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

Abstract

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 (As 2 O 3 ) is able to achieve quasi-total regression of antibody-and cell-mediated manifestations in MRL/lpr mice. As 2 O 3 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-␥, nitric oxide metabolite, TNF-␣, Fas ligand, and IL-10 levels and immune-complex deposits in glomeruli. As 2 O 3 restored cellular reduced glutathione levels, thereby limiting the toxic effect of nitric oxide, which is overproduced in MRL/lpr mice. Furthermore, As 2 O 3 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. (Blood. 2006;108:3967-3975)

Arsenic Trioxide Prevents Murine Sclerodermatous Graft-versus-Host Disease

“…A stock solution was prepared extemporaneously, as described above. As 2 O 3 was given 5 d/wk at a dose of 5 mg/g body weight, as described by Bobé et al (17). Control mice received i.p.…”

“…This ROS generation appears to be regulated through several pathways, including NADPH oxidase, mitochondrial electron transport chain, and inhibition of antioxidant enzymes (12)(13)(14). The ROS-mediated apoptosis triggered by As 2 O 3 can impact hematological tumor cells; under certain circumstances, it can also affect nontumor cells, such as keratinocytes, fibroblasts, or activated autoimmune lymphocytes (15)(16)(17).…”

Arsenic Trioxide Exerts Antitumor Activity through Regulatory T Cell Depletion Mediated by Oxidative Stress in a Murine Model of Colon Cancer

“…Recently, immunomodulatory properties of As 2 O 3 have been described. For instance, As 2 O 3 exerts therapeutic effects on lymphoproliferative and severe autoimmune disorders manifested in MRL/lpr mice (16) and enhances the immune response against myeloma cells or breast cancer cells (17,18).…”

De nouvelles perspectives thérapeutiques pour l’arsenic

“…Les souris MRL/lpr ont des atteintes cutanées (Figure 4) [24]. Par ailleurs, chez la souris MRL/lpr, on détecte une forte production de …”