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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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University of Pittsburgh
Schools of Medicine
United States
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Moliterno, R; Woan, M; Bentlejewski, C et al. (1995) Heat shock protein-induced T-lymphocyte propagation from endomyocardial biopsies in heart transplantation. J Heart Lung Transplant 14:329-37
Duquesnoy, R J; Demetris, A J (1995) Immunopathology of cardiac transplant rejection. Curr Opin Cardiol 10:193-206
Manez, R; White, L T; Linden, P et al. (1993) The influence of HLA matching on cytomegalovirus hepatitis and chronic rejection after liver transplantation. Transplantation 55:1067-71
Manez, R; White, L T; Kusne, S et al. (1993) Association between donor-recipient HLA-DR compatibility and cytomegalovirus hepatitis and chronic rejection in liver transplantation. Transplant Proc 25:908-9
Duquesnoy, R J; Kaufman, C; Zerbe, T R et al. (1992) Presence of CD4, CD8 double-negative and T-cell receptor-gamma-delta-positive T cells in lymphocyte cultures propagated from coronary arteries from heart transplant patients with graft coronary disease. J Heart Lung Transplant 11:S83-6
Zeevi, A; Uknis, M E; Spichty, K J et al. (1992) Proliferation of cytomegalovirus-primed lymphocytes in bronchoalveolar lavages from lung transplant patients. Transplantation 54:635-9
Kaufman, C; Zeevi, A; Zerbe, T R et al. (1992) IL-2-augmented primed-lymphocyte test responses of lymphocytes cultured from endomyocardial biopsies from heart transplant patients. Transplantation 54:1111-2
Zeevi, A; Eiras, G; Kaufman, C et al. (1991) Correlation between bioassayed plasma levels of FK 506 and lymphocyte growth from liver transplant biopsies with histological evidence of rejection. Transplant Proc 23:1406-8
Duquesnoy, R J; Trager, J D; Zeevi, A (1991) Propagation and characterization of lymphocytes from transplant biopsies. Crit Rev Immunol 10:455-80
Chen-Woan, M; Zerbe, T R; Zeevi, A et al. (1991) Diminished lymphocyte growth from endomyocardial biopsies from cardiac transplant patients on FK 506 immunosuppression. Transplant Proc 23:2941-2

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