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: 7384675
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7384675
• 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）： 胆固醇胆结石是一种常见的昂贵疾病，其发病机制复杂且不完全清楚，涉及遗传和环境因素。一般来说，当胆汁中胆固醇过饱和时，这些结石就会在胆囊中形成。然而，过饱和胆汁不足以产生胆固醇胆结石。导致胆固醇胆结石形成的环境因素在很大程度上尚不清楚，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率超过 50%。最近我们证明适应性免疫反应对胆固醇胆结石的形成有很大贡献。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。根据迄今为止生成的数据，这种形成的可能的生物学模型是 T 细胞介导的胆囊壁损伤，导致胆囊功能逐渐丧失。本研究的目的是严格表征适应性免疫反应如何促进胆固醇胆结石的发病机制。具体而言，本研究的目的是： 1. 确定哪些 T 细胞亚群有助于胆固醇胆石生成，并确定是否可以通过免疫操作来预防胆石生成。为了实现这一目标，T 细胞亚群（效应 T 细胞和调节性 T 细胞）将被转移到 Rag 2-/- 小鼠体内。此外，由于已知调节性 T 细胞可以改善多种 T 细胞介导的疾病，因此将利用转移研究来确定它们预防胆固醇胆结石的能力。最后，由于 T 细胞和成石胆汁促进胆囊中的 Th1 免疫反应，因此将分析缺乏 Th1 免疫的小鼠形成胆固醇胆结石的能力。 2. 从机制上了解T细胞如何促进胆固醇胆结石的形成。 T 细胞可以通过多种机制促进胆固醇胆结石的形成。由于已知炎症会改变肝脏脂质代谢和转运，因此我将首先确定 T 细胞是否会改变肝脏或胆囊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形成同时发生，并且由于在具有 T 细胞的小鼠中胆囊细胞因子表达显着改变，因此我将确定 T 细胞是否会损伤胆囊或在存在成石胆汁的情况下改变胆囊收缩性。最后，由于成核是胆固醇胆石生成的关键因素，我将确定 T 细胞是否改变胆囊胆汁成核的动力学。拟议的研究将系统地、机械地确定 T 细胞的滚动和适应性免疫在小鼠胆固醇胆结石形成中的作用。这些研究将为胆固醇胆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来探索适应性免疫和人类胆固醇胆结石形成的作用，并可能改变人类研究、诊断、预防和治疗该疾病的方式。