes exp ressing IL2 receptors) inhibited AChR antibody responses, and clinical EAMG moderately. in contrast, combined treatment with CTLA4Ig plus DA B(389)IL2 strikingly inhibited AChR antibody levels, and completely pr evented EAMG. Our results suggest that the therapeutic benefit of CTLA 4Ig may be due to overall inhibition of AChR antibody production as we ll as a shift in the antibody isotype repertoire. (C) 1998 Elsevier Sc ience B.V, All rights reserved.