NKT cells in lipoprotein Metabolism and atherosclerosis

NKT细胞在脂蛋白代谢和动脉粥样硬化中的作用

• 批准号: 7464157
• 负责人: GODFREY Shalom GETZ
• 金额: $ 37.2万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464157
• 关键词: Antiatherogenic; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Arterial Fatty Streak; Arteries; Atherosclerosis; Attention; Blood Vessels; CD1 Antigens; Cells; Chronic; Data; Development; Diet; Disease; Epithelial Cells; Family; Gene Expression; Goals; Hepatocyte; Homeostasis; Hyperlipidemia; Immune; Immune system; Immunoglobulin M; In Vitro; Inflammation; Inflammatory; Intestines; Link; Lipids; Lipoproteins; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Metabolism; Modeling; Modification; Mus; Plasma; Process; Production; Public Health; Reaction; Repression; Role; Series; Serum; Site; T-Lymphocyte; Tumor Necrosis Factor-Beta; Very low density lipoprotein; feeding; in vivo; killer T cell; lipid metabolism; low density lipoprotein inhibitor; oxidized lipid; response

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory disease involving both the innate and adaptive immune system that is initiated in response to hyperlipidemia and the retention and modification of lipids within the artery wall. The adaptive immune system has been shown to modulate the extent of atherosclerosis at selected arterial sites and to influence lipid/lipoprotein metabolism. Natural killer T (NKT) cells respond to lipid antigens presented by CD1 molecules on antigen presenting cells. Our results demonstrate that depending upon the presence of other immune cells, NKT cells are pro- or anti-atherogenic and can influence plasma lipids, especially VLDL, and either NKT cells or CD1d repress the specific production of IgM to oxidized lipids by B1 cells. In addition we have shown that the plasma of LDLR-/- mice contain antigen(s) that activate NKT cells in a CD1d dependent manner. In this proposal we will examine the effect of NKT cells and/or CD1d in the liver on lipid/lipoprotein metabolism (aim 1), in the vessel wall on atherosclerosis (aim 2), and on the specific repression of the production of IgM antibodies to oxidized lipids by B1 cells (aim 3). The effect of NKT cells/CD1d on all these processes is expected to contribute to the pro-atherogenic mechanism of NKT cells. A series of in vivo studies in which the level of NKT cells or expression of CD1d is manipulated are proposed along with in vitro studies to further investigate mechanism of action. In addition, we will attempt to identify the antigen in LDL or atherosclerotic plaques that activate NKT cells. These studies will contribute to our understanding of the role of the adaptive immune system and specifically T cells subclasses on lipoprotein homeostasis and atherosclerosis and will provide evidence for endogenous lipid antigens that stimulate iNKT cells. PUBLIC HEALTH RELEVANCE: The goal of these studies is to understand how iNKT cells, which respond to lipid antigens, influence lipoprotein metabolism and atherosclerosis. These studies will further our understanding of the role of the immune system in the chronic inflammation associated with atherosclerosis and provide an important link between hyperlipidemia and the development of atherosclerosis.

描述（由申请人提供）：动脉粥样硬化是一种慢性炎症性疾病，涉及先天性和适应性免疫系统，其起始于高脂血症以及动脉壁内脂质的滞留和改变。适应性免疫系统已被证明可以调节选定动脉部位的动脉粥样硬化程度并影响脂质/脂蛋白代谢。自然杀伤 T (NKT) 细胞对抗原呈递细胞上 CD1 分子呈递的脂质抗原作出反应。我们的结果表明，根据其他免疫细胞的存在，NKT 细胞具有促动脉粥样硬化或抗动脉粥样硬化作用，并且可以影响血浆脂质，尤其是 VLDL，并且 NKT 细胞或 CD1d 抑制 B1 细胞向氧化脂质特异性产生 IgM。此外，我们还发现 LDLR-/- 小鼠的血浆中含有以 CD1d 依赖性方式激活 NKT 细胞的抗原。在本提案中，我们将研究肝脏中的 NKT 细胞和/或 CD1d 对脂质/脂蛋白代谢的影响（目标 1）、血管壁中对动脉粥样硬化的影响（目标 2）以及对 B1 细胞产生针对氧化脂质的 IgM 抗体的特异性抑制（目标 3）。 NKT 细胞/CD1d 对所有这些过程的影响预计将有助于 NKT 细胞的促动脉粥样硬化机制。提出了一系列操纵 NKT 细胞水平或 CD1d 表达的体内研究以及体外研究，以进一步研究作用机制。此外，我们将尝试鉴定 LDL 或动脉粥样硬化斑块中激活 NKT 细胞的抗原。这些研究将有助于我们了解适应性免疫系统，特别是 T 细胞亚类对脂蛋白稳态和动脉粥样硬化的作用，并将为刺激 iNKT 细胞的内源性脂质抗原提供证据。公共健康相关性：这些研究的目的是了解对脂质抗原作出反应的 iNKT 细胞如何影响脂蛋白代谢和动脉粥样硬化。这些研究将进一步了解免疫系统在与动脉粥样硬化相关的慢性炎症中的作用，并提供高脂血症和动脉粥样硬化发展之间的重要联系。