The overall objective of this proposed Program Project is to elucidate the factors predisposing organ transplant recipients to develop cancer at a much higher frequency than that seen in the general population and to determine the host factors which contribute to the tumor regression seen in some cases upon reduction in immunosuppressive therapy. The University of Pittsburgh Medical and Health Care Division is a leading international center for organ transplantation, and a major complication of these procedures has been the frequent development (greater than 1%) of malignant disease, especially post-transplant lymphoproliferative disease (PTLD). The projects in this proposal are designed to understand better some of the pathogenetic and biological characteristics of this problem: Projects 1, 2 and 4 are designed primarily to prospectively evaluate the factors hat may contribute to the development of tumors which, although occurring at a high rate relative to the general population, affect only a small proportion of transplant recipients. Project 1 (Project leader: Dr. Monto Ho) is focused on the hypothesis that infection of the patients by Epstein-Barr virus (EBV), particularly as a primary infection in the immunosuppressed host, plays a strong role in the induction of PTLD. The possible contribution of other agents, particularly human B lymphotropic virus (HHV-6), will also be evaluated. Project 2 (Project Leader: Dr Theresa Whiteside) has been designed to evaluate the alterations in the immune system particularly in potential anti-tumor effector mechanisms, that are induced by organ transplantation and by administration of cyclosporine A (CsA) and other immunosuppressive treatments. In addition, by prospectively following the transplant recipients after the immunologic assessment, for possible development of malignant disease, it should be possible to determine a predictive profile of immunologic abnormalities. Project 3 (Project Leader: Dr. Theresa Whiteside) focuses on detailed studies of tumor infiltrating lymphocytes in liver tumors arising in patients transplanted for the treatment of primary hepatocellular carcinoma. Project 4 (Project Leader: Dr. Sandra Levy) is designed to examine psychosocial factors in transplant recipients which may contribute to disease development and progression.