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和 各种感染，包括艾滋病，并可能反映出有害的影响 香烟烟雾对免疫系统的影响。然而，通过这种方式 香烟烟雾对免疫系统的影响尚不清楚。我们的 结果表明，长期暴露在香烟烟雾中的大鼠会受到损害。 抗原介导的淋巴细胞活化(即减少 抗原诱导的Ca~(2+)反应)和慢性粒细胞白血病患者的T细胞 尼古丁处理的动物细胞内肌醇水平较高 1，4，5-三磷酸(IP3)，并在用抗CD3或ConA激活后，这些 细胞被滞留在细胞周期的G1期。这些研究表明 尼古丁可能是香烟的关键成分之一。 引起免疫抑制的烟雾。为了描述通过什么机制 尼古丁影响免疫系统，这是这一提议的工作假设 检测血管紧张素特异性T淋巴细胞无能是否密切相关 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 对照(CON)和尼古丁处理动物不同阶段的淋巴细胞 在抗原诱导的信号转导途径中，尤其是 近端细胞内钙升高，包括细胞内钙离子的活性 蛋白酪氨酸激酶和磷脂酶C-γ1。此外, 建议进行实验以确定尼古丁处理的T细胞是否发生G1期停滞 淋巴细胞反映IL-2基因和/或表达的变化 细胞周期蛋白和细胞周期蛋白依赖性蛋白激酶控制细胞周期的不同阶段 G1向S过渡。这些研究将提供关于以下方面的宝贵信息 慢性吸烟/尼古丁影响健康的机制 免疫系统，并可能有助于描绘抗原的途径(S) 受体介导的T淋巴细胞无能(“耐受”)，这可能是 T细胞在包括艾滋病在内的几种疾病中无反应。

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.