Role of Oxidative Stress in the Colonic Complications of Murine Syngeneic Graft-versus-host Disease

Abstract

Syngeneic graft-versus-host disease (SGVHD) develops in mice following lethal irradiation, reconstitution with syngeneic bone marrow (BM) and treatment with a short course of the immunosuppressive agent cyclosporine A (CsA). The development of SGVHD is a complex process resulting from the cooperative interaction of multiple effector cell populations and inflammatory mediators contributing to the pathogenesis of this inducible disease. Using gene ex- pression analysis, flow cytometric analysis and immunohistochemistry, time course studies revealed increased reactive oxygen and nitrogen species in the tissues of CsA-treated animals compared to bone marrow transplantation (BMT) con- trols during the induction of SGVHD (d0-21 post-BMT). Studies were undertaken to determine the effect of CsA-induced oxidative stress on the induction of SGVHD. In vivo treatment with the superoxide dismutase mimetic, manganese (III) meso-tetrakis (4-benzoic acid) porphyrin (MnTBAP), during (d0-21 post BMT), or after CsA therapy (>d21 post-BMT), caused a reduction in the development of clinical symptoms of SGVHD (weight loss, diarrhea). Interestingly, treatment with MnTBAP resulted in a significant reduction in the deposition of peroxynitrite in the colons of CsA-MnTBAP-treated versus control CsA-treated SGVHD animals. These studies suggest a role for oxidative stress in the development of mur- ine SGVHD.