Acute Graft-vs-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 presently understood. The effector cell populations responsible for GVHD involve donor T lymphocytes that potentially initiate a chain of cellular events in the host, culminating in specific target cell injury. Identification of effector mechanisms of GVHD and the donor/host combinations that result in activation of targeting functions have important immuno-therapeutic implications. This present proposal is focused at extending a database indicating that natural killer (NK) cells may be fundamental to lesion formation in GVHD. This study will be facilitated by the availability of a well- characterized murine model of GVHD in which morphologic effects of variations in highly-purified donor T cell inocula and donor/recipient strain combinations can be assessed. Moreover, development of a short-term organ culture system for murine skin will enable characterization of the effects of various putative effector cell populations and recombinant cytokines on target tissue isolated from systemic influences. Importantly, once effector mechanisms have been identified, both in vivo and in vitro, models may be manipulate using specific strategies for enhancement or abrogation of the target cell injury that is ultimately produced. In sum, in situ phenotypic aspects of lesion production and evolution will be determined by the use of both in vivo and in vitro model systems. Ultimate understanding of the nature and complexity of effector/target cell interactions in GVHD depends on the development of experimental models to test morphologic observations already documented in target tissues of man and experimental animals. This study seeks to elucidate the cellular pathology of GVHD in this manner. It is hoped that findings so generated will influence the development of strategies for treatment and prophylaxis of GVHD in humans.
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