Role of iNKT Cells in Autoimmunity and Atherosclerosis

iNKT 细胞在自身免疫和动脉粥样硬化中的作用

• 批准号: 7500836
• 负责人: AMY S MAJOR
• 金额: $ 38.38万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-25 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500836
• 关键词: Adoptive Transfer; Antigen-Presenting Cells; Antigens; Apolipoprotein E; Arteries; Atherosclerosis; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Biological Response Modifiers; Cardiac; Cell Count; Cells; Cholesterol; Chronic; Complication; Coronary heart disease; Development; Diet; Disease; Environment; Event; Fatty acid glycerol esters; Future Generations; Galactosylceramides; Glycolipids; Goals; Growth; Heart Diseases; Hyperlipidemia; Immune; Immune response; Immunity; Immunotherapy; In Vitro; Individual; Inflammatory; Inflammatory Response; Interleukin-12; Interleukin-4; Lesion; Life; Lupus; Mediating; Minority; Morbidity - disease rate; Mus; Pathogenesis; Population; Production; Public Health; Regulation; Reporting; Research Personnel; Risk; Role; System; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic Intervention; Thinking; United States; Woman; anergy; atherogenesis; base; cytokine; feeding; immunoregulation; in vivo; insight; killer T cell; mortality; novel; programs; prototype; response

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory disease associated with the activation of both innate and adaptive immune responses. Minority populations and young women with systemic lupus erythematosus are particularly prone to the development of atherosclerosis. Recently, a unique group of T lymphocytes, called invariant natural killer T (iNKT) cells, have been implicated in atherogenesis and lupus. This Project will test the hypothesis that iNKT cells are chronically activated during hyperlipidemia and that this conversion is uniquely involved in regulating and/or modulating an inflammatory response that exacerbates atherosclerosis and dysregulates immunity. This hypothesis is based on key preliminary studies demonstrating that (a) iNKT cell numbers and functions are altered in spontaneously hyperlipidemic apoE-deficient (apoE-/-) mice; (b) iNKT cells of apoE-/- mice express phenotypic markers distinct from wild type iNKT cells, suggesting activation; (c) absence of iNKT cells in apoE-/- mice reduces atherosclerosis but aggravates lupus; and (d) specific activation of iNKT cells in vivo is proatherogenic but protects against lupus. Based on these findings, the overall objective of this Project is to characterize the immunoregulatory mechanism(s) by which iNKT cells promote lesion formation in the artery wall. Our specific aims are to: (1) investigate the effects of hyperlipidemia and atherosclerosis on iNKT cell numbers and functions in apoE-/- mice; (2) investigate the role of cytokine production by iNKT cells and subsequent immune activation in atherosclerosis and (3) determine the role of iNKT cells in lupus-accelerated atherosclerosis. Relevance to Public Health: Coronary heart disease associated with atherosclerosis is the primary cause of mortality in the United States. At extremely high risk for suffering a fatal cardiac event are young women with lupus. Lupus-accelerated atherosclerosis is independent of cholesterol levels and is thought to be largely associated with autoimmune dysregulation. iNKT cells represent some of the most potent immune regulators. Therefore, understanding their significance in lupus and atherosclerosis will provide valuable insights for the future generation of immunotherapy to treat both lupus and heart disease.

描述（由申请人提供）：动脉粥样硬化是一种与先天和适应性免疫反应激活相关的慢性炎症性疾病。少数民族和年轻女性系统性红斑狼疮患者特别容易发展为动脉粥样硬化。最近，一种独特的T淋巴细胞群，称为不变自然杀伤T （iNKT）细胞，被认为与动脉粥样硬化和狼疮有关。该项目将验证iNKT细胞在高脂血症期间被慢性激活的假设，并且这种转化独特地参与调节和/或调节炎症反应，从而加剧动脉粥样硬化和免疫失调。这一假设是基于关键的初步研究，这些研究表明：(a)自发性高脂血症apoE-/-缺陷小鼠的iNKT细胞数量和功能发生改变；(b) apoE-/-小鼠的iNKT细胞表达与野生型iNKT细胞不同的表型标记，提示活化；(c) apoE-/-小鼠中iNKT细胞的缺失减少了动脉粥样硬化，但加重了狼疮；(d)体内iNKT细胞的特异性激活是致动脉粥样硬化，但对狼疮有保护作用。基于这些发现，本项目的总体目标是表征iNKT细胞促进动脉壁病变形成的免疫调节机制。我们的具体目标是：(1)研究高脂血症和动脉粥样硬化对apoE-/-小鼠iNKT细胞数量和功能的影响；(2)研究iNKT细胞产生细胞因子和随后的免疫激活在动脉粥样硬化中的作用；(3)确定iNKT细胞在狼疮加速动脉粥样硬化中的作用。