MECHANISM OF CIGARETTE SMOKE INDUCED IMMUNOSUPPRESSION

描述：（申请人摘要） 吸入烟草烟雾与癌症风险增加有关， 包括艾滋病在内的各种感染，并可能反映有害影响 香烟烟雾对免疫系统的影响 然而，通过这种方式， 吸烟对免疫系统的影响还不清楚。 我们 结果表明，大鼠慢性暴露于香烟烟雾损害 抗原介导的淋巴细胞活化（即，降低 抗原诱导的Ca 2+反应），和T细胞从慢性 尼古丁处理的动物表现出较高的细胞内肌醇水平 1，4，5-三磷酸（IP 3），并且在用抗CD 3或Con A活化后，这些 细胞停滞在细胞周期的G1期。 这些研究表明 尼古丁可能是香烟的关键成分之一 吸烟导致免疫抑制。 来描述 尼古丁会影响免疫系统，这是该提案的工作假设。 检查T淋巴细胞的Angen特异性无反应性是否与 与尼古丁在这些细胞中诱导的“激活”状态有关。 实验将包括建立T的功能能力 在不同步骤，对照组（CON）和尼古丁给药组动物的淋巴细胞 在抗原诱导的信号传导途径中，特别是步骤 接近于细胞内钙的升高，包括 蛋白酪氨酸激酶和磷脂酶C γ 1。 此外，本发明还提供了一种方法， 实验提出，以确定是否尼古丁处理的T细胞的G1期阻滞 淋巴细胞反映IL-2基因表达的变化，和/或 细胞周期蛋白和细胞周期蛋白依赖性激酶，它们控制细胞周期的各个阶段。 G1到S的过渡。 这些研究将提供有关以下方面的宝贵信息： 慢性吸烟/尼古丁影响 免疫系统，并可能有助于描绘抗原的途径 受体介导的T淋巴细胞无反应性（“耐受性”），这可能是导致 包括艾滋病在内的几种疾病中T细胞的无反应性。

DESCRIPTION: (Applicant's Abstract) 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.