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 purified 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 predominant IgG2 isotype pattern toward an IgG1 response. Challenge of rats previously treated with CTLA4Ig produced markedly lower AChR antibody responses compared to untreated controls, persistent inhibition of the IgG2b isotype, and no development of EAMG. Treatment of a secondary AChR response with CTLA4Ig or with DAB389IL2 (which kills lymphocytes expressing IL2 receptors) inhibited AChR antibody responses, and clinical EAMG moderately. In contrast, combined treatment with CTLA4Ig plus DAB389IL2 strikingly inhibited AChR antibody levels, and completely prevented EAMG. Our results suggest that the therapeutic benefit of CTLA4Ig may be due to overall inhibition of AChR antibody production as well as a shift in the antibody isotype repertoire.
McIntosh
K R
KR
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287-7519, USA.
Linsley
P S
PS
Bacha
P A
PA
Drachman
D B
DB
D000069594:Abatacept; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000627:therapeutic use*; D001323:Autoantibodies / Q000276:immunology; D060908:CTLA-4 Antigen; D004167:Diphtheria Toxin / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000032:analysis; D007132:Immunoglobulin Isotypes / Q000032:analysis; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007167:Immunotherapy; D007376:Interleukin-2 / Q000627:therapeutic use*; D009157:Myasthenia Gravis / Q000628:therapy*; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D012016:Reference Values
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001323:Autoantibodies; D060908:CTLA-4 Antigen; D004167:Diphtheria Toxin; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011950:Receptors, Cholinergic; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox; D000069594:Abatacept