Arsenic trioxide: a promising novel therapeutic agent for lymphoproliferative and autoimmune syndromes in MRL/lpr mice

• Published in: Blood 2006-12, Vol.108 (13), p.3967-3975
• Main Authors: Bobé, Pierre, Bonardelle, Danielle, Benihoud, Karim, Opolon, Paule, Chelbi-Alix, Mounira K.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Antinuclear - immunology; Antigen-Antibody Complex - immunology; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Apoptosis - immunology; Arsenic Trioxide; Arsenicals - pharmacology; Arsenicals - therapeutic use; Biochemistry, Molecular Biology; Caspases - immunology; Cytokines - immunology; Drug Evaluation, Preclinical - methods; Enzyme Activation - drug effects; Enzyme Activation - immunology; fas Receptor - immunology; Glutathione - immunology; Humans; Life Sciences; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - immunology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphoproliferative Disorders - drug therapy; Lymphoproliferative Disorders - immunology; Mice; Mice, Inbred MRL lpr; Nitric Oxide - immunology; Oxidation-Reduction - drug effects; Oxides - pharmacology; Oxides - therapeutic use; Syndrome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-04-020610

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-γ, nitric oxide metabolite, TNF-α, 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.