Article

Arsenic Trioxide Prevents Murine Sclerodermatous Graft-versus-Host Disease

Laboratoire EA 1833, Faculté de Médecine, Sorbonne Paris Cité, Université Paris Descartes, 75679 Paris Cedex 14, France.
The Journal of Immunology (Impact Factor: 5.36). 04/2012; 188(10):5142-9. DOI: 10.4049/jimmunol.1103538
Source: PubMed

ABSTRACT Chronic graft-versus-host disease (GVHD) follows allogeneic hematopoietic stem cell transplantation. It results from alloreactive processes induced by minor MHC incompatibilities triggered by activated APCs, such as plasmacytoid dendritic cells (pDCs), and leading to the activation of CD4 T cells. Therefore, we tested whether CD4(+) and pDCs, activated cells that produce high levels of reactive oxygen species, could be killed by arsenic trioxide (As(2)O(3)), a chemotherapeutic drug used in the treatment of acute promyelocytic leukemia. Indeed, As(2)O(3) exerts its cytotoxic effects by inducing a powerful oxidative stress that exceeds the lethal threshold. Sclerodermatous GVHD was induced in BALB/c mice by body irradiation, followed by B10.D2 bone marrow and spleen cell transplantation. Mice were simultaneously treated with daily i.p. injections of As(2)O(3). Transplanted mice displayed severe clinical symptoms, including diarrhea, alopecia, vasculitis, and fibrosis of the skin and visceral organs. The symptoms were dramatically abrogated in mice treated with As(2)O(3). These beneficial effects were mediated through the depletion of glutathione and the overproduction of H(2)O(2) that killed activated CD4(+) T cells and pDCs. The dramatic improvement provided by As(2)O(3) in the model of sclerodermatous GVHD that associates fibrosis with immune activation provides a rationale for the evaluation of As(2)O(3) in the management of patients affected by chronic GVHD.

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    • "Some reports describe immunostimulatory properties [19], whereas others highlight cytotoxic effects on lymphocytes [20] through their prooxidative activity [19,21]. In our hands, the immunomodulating properties could be related to the addition of the ROS overproduced in autoreactive B and T cells and of the ROS induced by DPTTS, as previously in HOCl mice treated with (PHTE)2NQ or arsenic trioxide [6,15,22]. The immunomodulatory properties of DPTTS are also characterized by a decrease in the splenic production of IL-4 and IL-13 in HOCl mice treated with this molecule. "
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