This proposal, representing a revised competing renewal, is concerned with the cellular pathology of acute graft-versus-host disease (GVHD), a major complication of human allogeneic bone marrow transplantation. Cutaneous GVHD is a manifestation of this condition in a target organ readily accessible for study: the skin. Although the cellular pathogenesis of cutaneous GVHD remains poorly understood, lesions are believed to result from interaction of alloreactive donor effector cells with skin target cells. thus, GVHD is a potential paradigm for a family of cytotoxic cutaneous reactions, ranging from erythema multiforme to lupus erythematosus to cytotoxicity in AIDS. Experimental GVHD using H-2 matched mice differing only at minor histocompatibility antigens has provided important insights into effector-target cell interactions in skin. Depending on donor-recipient strains employed, donor T cells of either a mature CD4 or CD8 phenotype may initiate cutaneous and visceral lesions. Although these effector T cells are capable of setting into motion early events in disease progression, cells that eventually infiltrate target tissue have a novel CD4+CD3-CD8-phenotype and appear to preferentially damage epithelial stem cells. Their entry into target sites is preceded by degranulation of perivascular mast cells which we and others have recently shown to be a potent source of tumor necrosis factor-alpha (TNF). TNF may, in turn, promote leukocyte adhesion to microvascular endothelium, and long with mast cell proteinases, contribute to target cell injury. These observations have resulted in the hypothesis that acute GVHD involves an initiation phase of mature donor T cell alloactivation and proliferation; a vasoinductive phase whereby effector T cells of unconventional phenotype infiltrate target tissue in concert with mast cell degranulation/TNF release; and a target phase in which epithelial stem cells are preferentially injured. In this continuation, we will test this hypothesis using experimental models that specifically address these issues. Contribution of mast cell secretory products and CD4+8-3-mononuclear effector cell products to keratinocyte toxicity will be addressed in relevant in vitro and in vivo systems. Recent methods to identify epithelial stem cells should clarify their role as cellular targets of these effector pathways. The role of skin adhesion molecule expression in effector cell homing will be investigated for the first time in experimental GVHD.
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