The primary cause of late cardiac allograft loss is a unique form of coronary vasculopathy which superficially resembles coronary atherosclerosis and occurs at a rate of 15 to 20% of patients per year. The diffuse nature and rapid development of the vascular involvement, and the limitation of that involvement to donor tissue suggests an immunologic mechanism. The working hypothesis of this proposal is that a chronic low grade immunologic reaction (cellular and/or humoral immunity) to donor endothelium results in endothelial cell production of factors which stimulate smooth muscle cell proliferation. By harvesting and growing donor aortic endothelium at the time of organ donation, an assay system has been developed to investigate the cardiac allograft recipient's immunologic response to their specific donor's vascular endothelium in-vitro. This study proposes to investigate the following: 1) The recipient's lymphocyte proliferative response and expression of activation antigens when exposed to their specific donor's endothelium. 2) the presence of donor endothelium-specific antibody in recipient serum. 3) the response of the donor endothelium to incubation with recipient lymphocytes, serum or both; specifically measuring the expression of MHC class 1 and class 2 antigen, assaying for endothelial cell cytotoxicity, and assaying for the presence of endothelial cell-derived growth factors which are known to stimulate smooth muscle cell proliferation. 4) the correlation of the above assays in individual cardiac transplant patients to their development of accelerated transplant atherosclerosis. By understanding the specific immunologic response by the recipient to their donor vascular tissue, the specific response of the vascular endothelium to humoral and cellular immunity, and its subsequent interaction with smooth muscle, it is anticipated that this study will provide a better understanding of the mechanisms for initiation and progression of cardiac transplant atherosclerosis.
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