T-Cell Dependent Immune Responses and Ethanol

描述(由申请人提供)：这项工作是长期战略的一部分，目的是确定导致酗酒者免疫异常的改变。除了被广泛报道的临床免疫缺陷和可能源于自身免疫的疾病外，我们和其他人已经证明，慢性酒精中毒患者有(A)持续激活的T淋巴细胞，(B)B细胞、T细胞和NK细胞中的淋巴细胞细小亚群丢失，(C)单核细胞激活，以及(D)体内和体外的一系列功能变化。我们现在提出五个交互项目(IRPG)来评估慢性酒精对先天性和获得性免疫系统组件的影响，以及两者与传染病病原体的相互作用。简而言之，这些项目是：(1)T细胞依赖的免疫反应与乙醇；(2)乙醇对小鼠B细胞室的影响；(3)树突状细胞功能与乙醇；(4)自然杀伤细胞与乙醇；(5)免疫反应在酒精性肝病中的作用。所有项目的一个关键特征是使用了一种慢性乙醇给药模型，我们已经证明这种模型对小鼠耐受性很好，可以长期给药，与在人类身上看到的情况成比例，而且重要的是，在许多免疫学参数上产生的变化与在慢性人类酗酒者中观察到的变化相似。这个项目，(1)T细胞依赖的免疫反应和酒精，将研究慢性酒精暴露对T细胞依赖的改变。我们在其他地方已经证明，慢性乙醇小鼠已经激活了T细胞。文献清楚地表明，酗酒者降低了T依赖性免疫，我们在初步数据中发现，慢性酒精暴露小鼠对单核细胞增生性李斯特菌LLO抗原的抗原特异性T细胞应答降低，对TNP-KLH的T依赖性体液应答也发生改变。我们现在建议评估长期酒精摄入后对李斯特菌抗原的CD4和CD8T细胞抗原特异性反应，加强免疫和戒断对这些乙醇减少反应的影响，以及几种评估慢性酒精暴露中记忆细胞存活的实验方案。在其他实验中，将在TH1和TH2占优势的小鼠中测量慢性乙醇对TH1和TH2驱动的体液反应的影响。为了明确区分慢性乙醇小鼠的T细胞是否对正常的多肽负载的骨髓树突状细胞的反应能力减弱，将在体外和体内进行实验。编码李斯特氏菌LLO蛋白的DNA疫苗将被用来试图增强乙醇减少的抗原特异性T细胞反应，并增加记忆细胞和抗原特异性细胞溶解T细胞反应，这在保护中是重要的。

DESCRIPTION (provided by applicant): This work is part of a long-term strategy to define the alterations leading to the immunologic abnormalities of the alcoholic. In addition to the widely reported clinical immune deficiency and disorders with possible autoimmune origins, we and others have demonstrated that chronic alcoholics have (a) persistently activated T lymphocytes, (b) lymphocyte fine subset losses in B cells, T cells, and NK cells, (c) monocyte activation, and (d) a range of functional changes in vivo and in vitro. We now propose five interactive projects (IRPG) to evaluate chronic ethanol effects on innate and adaptive immune system components and the interactions of both with infectious disease agents. In brief, the projects are: (1) T cell dependent immune responses and ethanol; (2) Effect of ethanol on the murine B cell compartment; (3) Dendritic cell function and ethanol; (4) Natural killer cells and ethanol; (5) The role of immune responses in alcoholic liver disease. A key feature of all projects is the use of a model of chronic ethanol administration which we have shown to be well tolerated by mice, can be administered for prolonged periods of time proportional to that seen in humans, and importantly, produces changes similar in many immunologic parameters to changes observed in chronic human alcoholics. This project, (1) T-cell dependent immune responses and ethanol, will investigate T cell dependent alterations by chronic ethanol exposure. We have shown elsewhere that chronic ethanol mice have activated T cells. The literature clearly shows that alcoholics have diminished T dependent immunity, and we have found in preliminary data that mice exposed to chronic ethanol have both decreased antigen-specific T cell responses to Listeria monocytogenes LLO antigen, and altered T dependent humoral response to TNP-KLH. We now propose to evaluate both CD4+ and CD8+ T cell antigen-specific responses to Listeria antigens after prolonged ethanol ingestion, the effect of boosting immunizations and withdrawal on these ethanol-diminished responses, and several experimental protocols to evaluate memory cell survival in chronic ethanol exposure. In other experiments, the effect of chronic ethanol on TH1 and TH2-driven humoral responses will be measured, in both TH1- and TH2-dominant mice. Experiments to distinguish clearly whether T cells from chronic ethanol mice have diminished capacity to respond to normal peptide-loaded bone marrow dendritic cells will be carried out both in vitro and in vivo. DNA vaccines encoding the Listeria LLO protein will be used to attempt to boost ethanol-diminished antigen-specific T cell responses, and to increase both memory cells and antigen-specific cytolytic T cell responses, which are important in protection.