CD1-restricted T cell response in atherosclerosis

动脉粥样硬化中 CD1 限制性 T 细胞反应

• 批准号: 6442758
• 负责人: Yong-Jian Geng
• 金额: $ 33.64万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6442758
• 关键词: CD1 molecule; T lymphocyte; antigen presentation; antigen receptors; atherosclerosis; autoantigens; cellular pathology; clinical research; cytokine; gene mutation; genetic polymorphism; genetically modified animals; human subject; laboratory mouse; lipids; natural killer cells; protein biosynthesis; systemic lupus erythematosus

DESCRIPTION (provided by applicant): The cluster of differentiation I (CD1) proteins represent a new class of antigen-presenting molecules, which structurally resemble MHC class I antigens and may restrict certain T lymphocyte responses to lipid antigens. There are two groups of CD1 molecules encoded by five CD1 genes (CD1a, b, c, d and e). Atherosclerotic lesions contain numerous T cells and CD1-positive macrophages and dendritic cells in addition to chemically modified lipids (e.g., cholesterol oxides or oxysterols and oxidized phospholipids) present in oxidized lipoproteins, raising the possibility that CD1-restricted T cells may exist in the lesions and respond to atherogenic lipid antigens presented by local macrophages and dendritic cells. The specific aims of this proposal are to determine (1) the CD1 isotype expression and CD1-restricted T cell response to lipid components of oxidized lipoproteins in atherosclerosis; (2) the association of an CD1 mutation or polymorphism with altered vascular autoimmunity in patients with SLE and atherosclerosis; (3) the cytokine production and pro-apoptotic function of CD1d-restricted NK T cells that are reactive to lipid antigens; and (4) the impact of knocking out CD1d gene on the T cell responses to lipid antigens and the development of atherosclerosis caused by apolipoprotein-E deficiency. The experimental procedures involve the analysis of T cell cytokine production and antigen receptor profiles, the evaluation of T cell response to CD1- lipid complexes, the assessment of genomic DNA sequences for CD1 genes, and the histopathological characterization of atherosclerotic lesions in the CD1/apolipoprotein-E double knockout mice recently established in our lab. Accomplishment of this project is anticipated to generate valuable information that help understand the immune mechanisms underlying vascular injury during atherogenesis.

描述（由申请人提供）： 分化 I (CD1) 蛋白簇代表了一类新的 抗原呈递分子，其结构类似于 I 类 MHC 抗原并可能限制某些 T 淋巴细胞对脂质的反应 抗原。有两组 CD1 分子，由 5 个 CD1 编码 基因（CD1a、b、c、d 和 e）。动脉粥样硬化病变含有大量T 细胞和 CD1 阳性巨噬细胞和树突状细胞 化学修饰的脂质（例如胆固醇氧化物或氧甾醇和 氧化磷脂）存在于氧化脂蛋白中，提高 病变中可能存在 CD1 限制性 T 细胞的可能性 对局部巨噬细胞呈递的致动脉粥样硬化脂质抗原作出反应 树突状细胞。该提案的具体目标是确定 (1) CD1同种型表达和CD1限制性T细胞反应 动脉粥样硬化中氧化脂蛋白的脂质成分； （2） CD1 突变或多态性与血管改变的关联 SLE 和动脉粥样硬化患者的自身免疫； (3)细胞因子 CD1d 限制性 NK T 细胞的产生和促凋亡功能 对脂质抗原有反应； (4)敲除CD1d的影响 T 细胞对脂质抗原反应的基因及其发育 载脂蛋白E缺乏引起的动脉粥样硬化。实验的 程序涉及 T 细胞细胞因子产生的分析和 抗原受体谱，评估 T 细胞对 CD1- 的反应 脂质复合物，CD1 基因基因组 DNA 序列的评估， 以及动脉粥样硬化病变的组织病理学特征 近期建立的CD1/载脂蛋白E双敲除小鼠 我们的实验室。该项目的完成预计将产生 有助于了解免疫机制的有价值的信息 动脉粥样硬化形成过程中潜在的血管损伤。