Acute and chronic graft versus host disease (GVHD) are a major limitation to the increased use of human allogeneic bone marrow transplantation. We have established a murine model of acute and chronic GVHD due to non-major histocompatibility antigens (non-H-2 antigens) which includes many features of human GVHD including scleroderma skin changes and immunodeficiency. Our purpose is to define the cellular mechanisms of acute and chronic GVHD particularly as they relate to human clinical transplantation. Histopathologically acute GVHD is characterized by the cytolytic destruction of recipient cells while chronic GVHD is due to increased collagen deposition. T lymphocytes from mice with acute and chronic GVHD will be clonally analysed to determine the relative frequency of recipient specific CTL, helper T lymphocytes that stimulate fibroblast collagen production and T lymphocytes with specificity for autologous Ia antigen (autoreactive T lymphocytes). The antigenic specificity of the cloned T lymphocytes will determine in both blastogenic and cytolytic assays using recombinant mice. The role of antigenic dose in the pathogenesis of GVHD will be studied by using strain combinations that differ at 3 or less non-H-2 antigens. The combination, B10.D2-BALB/c, in which bidirectional GVHD does not occur will be studied to determine if the lack of reciprocal GVHD is due to immunological or environmental factors. The collagen produced by the in vitro stimulation of cultured fibroblasts will be compared to in vivo collagen from mice with de novo chronic GVHD by determining the Type I/III collagen ratio. Since the in vitro lysis of lymphoid targets may be a poor model for in vivo GVHD, non-lymphoid targets (fibroblasts, keratinocytes) will be evaluated. The role of autologous Ia antigen expression in the pathogenesis of acute and chronic GVHD will be investigated by using Ia positive and negative non-lymphoid targets. The role of natural suppressor cells and autoreactive T lymphocytes in the pathogenesis of post-transplant immunodeficiency and immune dysregulation will be studied. In summary, this grant uses a murine model of non-H-2 GVHD to increase our understanding of human GVHD. The questions selected for study are those that have clinical relevance.
