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Chronic alcohol abuse disrupts CD8+T cell function

长期酗酒会破坏 CD8 T 细胞功能

基本信息

批准号：
7892733
负责人：
ROBERT T COOK
金额：
$ 26.71万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-25 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7892733
关键词：
Abstinence Adrenal Cortex Hormones Affect Age Agonist Alcohol abuse Alcohol consumption Alcohol withdrawal syndrome Animals Antigen Presentation Antigens Attenuated B-Lymphocytes Bone Marrow CD8-Positive T-Lymphocytes CD8B1 gene Cell Line Cell physiology Cells Chronic Cities Clinical Corticosterone Cytokine Signaling Data Defect Dendritic Cells Diet Elderly Environment Epitopes Ethanol Evaluation First Name Goals Human Human Resources Immune Immune system Immunodominant Epitopes Immunologic Deficiency Syndromes Impairment In Vitro Individual Ingestion Instruction Interleukin 2 Receptor Iowa Laboratories Length Ligands Listeria monocytogenes Literature Measures Medicine Memory Methods Modeling Mus Names Organism Peptides Peptidoglycan Peripheral Phenotype Population Principal Investigator Publications Publishing Receptor Signaling Recovery Registries Regulation Research Research Design Research Personnel Resources Role Serum Signal Pathway Signal Transduction Spleen Stimulus Stress T memory cell T-Cell Activation T-Lymphocyte Testing Time Toll-like receptors Universities Vertebrates Viral Water Withdrawal Work abstracting alcohol exposure anergy base college cooking human embryonic stem cell human subject immunoregulation in vivo interest meetings middle age mouse model pathogenic bacteria performance site problem drinker programs receptor expression research study response sex thymocyte

项目摘要

Chronic alcohol abuse disrupts CD8+ T cell function. In this component we will explore CD8+ T cell functional parameters after chronic ethanol exposure in mice. This work arises from many past observations in chronic human alcoholics who have increased CD8+ T cell activation markers, a shift toward a memory phenotype, and an increased rapid IFNy response after in vitro stimulation. Published work from our laboratories and others has shown comparable findings in CD8+ T cells from mouse spleen, after many weeks of 20% (w/v) ethanol in water ingestion. In recent work we have found that there is a deficient antigen- specific CDS primary response after inoculation with an attenuated strain of the intracellular pathogenic bacterium, Listeria monocytogenes. Additional findings include several subset alterations, reduced expression of the IL-2 receptor beta subunit, and a reduced proliferative rate. Of interest, these changes can be modeled in part by the administration of certain TLR agonists, and the chronic ethanol mice have demonstrable increases in circulating peptidoglycan. In this component we will examine CDS functional responses to CDS immunodominant epitopes and other stimuli. Aim #1 will evaluate CD8+ T cell memory responses to several defined epitopes after inoculation and later challenge of chronic ethanol mice. Recovery of the deficient CD8+ T cell response will be tested after ethanol withdrawal. Direct inoculation of ethanol mice with peptide loaded dendritic cells will be compared with standard inoculation with organisms. Aim #1 tests the hypotheses that a) both primary and memory responses of CD8+ T cells are affected by chronic ethanol; b) that these changes are irreversible; and c) that the defect is not one of antigen presentation in vivo. Aims #2 and #3 will focus on the abnormal signaling responses of CD8+ T cells from chronic ethanol mice, and comparisons with the alterations produced by certain TLR agonists. These aims are based on the observations in CD8+ T cells from chronic ethanol mice and/or TLR agonist treated normal mice, of reduced IL-2R-beta expression, reduced proliferative response of CD8+CD44lo cells and paradoxically increased "expression of activation markers. This component interacts strongly with the Animal Core, the Technical Core, and Research Components #2 & #4 and Pilot Component projects #3 & #4. The PI of Research Components #2 and #4 are collaborators in the experiments of Aim #1.

慢性酒精滥用会破坏CD8 + T细胞功能。在本部分中，我们将探讨CD8 + T细胞慢性乙醇暴露后小鼠的功能参数。这项工作源于许多过去的观察在CD8 + T细胞活化标志物增加的慢性人类酗酒者中，表型，并且体外刺激后快速IFNy反应增加。发表的作品从我们的实验室和其他实验室已经在小鼠脾脏的CD8 + T细胞中显示了类似的发现， 20%（w/v）乙醇水摄入。在最近的研究中我们发现有一种缺陷抗原- 接种细胞内致病性大肠杆菌减毒株后的特异性CDS初级应答细菌，单核细胞增生李斯特菌。其他发现包括几个子集的改变，减少 IL-2受体β亚基的表达，以及降低的增殖率。有趣的是，这些变化可以部分通过给予某些TLR激动剂来建模，并且慢性乙醇小鼠具有循环肽聚糖明显增加。在本部分中，我们将研究CDS功能对CDS免疫显性表位和其他刺激的应答。目标#1将评价CD8 + T细胞记忆慢性乙醇小鼠在接种和随后的攻击后对几个确定的表位的应答。将在乙醇停药后检测缺陷型CD8 + T细胞应答的恢复。直接接种将具有负载肽的树突细胞的乙醇小鼠与用生物体的标准接种进行比较。目的#1测试以下假设：a）CD8 + T细胞的初级和记忆应答都受到以下因素的影响：慢性乙醇; B）这些变化是不可逆的;以及c）缺陷不是抗原缺陷体内表达。目的#2和#3将集中于来自人的CD8 + T细胞的异常信号传导应答。慢性乙醇小鼠，并与某些TLR激动剂产生的改变进行比较。这些目标基于来自慢性乙醇小鼠和/或TLR激动剂治疗的正常小鼠的CD8 + T细胞中的观察结果。 IL-2R-β表达降低，CD8 + CD44lo细胞增殖反应降低，相反地增加"活化标记物的表达。该组件与动物强烈相互作用核心、技术核心、研究组件#2和#4以及试验组件项目#3和#4。的研究组件#2和#4的PI是目标#1实验的合作者。