This research project deals with the propagation and characterization of lymphocytes from endomyocardial biopsies from cardiac transplant patients. Biopsy-grown T cells frequently show reactivity towards the donor in proliferation and cytotoxicity assays. Their HLA specificity can be assessed with informative cell panels and in blocking studies with monoclonal antibodies specific for class I and class II HLA antigens. In several ways we have demonstrated the diagnostic and prognostic value of biopsy growth and donor specific alloreactivity. Most notable are recent observations that lymphocyte growth from histologically negative biopsies predicts a subsequent rejection episode. One objective of this renewal proposal is to develop a biopsy growth assay for monitoring heart transplant patients. We also intend to develop other clinically useful procedures including assays for immunosuppressive drug sensitivity of biopsy grown cells. Previous studies of serial biopsies have given some insight into the kinetics of alloreactive lymphocyte infiltration into the cardiac allograft. Experimental evidence has suggested a sequential infiltration of class I followed by class II specific cells through the vascular endothelium during the early post transplant period. However, other mechanisms of lymphocyte infiltration must be considered and the involvement of interstitial dendritic cells. Studies are designed under the second objective to delineate the various infiltration patterns and the types of cells involved during the early phases of rejection. These studies include immunohistochemical analysis of HLA antigen expression and the detection of various cell types. We will also evaluate the risk of blood transfusion induced sensitization in patients with a previous artificial heart bridge. A serious long-term complication of heart transplantation is the development of accelerated coronary artery disease due to chronic rejection. The third objective deals with studies on the functional characteristics of lymphocytes infiltrating arterial lesions. They may provide information about cellular immune mechanisms of coronary artery disease in long-term cardiac transplant survivors. These studies will lead to a better understanding of lymphocyte infiltration of cardiac allografts and provide opportunities for clinical laboratory assays useful in the monitoring of cardiac transplant patients.
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