Alcoholism: Modulation & Function of Lymphocyte Subsets

描述（由申请人提供）：慢性酒精滥用导致免疫 缺乏和自身免疫表现的增加。显著 酗酒者中肺炎和其他传染病的增加导致 与非滥用人群相比，滥用者的发病率和医疗费用更高。我们 这项工作是一项长期战略的一部分，以确定导致 酒精中毒者的正常免疫功能丧失。其他人和我们已经表明 之前的研究表明，长期酗酒者的T细胞，单核细胞， 和选择性淋巴细胞亚群丢失。在酒精的实验啮齿动物模型中 给药后，脾淋巴细胞群和功能的变化 已经发现，Th 1细胞因子如IFN单核细胞的产生减少， 在短期酒精饮食后的小鼠中得到证实。相比之下， 最近将小鼠置于长期酒精中，并同意最初的抑制 IFN单核细胞的激活确实发生，但6周后， 这与人类酗酒者中所证实的激活类似。激活 慢性酒精小鼠中的参数包括1）增加的CD 4 + 通过T细胞受体（TCR）对刺激的反应性， CD 40配体和其他活化标志物的上调; 2）快速增加 通过CD 4+和CD 8 + T细胞产生IFN单核细胞; 3）增加单核细胞 数量，以及参与第二信号的分子的上调 T细胞，CD 80和CD 86。这些在老鼠身上的发现表明， 先天免疫系统（特别是单核细胞）首先被慢性炎症激活。 酒精滥用，然后通过活化的单核细胞活化T细胞。我们 将在几个实验中测试这种和其他T细胞活化和丧失的机制。 的方式我们将：1）评估慢性单核细胞的刺激作用， 酒精对小鼠T细胞活化的影响; 2）确定是否有 是通过CD 28作用于T细胞活化的第二信号要求， 酒精小鼠; 3）通过暴露于定义的 细菌DNA的替代品，并确定这种产品是否改变 T细胞平衡（抗原特异性T细胞损失和Th 1/Th 2偏斜） 酒精小鼠;以及4）通过评估继续在人类酗酒者中的工作 在再刺激试验中，Th 1/Th 2偏斜，以及它们激活的 单核细胞在通过TCR刺激后对T细胞增殖活性的影响。

DESCRIPTION (provided by applicant): Chronic alcohol abuse causes immune deficiency and an increase in manifestations of autoimmunity. Significant increases in pneumonia and other infectious diseases in alcoholics result in major morbidity and medical expense compared with non-abusing populations. Our work is part of a long-term strategy to define the alterations leading to the loss of normal immunologic function in the alcoholic. Others and we have shown previously that chronic alcoholics have activated T cells, activated monocytes, and selective lymphocyte subset loss. In experimental rodent models of alcohol administration, changes in splenic lymphocyte populations and function have been found, and a reduction in Th1 cytokine production such as IFN monocyte has been demonstrated in mice after short-term alcohol diets. In contrast, we have recently placed mice on longer-term alcohol, and agree that initial suppression of IFN monocyte does occur, but after 6 weeks, increasing activation is seen which is similar to the activation demonstrated in human alcoholics. Activation parameters in the chronic alcoholic mice include 1) increased CD4+ responsiveness to stimulation through the T cell receptor (TCR), with increased upregulation of CD40 ligand and other activation markers; 2) increased rapid production of IFN monocyte by both CD4+ and CD8+ T cells; 3) increased monocyte numbers, and up-regulation of the molecules involved in second signal transmission to T cells, CD80 and CD86. These findings in mice suggest that the innate immune system (especially monocytes) is first activated by chronic alcohol abuse, followed by activation of T cells by the activated monocytes. We will test this and other mechanisms of T cell activation and loss in several ways. We will: 1) evaluate the stimulatory effect of the monocytes of chronic alcoholic mice on the activation of their T cells; 2) determine whether there is a second signal requirement acting through CD28 for T cell activation in the alcoholic mice; 3) mimic bacterial translocation by exposure to defined substitutes for bacterial DNA, and determine whether this products alterations of the T cell balance (antigen-specific T cell loss, and Th1/Th2 skewing) in the alcoholic mice; and 4) continue the work in human alcoholics by evaluation in restimulation assays, of Th1/Th2 skewing, and the effects of their activated monocytes on T cell proliferative activity after stimulation through the TCR.