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

MRL/lpr mice develop a human-lupus-like 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 antibodyand 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, tumor necrosis factor-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. For personal use only. on August 31, 2017. by guest www.bloodjournal.org From