T CELLS AND CYTOKINES IN PULMONARY FIBROSIS

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DESCRIPTION (Adapted from the applicant's abstract): The principal side effect of bleomycin (BLM), an antineoplastic antibiotic, is the induction of pulmonary fibrosis. Using the well established murine model of BLM-induced pulmonary fibrosis, the investigators propose to determine the role of non-T cell cytokines and T-cells in the induction and maintenance of pulmonary fibrosis. Preliminary data of the investigators indicate that BLM induces pulmonary fibrosis in C57BL/6 mice lacking B and T cells (SCID mice) and (C57BL/6 SCID X CB.17 SCID) F1 mice but not in CB.17 SCID mice. Recently, the investigators demonstrated that C57BL/6 mice in which pulmonary fibrosis was induced with intratracheal (i.t.) BLM exhibited marked systemic suppression in their ability to generate anti-sheep erythrocyte plaque-forming cell responses. Immunosuppression was not caused by BLM per se and was a general consequence of fibrosis and was independent of the method by which fibrosis was induced. The unifying hypothesis of this proposal is that underlying cytokine-mediated events induced by BLM initiate pulmonary fibrosis and are also responsible for the immunosuppression that is associated with the disorder. The aims are: 1) To investigate the role of T cell and non-T cell cytokines in initiating and maintaining bleomycin (BLM)-induced pulmonary fibrosis in mice. SCID mice and their euthymic counterparts will be used to determine the non-T cell cytokines which are important for the development of fibrosis and to differentiate the non-T cell mediated from the T cell associated components of the disease. The role of BLM-induced reactive oxygen intermediates in regulation of early profibrogenic cytokines will be analyzed and mice resistant to BLM-induced fibrosis will be manipulated to make them BLM-susceptible so as to be able to identify the early cytokine events involved in BLM-sensitivity. 2) To determine the basis of immunosuppression that is seen in BLM-induced pulmonary fibrosis. The hypothesis that BLM-induced alterations in the balance between Th1 and Th2 helper T cell populations is at least in part responsible for immunosuppression will be tested. Since TGF-b, NO and IFN-g are induced during BLM initiated pulmonary fibrosis and these products have been shown to be immunosuppressive they will serve as starting points to investigate the mechanism of immunosuppression.