Arsenic trioxide: A promising novel therapeutic agent for lymphoproliferative and autoimmune syndromes in MRL/lpr mice.
MRL/lpr mice develop a human lupuslike syndrome and, as in autoimmune lymphoproliferative syndrome (ALPS), massive lymphoproliferation due to inactivation of Fas-mediated apoptosis. Presently, no effective therapy exists for ALPS, and long term, therapies for lupus are hazardous. We show herein that arsenic trioxide (As2O3) is able to achieve quasi-total regression of antibody- and cell-mediated manifestations in MRL/lpr mice. As2O3 activated caspases and eliminated the activated T lymphocytes responsible for lymphoproliferation and skin, lung, and kidney lesions, leading to significantly prolonged survival rates. This treatment also markedly reduced anti-DNA autoantibody, rheumatoid factor, IL-18, IFN-gamma, nitric oxide metabolite, TNF-alpha, Fas ligand, and IL-10 levels and immune-complex deposits in glomeruli. As2O3 restored cellular reduced glutathione levels, thereby limiting the toxic effect of nitric oxide, which is overproduced in MRL/lpr mice. Furthermore, As2O3 protected young animals against developing the syndrome and induced almost total disease disappearance in older affected mice, thereby demonstrating that it is a novel promising therapeutic agent for autoimmune diseases.
Bobé
Pierre
P
Centre National de la Recherche Scientifique (CNRS), Unite Propre de Recherche (UPR) 9045, Villejuif, France. bobe@infobiogen.fr
Bonardelle
Danielle
D
Benihoud
Karim
K
Opolon
Paule
P
Chelbi-Alix
Mounira K
MK
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D020169:Caspases / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005978:Glutathione / Q000276:immunology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009569:Nitric Oxide / Q000276:immunology; D010084:Oxidation-Reduction / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D013577:Syndrome; D019014:fas Receptor / Q000276:immunology
D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D000970:Antineoplastic Agents; D001152:Arsenicals; D016207:Cytokines; D010087:Oxides; D019014:fas Receptor; D009569:Nitric Oxide; D020169:Caspases; D005978:Glutathione; D000077237:Arsenic Trioxide