The role of T-cells and Th 1 immunity in cholesterol gallstones

T 细胞和 Th 1 免疫在胆固醇胆结石中的作用

• 批准号: 7499020
• 负责人: Kirk James Maurer
• 金额: $ 13.53万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-22 至 2008-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7499020
• 关键词: B-Lymphocytes; Bile fluid; Biliary; Biliary calculi; Biological Models; CD4 Positive T Lymphocytes; CD8B1 gene; Calculi; Cell Separation; Cells; Cholecystitis; Cholelithiasis; Cholesterol; Complex; Contracts; Cytotoxic T-Lymphocytes; Data; Diagnosis; Disease; Environmental Risk Factor; Eragrostis; Event; Fluorescence; Gallbladder; Genetic; Goals; Hepatic; Human; Immune; Immune response; Immunity; In Vitro; Inbred C57BL Mice; Inflammation; Kinetics; Leucocytic infiltrate; Lipids; Mediating; Microscopic; Modeling; Molecular; Mus; Pathogenesis; Phenotype; Prevalence; Production; Rate; Research Personnel; Role; Series; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Wild Type Mouse; base; cell injury; cytokine; in vivo; insight; lipid metabolism; loss of function; prevent; programs; treatment effect

DESCRIPTION (provided by applicant): Cholesterol gallstones are a common costly disease with a complex incompletely understood pathogensesis [sic] involving genetic and environmental contributions. In general, these stones form in the gallbladder when bile is supersaturated with cholesterol. However, supersaturated bile is not sufficient to produce cholesterol gallstones. The environmental factors which contribute to cholesterol gallstone formation are largely unknown and recent studies indicate that, in humans, unique environmental factors demonstrate a greater than 50% contribution to gallstone formation. Recently we demonstrated that the adaptive immune response contributes greatly to cholesterol gallstone formation. We hypothesize that adaptive immune stimulation is one of the environmental factors contributing to cholesterol gallstones in humans. Based upon the data generated to date a likely biological model for this formation is T-cell mediated damage to the gallbladder wall leading to a progressive loss of function of the gallbladder. The goal of this study is to rigorously characterize how the adaptive immune response contributes to the pathogenesis of cholesterol gallstones. Specifically the aims of this study are: 1. To determine which T-cell subsets contribute to cholesterol cholelithogenesis and to determine if cholelithogenesis can be prevented by immunological manipulation. To accomplish this aim T cell subsets (effector T-cells and regulatory T cells) will be transferred to Rag 2-/- mice. Furthermore, because regulatory T-cells are known to ameliorate numerous T-cell mediated diseases, their ability to prevent cholesterol gallstones will be determined utilizing transfer studies. Finally, because T- cells and lithogenic bile promote a Th1 immune response in the gallbladder the ability of mice deficient in Th1 immunity to form cholesterol gallstones will be analyzed. 2. To mechanistically understand how T-cells promote cholesterol gallstone formation. There are several mechanisms whereby T-cells may promote cholesterol gallstone formation. Since inflammation is known to alter hepatic lipid metabolism and transport I will first determine if T-cells alter the concentration of biliary lipids in hepatic or gallbladder bile. Next, because inflammation and gallbladder wall damage occur concurrently with gallstone formation and because gallbladder cytokine expression is markedly altered in mice possessing T-cells I will be determine if T-cells damage the gallbladder or alter gallbladder contractility in the presence of lithogenic bile. Finally, because nucleation is a key factor in cholesterol cholelithogenesis I will determine if T-cells alter the kinetics of gallbladder bile nucleation. The proposed studies will systematically and mechanistically determine the roll of T-cells and adaptive immunity in murine cholesterol gallstone formation. These studies will provide detailed insight into the pathogenesis of cholesterol gallstones. This murine model should provide a framework with which to explore the role of adaptive immunity and human cholesterol gallstone formation and may alter the way the disease is studied, diagnosed, prevented and treated in humans.

描述(由申请人提供)： 胆固醇结石是一种常见的、代价高昂的疾病，其发病机制复杂而不完全清楚，涉及遗传和环境因素。一般来说，当胆汁中的胆固醇过饱和时，这些结石就会在胆囊中形成。然而，过饱和的胆汁不足以产生胆固醇结石。导致胆固醇结石形成的环境因素在很大程度上是未知的，最近的研究表明，在人类中，独特的环境因素对胆结石形成的贡献超过50%。最近，我们发现获得性免疫反应在胆固醇结石的形成中起着重要作用。我们假设适应性免疫刺激是导致人类胆固醇结石的环境因素之一。基于到目前为止产生的数据，这种形成的一个可能的生物学模型是T细胞介导的胆囊壁损伤，导致胆囊壁功能的进行性丧失。这项研究的目的是严格描述获得性免疫反应如何在胆固醇结石的发病机制中起作用。明确地说，本研究的目的是：1.确定哪些T细胞亚群与胆固醇结石的发生有关，并确定是否可以通过免疫操作来预防胆结石的发生。为了实现这一目标，T细胞亚群(效应器T细胞和调节性T细胞)将被转移到RAG 2-/-小鼠。此外，由于调节性T细胞已知可以改善许多T细胞介导的疾病，它们预防胆固醇结石的能力将通过转移性研究来确定。最后，由于T细胞和致石胆汁促进了胆囊中的Th1免疫反应，因此将对Th1免疫缺陷小鼠形成胆固醇结石的能力进行分析。2.从机制上了解T细胞如何促进胆固醇结石的形成。T细胞可以通过几种机制促进胆固醇结石的形成。既然已知炎症会改变肝脏的脂肪代谢和转运，我将首先确定T细胞是否会改变肝脏或胆汁中胆汁脂质的浓度。接下来，由于炎症和胆囊壁损伤与胆结石的形成同时发生，而且拥有T细胞的小鼠的胆囊细胞因子表达显著改变，因此我将确定T细胞在致结石胆汁存在时是否会损害胆囊壁或改变胆囊壁的收缩能力。最后，由于成核是胆固醇结石形成的关键因素，我将确定T细胞是否改变了胆汁成核的动力学。拟议的研究将系统和机械地确定T细胞在小鼠胆固醇结石形成中的滚动和获得性免疫。这些研究将为胆固醇结石的发病机制提供详细的见解。这种小鼠模型应该提供一个框架，用来探索获得性免疫和人类胆固醇结石形成的作用，并可能改变人类研究、诊断、预防和治疗这种疾病的方式。