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以下假设：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产生了重要贡献。来自人类和小鼠研究的充分证据表明，T淋巴细胞在驱动动脉粥样硬化疾病中炎症中起着重要作用。我们实验室的研究表明，调节T细胞免疫的生理机制，包括辅助T细胞子集分化的调节，共刺激性/共抑制性途径和调节性T细胞，都显着影响促动脉粥样硬化的T细胞反应。此外，我们已经确定他汀类药物通过上调转录因子KLF2抑制炎症效应T细胞反应。这些发现是拟议项目的基础，其广泛的目标是发现治疗方法改变或阻断动脉中的致病性T细胞反应。该目标将通过在体外和体内进行小鼠和人树突状细胞，巨噬细胞和T细胞的实验来追求。这项工作将被组织到以下三个相互关联的特定目的中：1-基于树突状细胞中KLF2的诱导，开发耐受性T细胞的方法。 2-开发方法在长期高胆固醇血症的情况下，在动脉粥样硬化病变中维持调节性T细胞（TREG）反应。 3-确定PD-1介导的抑制促进质性免疫反应的细胞基础。将采用几种实验方法，包括：药理学操纵和树突状细胞在动脉粥样硬化易易于的小鼠菌株之间的过继转移；谱系特定的CRE-LOX介导的调节基因缺失，包括DCS中的KLF2和T细胞和髓样细胞中的PD-1，全部在动脉粥样硬化易发性的肉中；以及胆固醇诱导的先天炎症对Treg生存力和表型的影响的分析。在每个目标中提出的工作介绍了我们所知道的动脉粥样硬化疾病中T细胞调节的不同基本机制与以前的工作有关。这些机制中的每一个都可能会影响其他机制，我们将研究这些相互作用。总体而言，获得的信息将与心血管疾病的免疫治疗方法的发展直接转化相关。