Graft versus host disease (GVHD), a major complication of human bone marrow transplantation, accounts for significant morbidity and mortality in this patient population. Cutaneous GVHD is a manifestation of this condition in a target organ readily accessible for study: the skin. The cellular events and interactions responsible for the initiation and progression of GVHD are not currently understood. The goal of this proposal is to identify phenotypically skin cells potentially important as initiators, effectors, and targets in GVHD. In addition, we will assess the functional interactions of cells so identified in vitro. Our study will be facilitated by: (1) the availability of a range of informative clinical settings (major histocompatability class I/class II matched and mismatched, with and without T-cell depletion); (2) the study of sequential biopsies throughout the courses of disease; (3) the use of cell sorting techniques to identify phenotypes of mononuclear cells in peripheral blood at the time of skin biopsy; and (4) the ability to culture skin cells: endothelial cells, dermal fibroblasts and keratinocytes -- the relevant target cell population in GVHD. Specific in vitro studies will assess activation of T-helper/inducer cells by skin cells, skin cell cytolysis by mononuclear effector cells, and mononuclear cell-mediated modulation of dermal fibroblast growth and collagen biosynthesis. The role of inducible class II antigens on skin cells in GVHD will be specifically addressed in these studies. Ultimate understanding of the morphology and functional interactions of effector and target cells in GVHD depends on both identification in situ and study in vitro of these cells from human tissues. This study seeks to elucidate the cellular pathology of GVHD in this manner. Our findings could influence development of immunotherapeutic strategies for treatment and prophylaxis of GVHD in man. (TT)
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