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: 8551362
• 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/8551362
• 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; public health relevance; 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.

描述（申请人提供）：肝脏是针对丙型肝炎病毒（HCV）和乙型肝炎病毒（HBV）等病原体产生免疫反应的重要部位，也是酒精代谢的主要部位。长期饮酒和肝脏感染都会导致免疫抑制；然而，两者之间的相互作用尚未明确定义。研究表明，长期接触酒精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，例如库普弗细胞、肝窦内皮细胞和肝星状细胞，能够将抗原呈递给 CD4+ 和 CD8+ T 细胞。这些肝脏 APC 激活肝脏内 T 细胞的能力使得它们在评估长期酒精暴露导致的 T 细胞反应失调时至关重要。我建议首先使用显微镜、蛋白质印迹、qRT-PCR 和体外细胞测定等多种方法来研究慢性酒精暴露对肝脏 APC 群体细胞生物学的影响，以研究存在和不存在的抗原呈递途径酒精。具体来说，我将重点关注自噬和免疫蛋白酶体诱导，因为这些途径可能对肝脏内的抗原呈递很重要，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。为了补充这些关于 APC 的研究，我接下来将通过确定酒精处理的肝脏 APC 如何影响 T 细胞反应来研究慢性酒精暴露如何影响抗原特异性 T 细胞反应，并在功能上表征由此产生的活化 T 细胞。这些研究将为免疫系统在长期酒精暴露的情况下启动针对肝脏病原体的有效 T 细胞反应的能力提供宝贵的知识。此外，这些研究将为利用自噬和免疫蛋白酶体进行肝内抗原呈递提供新的见解。