T-Cell Dependent Immune Responses and Ethanol

描述（由申请人提供）：这项工作是确定导致酗酒者免疫异常的改变的长期策略的一部分。 除了广泛报道的临床免疫缺陷和可能由自身免疫引起的疾病之外，我们和其他人已经证明，慢性酗酒者具有（a）持续激活的T淋巴细胞，（b）B细胞、T细胞和NK细胞中淋巴细胞精细亚群的损失，（c）单核细胞激活，以及（d）体内和体外的一系列功能变化。 我们现在提出五个互动项目（IRRPG）来评估慢性乙醇对先天性和适应性免疫系统组成部分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) 树突状细胞功能和乙醇； (4)自然杀伤细胞和乙醇； (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慢性乙醇给药模型，我们已证明该模型对小鼠具有良好的耐受性，可以与人类中观察到的长时间给药成比例，并且重要的是，产生的许多免疫参数变化与在人类慢性酗酒者中观察到的变化相似。 该项目 (1) T 细胞依赖性免疫反应和乙醇，将研究慢性乙醇暴露引起的 T 细胞依赖性改变。 我们在其他地方已经证明，慢性乙醇小鼠具有激活的 T 细胞。 文献清楚地表明，酗酒者会降低 T 依赖性免疫，我们在初步数据中发现，长期接触乙醇的小鼠不仅降低了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，而且改变了对 TNP-KLH 的 T 依赖性体液反应。 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，以及评估慢性乙醇暴露中记忆细胞存活的几个实验方案。 在其他实验中，将在 TH1 和 TH2 主导的小鼠中测量长期乙醇对 TH1 和 TH2 驱动的体液反应的影响。 将在体外和体内进行实验，以清楚地区分慢性乙醇小鼠的 T 细胞对正常肽负载骨髓树突状细胞的反应能力是否减弱。 编码李斯特菌 LLO 蛋白的 DNA 疫苗将用于尝试增强乙醇减弱的抗原特异性 T 细胞反应，并增强记忆细胞和抗原特异性溶细胞 T 细胞反应，这对于保护至关重要。

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.