This project deals with the isolation and characterization of lymphocytes grown from endomyocardial biopsies from heart transplant patients. We have developed methodologies of growing activated lymphocytes from heart transplant biopsies. These cultured cells frequently exhibit alloreactivity towards donor histocompatibility antigens. Studies are proposed to analyze the allospecificity patterns of these lymphocytes and compare them with the allospecificity of lymphocytes derived from peripheral blood. This will be done in secondary proliferation assays using well-defined HLA-typed cell panels. Additional blocking studies will be performed with class I and class II specific monoclonal antibodies to verify the allospecificity of heart biopsy-grown lymphocytes. We are interested in extending our preliminary observations demonstrating that many biopsies yield alloreactive T lymphocytes with restricted allospecificity patterns. Particularly relevant are studies showing the class I specificity of lymphocytes grown from early biopsies. On the other hand, later biopsies primarily yield class II specific lymphocytes. Studies are proposed to evaluate the possible mechanisms of the sequential infiltration of different types of alloreactive T cells in the allograft. These studies will analyze the recognition of class I and class II HLA antigens on vascular endothelial cells by alloactivated T cells during the cardiac allograft response. An important aspect of this study is the relevance of the presence of various types of alloreactive T cells to the outcome of the transplant. Studies are proposed to evaluate a possible association between the presence of donor-specific cytolytic T cells and transplant rejection. Also, we are interested to know why it is possible to grow alloreactive T cells from transplant biopsies from patients with long-term transplant survival. Studies are designed to determine the presence of suppressor cells contributing to allograft tolerance. Experiments are also planned to determine whether lymphocytes from long-surviving transplants have greater sensitivity to immunosuppressive drugs than lymphocytes from rejecting transplants. These studies may provide valuable information about cell-mediated immune responses to cardiac transplants. Besides learning more about T cell allorecognition in the cardiac allograft response, this project may also generate data and concepts which could be clinically useful in the management of the heart transplant patient.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023467-02
Application #
3135598
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1986-12-01
Project End
1989-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
Keenan, R; Kaufman, C; Zeevi, A et al. (1991) Phenotypic T-cell changes in thoracic transplant recipients immunosuppressed with FK 506. Transplant Proc 23:1162-4
Eiras, G; Hashem, H; Zeevi, A et al. (1991) The immunosuppressive activity of the aldehydic transformation of cyclosporine on alloreactive T-cells. J Clin Pharmacol 31:72-5
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

Showing the most recent 10 out of 44 publications