T-Cell Dependent Immune Responses and Ethanol

T 细胞依赖性免疫反应和乙醇

• 批准号: 7101961
• 负责人: ROBERT T COOK
• 金额: $ 46.21万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101961
• 关键词: Listeria; T lymphocyte; active immunization; alcoholic beverages; cellular immunity; cytokine; cytolysis; dendritic cells; humoral immunity; immunologic memory; laboratory mouse; peptides; vector vaccine

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.

描述（由申请人提供）：这项工作是一项长期战略的一部分，以确定导致酒精中毒的免疫异常的改变。 除了广泛报道的临床免疫缺陷和可能的自身免疫起源的疾病，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）淋巴细胞细亚群损失的B细胞，T细胞和NK细胞，（c）单核细胞活化，（d）一系列的功能变化在体内和体外。 我们现在提出了五个互动项目（IRPG），以评估慢性乙醇对先天性和适应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，我们已经证明小鼠耐受性良好，可以与人类中观察到的时间成比例地延长给药时间，重要的是，在许多免疫学参数中产生的变化与在慢性人类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，将研究长期乙醇暴露引起的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，酗酒者具有降低的T依赖性免疫，并且我们在初步数据中发现，暴露于慢性乙醇的小鼠具有降低的对单核细胞增生李斯特菌LLO抗原的抗原特异性T细胞应答，以及改变的对TNP-KLH的T依赖性体液应答。 我们现在建议评估长期摄入乙醇后对李斯特菌抗原的CD 4+和CD 8 + T细胞抗原特异性反应，增强免疫和撤药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种实验方案。 在其他实验中，将在TH 1和TH 2显性小鼠中测量慢性乙醇对TH 1和TH 2驱动的体液应答的影响。 将在体外和体内进行实验，以清楚地区分来自慢性乙醇小鼠的T细胞是否具有降低的对正常肽负载的骨髓树突状细胞的反应能力。 编码李斯特菌LLO蛋白的DNA疫苗将用于尝试增强乙醇减少的抗原特异性T细胞应答，并增加记忆细胞和抗原特异性细胞溶解性T细胞应答，这在保护中是重要的。