Regulation of T Cell Responses in Atherosclerosis

动脉粥样硬化中 T 细胞反应的调节

• 批准号: 8452083
• 负责人: ANDREW H LICHTMAN
• 金额: $ 40.02万
• 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: 2007-02-12 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452083
• 关键词: Address; Adoptive Transfer; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen Presentation; Arterial Fatty Streak; Arteries; Atherosclerosis; Autoantigens; Autoimmune Diseases; Automobile Driving; Biological; Blood Vessels; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cells; Cessation of life; Cholesterol; Chronic; Clinical; Data; Defect; Dendritic Cell Therapy; Dendritic Cells; Deposition; Development; Disease; Enhancing Lesion; Eragrostis; Event; Genetic; Growth; Helper-Inducer T-Lymphocyte; Human; Immune response; Immunity; Immunotherapeutic agent; In Vitro; Inflammation; Inflammatory; Interleukin-1; Interleukin-18; Laboratories; Lesion; Lipoproteins; Mediating; Methods; Morbidity - disease rate; Mouse Strains; Mus; Myeloid Cells; Pathway interactions; Phenotype; Physiological; Play; Process; Publishing; Recruitment Activity; Regulation; Regulator Genes; Regulatory T-Lymphocyte; Role; Rupture; Signal Transduction; Sirolimus; Smooth Muscle Myocytes; System; T cell regulation; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; To autoantigen; Up-Regulation; Vascular Endothelial Cell; Work; artery occlusion; atheroprotective; base; cell type; clinically relevant; human FRAP1 protein; hypercholesterolemia; in vivo; mTOR inhibition; macrophage; mevalonate; microorganism antigen; monocyte; mortality; peripheral tolerance; research study; response; transcription factor; tumor

DESCRIPTION (provided by applicant): Compelling evidence supports the hypothesis that inflammation contributes significantly to the development of atherosclerotic lesions and to the catastrophic clinical events associated with unstable lesions. Ample evidence from both human and mouse studies indicate that T lymphocytes play important roles in driving inflammation in atherosclerotic disease. Studies from our laboratory have shown that physiologic mechanisms of regulation of T cell immunity, including modulation of helper T cell subset differentiation, co-stimulatory/co-inhibitory pathways, and regulatory T cells, all significantly impact pro-atherogenic T cell responses. Furthermore, we have established that statins suppress inflammatory effector T cell responses through up-regulation of the transcription factor KLF2. These finding serve as the basis for the proposed project, with the broad objective of discovering ways to therapeutically alter or block the pathogenic T cell responses in arteries. This objective will be pursued through experiments with both mouse and human dendritic cells, macrophages and T cells, both in vitro and in vivo. The work will be organized into the following three interrelated Specific Aims: 1- Develop methods of tolerizing proatherogenic T cells based on induction of KLF2 in dendritic cells. 2- Develop approaches to sustain regulatory T cell (Treg) responses in atherosclerotic lesions under conditions of prolonged hypercholesterolemia. 3- Determine the cellular basis of PD-1 mediated suppression of proatherogenic immune responses. Several experimental approaches will be taken including: pharmacologic manipulation and adoptive transfer of dendritic cells between atherosclerotic-prone mouse strains; lineage specific cre-lox mediated deletion of regulatory genes including KLF2 in DCs and PD-1 in T cells and myeloid cells, all in atherosclerotic-prone mince; and analyses of the effects of cholesterol-induced innate inflammation on Treg viability and phenotype. The work proposed in each Aim address a different basic mechanism of the regulation of T cells in atherosclerotic disease that we know is relevant from our previous work. Each of these mechanisms will likely impact the others, and we will study these interactions. Overall, the information obtained will be of direct translational relevance to the development of immunotherapeutic approaches for cardiovascular disease.

描述(由申请人提供)：令人信服的证据支持炎症对动脉粥样硬化病变的发展以及与不稳定病变相关的灾难性临床事件有重大贡献的假设。来自人类和小鼠研究的大量证据表明，T淋巴细胞在推动动脉粥样硬化性疾病的炎症中发挥着重要作用。我们实验室的研究表明，调节T细胞免疫的生理机制，包括调节辅助性T细胞亚群分化、共刺激/共抑制途径和调节性T细胞，都显著影响致动脉粥样硬化的T细胞反应。此外，我们已经证实他汀类药物通过上调转录因子KLF2来抑制炎症效应T细胞反应。这些发现是拟议项目的基础，其广泛目标是发现从治疗上改变或阻断动脉中致病T细胞反应的方法。这一目标将通过在体外和体内用小鼠和人的树突状细胞、巨噬细胞和T细胞进行实验来实现。这项工作将被组织成以下三个相互关联的具体目标：1-基于树突状细胞中KLF2的诱导，开发耐受致动脉粥样硬化的T细胞的方法。2-开发在长期高胆固醇血症条件下维持动脉粥样硬化病变中调节性T细胞(Treg)反应的方法。3-确定PD-1介导的抑制致动脉粥样硬化免疫反应的细胞基础。将采取几种实验方法，包括：药物操纵和在易患动脉粥样硬化的小鼠品系之间过继转移树突状细胞；谱系特异性cre-lox介导的调控基因的缺失，包括DC中的KLF2和T细胞和髓样细胞中的PD-1，所有这些都在易患动脉粥样硬化的小鼠中；以及分析胆固醇诱导的先天炎症对Treg活性和表型的影响。在每个目标中提出的工作解决了在动脉粥样硬化性疾病中调节T细胞的不同的基本机制，我们知道这与我们之前的工作相关。这些机制中的每一种都可能影响其他机制，我们将研究这些相互作用。总体而言，所获得的信息将直接与心血管疾病免疫治疗方法的发展相关。