Inhalation of Tobacco smoke is associated with increased risks of cancer and various infections including AIDS, and may reflect the deleterious effects of cigarette smoke on the immune system. However, the manner through which cigarette smoke affects the immune system is not clearly understood. Our results indicate that chronic exposures of rats to cigarette smoke impairs the antigen-mediated activation of lymphocytes (i.e., decreased antigen-induced Ca2+ response), and T cells from chronically nicotine-treated animals exhibit higher intracellular levels of inositol 1,4,5-triphosphate (IP3) and, upon activation with anti-CD3 or Con A, these cells are arrested in the G1 phase of the cell cycle. These studies suggest that nicotine may be the key or one of the key constituents of cigarette smoke causing immunosuppression. To delineate the mechanism through which nicotine affects the immune system, the working hypothesis of this proposal examines whether the angen-specific anergy of T Iymphocytes is intimately linked to a state of """"""""activation"""""""" induced by nicotine in these cells. Experiments will include establishing the functional competency of T Iymphocytes from control (CON) and nicotine treated animals at various steps in the antigen-induced signal transduction pathway, in particular, the steps proximal to elevation of intracellular calcium including the activity of protein tyrosine kinases and phospholipase C gamma1. In addition, experiments are proposed to determine if the G1 arrest of nicotine-treated T lymphocytes reflects changes in the expression of the IL-2 gene and/or cyclins and cyclin-dependent kinases which control the various stages of the G1 to S transition. These studies will provide valuable information about the mechanism through which chronic cigarette smoking/nicotine affects the immune system and may help in delineating a pathway(s) for the antigen receptor-mediated T lymphocyte anergy (""""""""tolerance""""""""), which may account for the unresponsiveness of T cells in several diseases including AIDS.
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