There is accumulating evidence that allograft rejection and certain other manifestations of cell-mediated immunity involve, in part, the interaction of T lymphocytes and endothelial cells. The importance of endothelial cells in immune responses to organ grafts derives from their interposition between inflammatory cells and target tissues, their ability to function as antigen-presenting cells and their ability to undergo a series of changes termed """"""""activation"""""""" which eventuate certain of the pathological and clinical manifestations of cell-mediated immunity. Heparan sulfate proteoglycan is a biologically active component of endothelial cell membranes and extracellular matrices. It has a role in many of the normal functions of blood vessels including the maintenance of a barrier to egress of blood cells and plasma proteins, and the prevention of thrombosis. The loss of heparan sulfate from endothelium has been thought to contribute to the pathogenesis of allograft rejection, autoimmune arthritis, and tumor metastases. This application proposes investigation of the mechanisms by which the interaction between T cells and endothelial cells promotes the enzymatic cleavage and loss of heparan sulfate from cultured endothelial cells and the relationship of this process to T cell activation. The effects of heparan sulfate on the synthesis of cytokines and on the activation and functioning of T cells, macrophages and endothelial cells will be tested in order to deduce its potential contribution to graft rejection.
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