Alcoholism: Modulation & Function of Lymphocyte Subsets

描述(申请人提供)：长期酗酒导致免疫 自身免疫缺陷和增加的表现。意义重大 酗酒者肺炎和其他传染病的增加导致 与非虐待人群相比，主要发病率和医疗费用。我们的 工作是长期战略的一部分，以确定导致 酗酒者的正常免疫功能丧失。其他人和我们已经展示了 在此之前，慢性酗酒者激活了T细胞，激活了单核细胞， 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，脾淋巴细胞亚群和功能的变化有 发现，Th1细胞因子的产生减少，如干扰素单核细胞 已在短期饮酒后的小鼠身上得到证实。相比之下，我们有 最近给小鼠长期饮酒，并同意最初的抑制 干扰素单核细胞的活性确实存在，但在6周后，发现激活增加 这与人类酗酒者表现出的激活相似。激活 慢性酒精中毒小鼠的参数包括：1)CD4+升高 通过T细胞受体(TCR)对刺激的反应性，随着 CD40配体和其他激活标志物的上调；2)快速增加 CD4+和CD8+T细胞同时产生干扰素；3)单核细胞增多 数字和参与第二信号的分子的上调 向T细胞、CD80和CD86传递。这些在老鼠身上的发现表明， 先天免疫系统(尤其是单核细胞)首先由慢性 酒精滥用，随后被激活的单核细胞激活T细胞。我们 我将在几个方面测试这个和其他T细胞激活和丢失的机制 方式。我们将：1)评估慢性粒细胞白血病患者单核细胞的刺激作用。 对酒精中毒小鼠T细胞的激活作用；2)确定是否有 是通过CD28作用于T细胞活化的第二信号需求 酒精中毒的小鼠；3)通过暴露于特定的 细菌DNA的替代品，并确定该产品是否会改变 T细胞平衡(抗原特异性T细胞丢失和Th1/Th2歪斜) 酒精中毒小鼠；以及4)通过评估继续在人类酒精中毒患者身上的工作 在重新刺激试验中，Th1/Th2偏斜及其激活的影响 单核细胞经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.