T-Cell Dependent Immune Responses and Ethanol

描述（由申请人提供）：这项工作是定义导致嗜酒者免疫异常的改变的长期战略的一部分。除了广泛报道的临床免疫缺陷和疾病与可能的自身免疫性起源外，我们和其他人已经证明慢性酗酒者有(a)持续激活的T淋巴细胞，(b) b细胞、T细胞和NK细胞的淋巴细胞细亚群损失，(c)单核细胞激活，以及(d)体内和体外一系列功能改变。我们现在提出了五个相互作用项目（IRPG）来评估慢性乙醇对先天和适应性免疫系统成分的影响以及两者与传染病因子的相互作用。简而言之，项目包括：(1)T细胞依赖性免疫反应和乙醇；(2)乙醇对小鼠B细胞区室的影响；(3)树突状细胞功能与乙醇；(4)自然杀伤细胞和乙醇；(5)免疫应答在酒精性肝病中的作用。所有项目的一个关键特征是使用慢性乙醇管理模型，我们已经证明小鼠对其具有良好的耐受性，可以在与人类成比例的长时间内进行管理，重要的是，在许多免疫参数中产生与慢性人类酗酒者观察到的变化相似的变化。这个项目，(1)T细胞依赖性免疫反应和乙醇，将研究慢性乙醇暴露对T细胞依赖性的改变。我们已经在其他地方证明了慢性乙醇小鼠激活了T细胞。文献清楚地表明，酗酒者的T依赖性免疫减弱，我们在初步数据中发现，暴露于慢性乙醇的小鼠对单核细胞增生李斯特菌LLO抗原的抗原特异性T细胞反应降低，对TNP-KLH的T依赖性体液反应改变。我们现在建议评估长期摄入乙醇后CD4+和CD8+ T细胞对李斯特菌抗原的抗原特异性反应，增强免疫和退出对这些乙醇减少反应的影响，以及评估慢性乙醇暴露下记忆细胞存活的几种实验方案。在其他实验中，慢性乙醇对TH1和th2优势小鼠的TH1和th2驱动的体液反应的影响将被测量。为了明确区分慢性乙醇小鼠的T细胞对正常的装载多肽的骨髓树突状细胞的反应能力是否减弱，将在体外和体内进行实验。编码李斯特菌LLO蛋白的DNA疫苗将被用于尝试增强乙醇减少抗原特异性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.