Cyclosporine A (CsA) is an immunosuppressive agent which has been used to prevent solid organ transplant rejection and graft-versus-host disease (GVHD) following bone marrow transplantation (BMT). Interestingly, upon cessation of CsA treatment, following autologous or syngeneic BMT, a disease similar to GVHD develops in humans and rodents. While the mechanisms responsible for the induction and pathogenesis of syngeneic GVHD largely remain unclear, self-reactive or autoreactive T cell responses have been described in the rat model. Furthermore, autoreactive T cells have been implicated in allogeneic GVHD in both humans and murine systems, as well as in the development of autoimmune disorders. Using a recently developed strain specific murine model of syngeneic GVHD, the autoreactive effector mechanisms present in syngeneic GVHD mice will be analyzed. In particular, proliferative and cytotoxic effector mechanisms present in the periphery and target organs of diseased animals, will be examined at the population and clonal level. A complete analysis of V-beta T cell receptor usage will be performed to analyze CsA-mediated alterations in tolerance induction to determine if T cells bearing self-reactive are generated in syngeneic GVHD mice. To assess strain variability in the induction of syngeneic GVHD, epithelial cells, isolated from the major target organ (large intestine) of CsA-treated inducible and non-inducible strains of mice, will be analyzed for differences in the ability to stimulate selected in vitro immune responses. Finally, as the histopathology present in the large intestine of syngeneic GVHD mice is strikingly similar to that observed in the intestinal tract of humans with inflammatory bowl disease (IBD), experiments have been designed to determine whether murine syngeneic GVHD effectively models human IBD based on intestinal cytokine profiles obtained from each disease. The use of syngeneic GVHD models presents a unique opportunity to study the generation and consequences of altered immune responses, and will contribute to a more complete understanding of such responses in GVHD and other inflammatory and autoimmune disorders.
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| Flanagan, D L; Jennings, C D; Bryson, J S (1999) Th1 cytokines and NK cells participate in the development of murine syngeneic graft-versus-host disease. J Immunol 163:1170-7 |
| Bryson, J S; Jennings, C D; Caywood, B E et al. (1997) Enhanced graft-versus-host disease in older recipient mice following allogeneic bone marrow transplantation. Bone Marrow Transplant 19:721-8 |
| Bryson, J S; Lake-Bullock, H; Pflugh, D L et al. (1995) In vivo reactivity of T cell clones isolated from mice with syngeneic graft-versus-host disease. Transplantation 60:171-8 |
| Bryson, J S; Jennings, C D; Caywood, B E et al. (1993) Thy1+ bone marrow cells regulate the induction of murine syngeneic graft-versus-host disease. Transplantation 56:941-5 |
