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: 8816114
• 负责人: ANDREW H LICHTMAN
• 金额: $ 41.4万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816114
• 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这样的假设：炎症显着促进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。来自人类和小鼠研究的大量证据表明，T 淋巴细胞在驱动动脉粥样硬化疾病炎症中发挥重要作用。我们实验室的研究表明，T 细胞免疫调节的生理机制，包括调节辅助 T 细胞亚群分化、共刺激/共抑制途径和调节性 T 细胞，都会显着影响促动脉粥样硬化 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 来抑制炎症效应 T 细胞反应。这些发现是拟议项目的基础，其广泛目标是发现治疗性改变或阻断动脉中致病性 T 细胞反应的方法。这一目标将通过小鼠和人类树突状细胞、巨噬细胞和 T 细胞的体外和体内实验来实现。这项工作将分为以下三个相互关联的具体目标： 1- 开发基于树突状细胞中 KLF2 诱导的致动脉粥样硬化 T 细胞耐受方法。 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 介导的促动脉粥样硬化免疫反应抑制的细胞基础。将采取几种实验方法，包括：药理操作和树突状细胞在易发生动脉粥样硬化的小鼠品系之间的过继转移；谱系特异性 cre-lox 介导的调节基因删除，包括 DC 中的 KLF2 以及 T 细胞和骨髓细胞中的 PD-1，所有这些都存在于易发生动脉粥样硬化的肉糜中；并分析胆固醇诱导的先天性炎症对 Treg 活力和表型的影响。每个目标中提出的工作都涉及动脉粥样硬化疾病中 T 细胞调节的不同基本机制，我们知道这些机制与我们之前的工作相关。这些机制中的每一种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，所获得的信息将与心血管疾病免疫治疗方法的开发具有直接的转化相关性。

项目成果

The influence of innate and adaptive immune responses on atherosclerosis.

• DOI: 10.1146/annurev-pathol-020712-163936
• 发表时间: 2014
• 期刊: Annual review of pathology
• 作者: Witztum JL;Lichtman AH
• 通讯作者: Lichtman AH

Treating atherosclerosis with regulatory T cells.

• DOI: 10.1161/atvbaha.114.303568
• 发表时间: 2015-02
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Foks AC;Lichtman AH;Kuiper J
• 通讯作者: Kuiper J

IL-23R Deficiency Does Not Impact Atherosclerotic Plaque Development in Mice.

• DOI: 10.1161/jaha.117.008257
• 发表时间: 2018-04-04
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Engelbertsen D;Depuydt MAC;Verwilligen RAF;Rattik S;Levinsohn E;Edsfeldt A;Kuperwaser F;Jarolim P;Lichtman AH
• 通讯作者: Lichtman AH

T cell costimulatory and coinhibitory pathways in vascular inflammatory diseases.

• DOI: 10.3389/fphys.2012.00018
• 发表时间: 2012
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Lichtman AH

Dendritic Cell KLF2 Expression Regulates T Cell Activation and Proatherogenic Immune Responses.

• DOI: 10.4049/jimmunol.1600206
• 发表时间: 2016-12-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Alberts-Grill N;Engelbertsen D;Bu D;Foks A;Grabie N;Herter JM;Kuperwaser F;Chen T;Destefano G;Jarolim P;Lichtman AH
• 通讯作者: Lichtman AH