The major objective of the proposed study is to clarify the mechanism of lymphoma development in patients receiving immunosuppressive treatment. Cyclosporine (CsA) is presently one of the most successful immunosuppressants used in clinical organ transplantation but its use has been shown to be associated with the development of lymphomas. During the past 2 years of support, we demonstrated the promoting action of CsA for the induction of murine lymphoid tumors of either T or B cell lineage depending upon the types of initiating agents given. We postulate that the most plausible explanation for the promoting action of CsA is its interference with T-cell maturation in the thymus and its stimulation of B-cell proliferation in the lymph nodes. In this renewal application we will extend our studies in several directions. We will explore the mechanism underlying complex interactions of chemical carcinogens, radiation and retroviruses in the development of lymphoid tumors by exploiting the rat model of Moloney murine leukemia virus-induced lymphomas in conjunction with CsA as a tumor promoter. We will determine whether CsA has any effects on the induction of epithelial tumors using the model of urethane induced pulmonary adenoma in mice. We will further define the effects of CsA on T-cell maturation in the thymus with the use of a flow cytometry and T-cell differentiation antigens. Attempts will be made to determine whether selected thymic hormones may counteract the effects of CsA on the thymus. Functions of some of the cellular protooncogenes have been implicated to the control of cellular differentiation and/or cell proliferation. We will investigate the transcriptional expression of selected cellular protooncogenes in thymocytes (thymus) and lymphocytes (lymph nodes) os CsA- treated mice with or without initiation, to clarify to what extent changes in protooncogene expression correlate with the disturbance of thymocyte differentiation and proliferation of lymphocytes. These studies will provide better insight into not only the mechanism of CsA-promotion of lymphoid malignancies but also the basic aspects of CsA-action on immune systems.
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