Syngeneic graft-vs.-host disease (SGVHD) develops in rodents following the treatment of lethally irradiated, bone marrow (BM) reconstituted animals with a short course of the immunosuppressive agent cyclosporine A (CsA). Using an in vivo depletion approach, we recently demonstrated that CD4(+), but not CD8(+), T cells participated in inducing SGVHD. Studies were therefore undertaken to adoptively transfer SGVHD into lethally irradiated, syngeneic BM reconstituted secondary recipients. Whole T cell populations as well as purified CD4(+)T cells isolated from SGVHD, but not normal or transplant control, animals mediated the transfer of SGVHD into secondary recipients. These cells have an apparent specificity for enteric bacterial antigens. The pathologic process that developed was identical to that observed in the animals with de novo SGVHD after syngeneic BMT and CsA therapy. It was shown that a radiation-sensitive mechanism prevented the transfer of SGVHD into normal, nonirradiated secondary recipients. The ability to reproducibly transfer SGVHD into secondary recipients will enhance our ability to study regulatory mechanisms that are altered during CsA therapy and permit the development of murine CsA-induced SGVHD.

AM, Bryson JS. Association between chronic liver and colon inflammation during the development of murine syngeneic graft-versus-host disease.

These results demonstrate that after lethal irradiation and in the absence of donor T cells, T cells of recipient origin can expand and mediate the induction of CsA-induced SGVHD.

Syngeneic graft vs. host disease (SGVHD) was first described as a graft vs. host disease-like syndrome that developed in rats following syngeneic bone marrow transplantation (BMT) and cyclosporin A (CsA) treatment. SGVHD can be induced by reconstitution of lethally irradiated mice with syngeneic bone marrow cells followed by 21 days of treatment with the immunosuppressive agent CsA. Clinical symptoms of the disease appear 2–3 wk following cessation of CsA therapy, and disease-associated inflammation occurs primarily in the colon and liver. CD4+T cells have been shown to play an important role in the inflammatory response observed in the gut of SGVHD mice. Time-course studies revealed a significant increase in migration of CD4+T cells into the colon during CsA therapy, as well as significantly elevated mRNA levels of TNF-α, proinflammatory chemokines, and cell adhesion molecules in colonic tissue of CsA-treated animals compared with BMT controls, as early as day 14 post-BMT. Homing studies revealed a greater migration of labeled CD4+T cells into the gut of CsA-treated mice at day 21 post-BMT than control animals via CsA-induced upregulation of mucosal addressin cell adhesion molecule. This study demonstrates that, during the 21 days of immunosuppressive therapy, functional mechanisms are in place that result in increased homing of CD4+T effector cells to colons of CsA-treated mice.

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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 expression 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) controls 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 murine SGVHD.

Syngeneic graft‐vs‐host disease (SGVHD) is induced by reconstituting lethally irradiated mice with syngeneic bone marrow followed by a 21 day treatment with the immunosuppressive agent cyclosporine A (CsA). Symptoms of the disease appear 2–3 weeks following cessation of CsA therapy and disease‐associated inflammation occurs primarily in the colon and liver. Irradiation and CsA are both required for the development of SGVHD and both contribute to the production of oxidative stress. Time course studies revealed increased reactive oxygen and nitrogen species in CsA treated animals compared to BMT controls. Studies also demonstrated increased migration of CD4+T cells into the colon during CsA therapy. In addition, increased colon mRNA levels of proinflammatory cytokines (TNF‐α, IL‐12) and cell adhesion molecules (CAMs) were observed as early as day 14‐post BMT in colon of CsA treated animals. Since reactive oxygen species (ROS) are known to mediate CsA toxicity, studies were undertaken to determine the effect of CsA‐induced oxidative stress on the induction of SGVHD. Treatment with the antioxidant MnTBAP, during CsA therapy, caused a reduction in SGVHD development as well as decreased colon mRNA levels for iNOS, CAMs and proinflammatory cytokines. These studies suggest a role for oxidative stress in the development of intestinal pathology associated with murine SGVHD. Research support: NIH Grant P01‐CA092372.