Effect of Chronic Alcohol on Liver APC and Ag-Specific T-Cells

长期饮酒对肝脏 APC 和 Ag 特异性 T 细胞的影响

• 批准号: 8314590
• 负责人: Katherine Brempelis
• 金额: $ 4.22万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-16 至 2015-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314590
• 关键词: Activities of Daily Living; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcoholic liver damage; Alcohols; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Autophagocytosis; Biological Assay; CD8B1 gene; Cell physiology; Cells; Cellular biology; Chronic; Chronic Hepatitis C; Cirrhosis; Complement; Dendritic Cells; Development; Endothelial Cells; Environment; Ethanol; Ethanol Metabolism; Generations; Goals; Hepatic Stellate Cell; Hepatitis B Virus; Hepatitis C; Hepatitis C Incidence; Hepatitis C virus; Hepatocyte; Immune response; Immune system; Immunologic Deficiency Syndromes; Immunosuppression; Impairment; In Vitro; Individual; Infection; Interleukin-2; Invaded; Knock-out; Knowledge; Kupffer Cells; Lead; Link; Listeria monocytogenes; Liver; Methods; Microscopy; Modeling; Mus; Pathway interactions; Phenotype; Population; Predisposition; Primary carcinoma of the liver cells; Process; Production; Proteins; Research; Series; Severities; Site; Spleen; Surface; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; TLR4 gene; Testing; United States; Western Blotting; alcohol effect; alcohol exposure; cell type; chronic alcohol ingestion; cytokine; feeding; insight; intrahepatic; liver infection; mouse model; pathogen; response; synergism; transcription factor

DESCRIPTION (provided by applicant): The liver is an important site for the development of an immune response against pathogens such as Hepatitis C virus (HCV) and Hepatitis B virus (HBV), as well as the main site of alcohol metabolism. Both chronic alcohol consumption and liver infection can lead to immunosuppression; however the interaction between the two is not well defined. Studies suggest that long-term alcohol exposure affects both antigen presenting cells (APCs) and also antigen-specific T cell responses. In the liver environment, multiple populations of APCs, such as the Kupffer cells, liver sinusoidal endothelial cells, and hepatic stellate cells, are capable of antigen presentation to CD4+ and CD8+ T cells. The capacity of these liver APCs to activate T cells within the liver makes them essential to study when evaluating the dysregulation of T cell responses by long-term alcohol exposure. I propose to first study the effects of chronic alcohol exposure on the cell biology of the liver APC populations by using multiple methods such as microscopy, western blotting, qRT-PCR, and in vitro cell assays to study antigen presentation pathways in the presence and absence of alcohol. Specifically, I will focus on autophagy and immunoproteasome induction as these pathways may be important for antigen presentation within the liver, and there is already some evidence that they are affected by alcohol in other cell types. To complement these studies on APCs, I will next study how the antigen-specific T cell response is affected by chronic alcohol exposure by determining how alcohol-treated liver APCs affect the T cell response, and functionally characterize the resulting activated T cells. These studies will provide valuable knowledge on the capability of the immune system to prime an effective T cell response against liver pathogens in the presence of long-term alcohol exposure. Furthermore, these studies will provide new insights into the use of autophagy and the immunoproteasome for intrahepatic antigen presentation. PUBLIC HEALTH RELEVANCE: The incidence of HCV is high among the alcohol-abusing population in the United States. The effects of chronic alcohol exposure on antigen presentation within the liver and the subsequent development of an antigen-specific T cell response against liver infection are poorly understood. In this project I will use a mouse model to assess the effects of alcohol on the generation of an effective immune response in the liver.

描述（由申请人提供）：肝脏是针对病原体（例如丙型肝炎病毒（HCV）和丙型肝炎病毒（HBV）以及酒精代谢的主要部位开发免疫反应的重要部位。慢性酒精消耗和肝感染都可以导致免疫抑制。但是，两者之间的相互作用尚未很好地定义。研究表明，长期酒精暴露会影响抗原呈递细胞（APC）和抗原特异性T细胞反应。在肝脏环境中，多个APC群体（例如kupffer细胞，肝窦内皮细胞和肝星状细胞）能够抗原呈现给CD4+和CD8+ T细胞。这些肝APC激活肝脏内T细胞的能力使其在评估通过长期酒精暴露的T细胞反应失调时研究至关重要。我建议首先研究慢性酒精暴露对肝APC群体细胞生物学的影响，例如使用显微镜，蛋白质印迹，QRT-PCR和体外细胞分析，以研究存在和不存在的抗原表现途径酒精。具体而言，我将重点关注自噬和免疫蛋白酶体诱导，因为这些途径对于肝脏内的抗原表现可能很重要，并且已经有一些证据表明它们在其他细胞类型中受到酒精的影响。为了补充APC的这些研究，我将下一步研究抗原特异性T细胞反应如何通过确定酒精处理的肝APC如何影响T细胞反应并在功能上表征所得激活的T细胞来影响慢性酒精暴露。这些研究将提供有关免疫系统在长期酒精暴露存在下针对肝病病原体有效T细胞反应的能力的宝贵知识。此外，这些研究将为使用自噬和免疫蛋白酶体用于肝内抗原呈递的新见解。 公共卫生相关性：美国饮酒人群中HCV的发病率很高。慢性酒精暴露对肝脏内抗原表现的影响以及随后对肝脏特异性T细胞反应对肝感染的发展。在这个项目中，我将使用小鼠模型来评估酒精对肝脏中有效免疫反应产生的影响。