Alcohol induced enrichment of regulatory T cells

酒精诱导调节性 T 细胞富集

• 批准号: 7743353
• 负责人: MAKIO IWASHIMA
• 金额: $ 7.48万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-10 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743353
• 关键词: 1-Butanol; Affect; Alcohol consumption; Alcohols; Antigen Receptors; Autoimmune Diseases; Binding; CD4 Positive T Lymphocytes; Cells; Choline; Chronic; Data; Enzyme Inhibition; Enzymes; Equilibrium; Ethanol; Frequencies; Gene Expression; Genes; Goals; Growth; Hepatitis C virus; Hydrolysis; Immune response; Immunosuppressive Agents; In Vitro; Infection; Infectious Agent; Knockout Mice; Lecithin; Lipid Bilayers; Lipids; Lymphocyte; Mediating; Molecular; Mus; Mycobacterium tuberculosis; Phosphatidic Acid; Phospholipase D; Phospholipids; Population; Procedures; Production; Proteins; Recruitment Activity; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Protein; T-Lymphocyte; Testing; Tissue Transplantation; base; chronic alcohol ingestion; human FRAP1 protein; in vivo; infectious disease treatment; knockout gene; public health relevance; research study; response; second messenger; tool

DESCRIPTION (provided by applicant): Alcohol has long been known to cause suppressive effect on immune responses. Chronic consumption of alcohol is often associated with a higher frequency of chronic infection with agents such as hepatitis C virus. However, the precise molecular mechanism for how alcohol suppresses immune response is currently not clearly identified. One of the endogenous molecules affected by alcohol is phospholipase D (PLD). PLD is an enzyme that catalyzes hydrolysis of phosphatidyl choline, a major phospholipid found in lipid bilayers, into phosphatidic acid (PA) and choline. PA is an active second messenger that recruits and activates its target proteins. In the presence of alcohol, particularly primary alcohol (1-alcohol) such as ethanol and 1-butanol, PLD catalyzes transphosphatidylation instead of hydrolysis. As a result, production of PA is significantly reduced when 1-alcohol is present. Our preliminary studies demonstrate that, in the presence of 1-alcohol, antigen receptor- induced proliferation of CD4? effector T cells was severely impaired while expansion of CD4? remains intact. As a consequence, T cells expanded in the presence of 1-alcohol were markedly enriched for regulatory T cells that impose suppressive effects on immune responses both in vitro and in vivo. Similar effect was observed by gene knockdown of PLD. Based on these data, we hypothesize that PLD is a target of alcohol-induced enrichment of Tregs. In this study, we will use our recently established conditional gene knockout mice of PLD1 and PLD2 gene and determine if PLD signal inhibition makes T cells more sensitive to alcohol induced Treg enrichment both in vitro and in vivo. Successful completion of this study will contribute to better treatment of infectious diseases among heavy alcohol consumers. Moreover, it may provide potential procedures for enrichment of regulatory T cells and help the treatment of autoimmune disease and tissue transplantation. PUBLIC HEALTH RELEVANCE: This project will help understanding the mechanism by which alcohol suppresses immune responses and may help developing a new tool to develop treatment for autoimmune disorders using alcohol. Our preliminary data show that exposure of lymphocytes causes enrichment for immunosuppressive subset of cells. This study will analyze is this effect is mediated by inhibition of an enzyme called phospholipase D using genetically manipulated mice that lack expression of this enzyme.

描述（由申请人提供）：长期以来，已知酒精会对免疫反应产生抑制作用。长期饮酒通常与更高频率的慢性感染有关，如丙型肝炎病毒。然而，酒精如何抑制免疫反应的精确分子机制目前还不清楚。受酒精影响的内源性分子之一是磷脂酶D（PLD）。PLD是一种催化磷脂酰胆碱水解成磷脂酸（PA）和胆碱的酶，磷脂酰胆碱是脂双层中发现的主要磷脂。PA是一种活跃的第二信使，招募并激活其靶蛋白。在醇，特别是伯醇（1-醇）如乙醇和1-丁醇的存在下，PLD催化转磷脂而不是水解。因此，当存在1-醇时，PA的产生显著降低。我们的初步研究表明，在1-醇的存在下，抗原受体诱导的CD 4？效应T细胞严重受损，而CD 4？仍然完好无损。因此，在1-醇存在下扩增的T细胞明显富集了对体外和体内免疫应答施加抑制作用的调节性T细胞。PLD的基因敲除也观察到类似的效果。基于这些数据，我们假设PLD是酒精诱导的TdR富集的靶点。在这项研究中，我们将使用我们最近建立的PLD 1和PLD 2基因的条件基因敲除小鼠，并确定PLD信号抑制是否使T细胞对酒精诱导的Treg富集在体外和体内更敏感。这项研究的成功完成将有助于更好地治疗酗酒者中的传染病。此外，它可能提供潜在的程序，富集调节性T细胞，并帮助治疗自身免疫性疾病和组织移植。公共卫生关系：该项目将有助于了解酒精抑制免疫反应的机制，并可能有助于开发一种新的工具来开发使用酒精治疗自身免疫性疾病的方法。我们的初步数据表明，淋巴细胞的暴露导致免疫抑制细胞亚群的富集。这项研究将分析这种效应是通过抑制一种称为磷脂酶D的酶介导的，使用缺乏这种酶表达的遗传操作小鼠。