Regulation of T Cell Responses in Atherosclerosis

动脉粥样硬化中 T 细胞反应的调节

基本信息

批准号：
7568264
负责人：
ANDREW H LICHTMAN
金额：
$ 47.15万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-12 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7568264
关键词：
Acute Address Adoptive Transfer Agonist Anti-Inflammatory Agents Anti-inflammatory Antigen-Presenting Cells Antigens Arterial Fatty Streak Asses Atherosclerosis Autoimmunity Binding Biological Assay Bone Marrow CD4 Positive T Lymphocytes Cell Differentiation process Cell physiology Cells Cellular Immunity Chimera organism Cholesterol Chronic Clinical Collagen Cultured Cells Data Development Disease Disease Progression Endothelial Cells Equilibrium Family Goals Heat shock proteins Hematopoietic Immune response Immunohistochemistry In Vitro Inflammation Interferons Interleukin-2 Knowledge Laboratories Lead Lesion Ligands Lipoproteins Lymphoid Tissue Mediating Mediator of activation protein Morbidity - disease rate Mus Pathogenesis Pathway interactions Phenotype Population Production Publishing Regulation Regulatory Pathway Reporter Research Personnel Role Signal Transduction Smooth Muscle Myocytes Syndrome T cell regulation T-Lymphocyte T-bet protein Th1 Cells Therapeutic Transgenes Work atheroprotective cell mediated immune response cell type cytokine hypercholesterolemia immunoregulation in vivo member microbial mortality mouse model oxidized low density lipoprotein programs receptor response

项目摘要

DESCRIPTION (provided by applicant): Chronic inflammation is a fundamental component of atherosclerosis, and is promoted by T-cells specific for antigens within lesions. Work in the applicant's laboratory has established the importance Th1 cell differentiation and B7-family costimulators to pro-atherogenic T cell responses. Although there have been important recent advances in the field of T cell regulation, there has been little application of this knowledge to atherosclerosis. Our preliminary data indicate that there are systemic changes in regulatory T cells (Treg) in the setting of hypercholesterolemia, and there is a potentially important connection between the T cell costimulatory molecule ICOS and Treg activity. The objective of this proposal is to achieve a better understand of the regulatory pathways that can limit pro-atherogenic T cell responses. Three specific Aims are proposed. In Aim 1, we will determine if and how regulatory T cells (Treg) influence pro-atherogenic effector T cells responses and lesion development. We hypothesize that hypercholesterolemia leads to enhancement of both effector CD4+ T cell responses and compensatory systemic Treg responses. Treg will be enumerated in lymphoid tissue and lesions in LDLR KO mice, including FoxP3-GFP/LDLR reporter mice. Functional assays will be performed on Treg isolated from LDLR KO mice, and Treg effects on atherosclerosis and CD4+ T cell responses to atheroantigens will be examined by in vivo adoptive transfer and depletion studies. In Aim 2, we will characterize the mechanisms by which the ICOS on T cells regulates atherosclerotic lesion development and maturation. We hypothesize that ICOS exerts an atheroprotective role by enhancing Treg-mediated suppression of plaque-antigen specific effector T cells and/or by skewing the effector phenotype of plaque-antigen specific effector T cells. We will analyze extent and phenotype of lesions, as well as effector and Treg responses to atheroantigens, in ICOS and ICOS ligand deficient LDLR KO mice. Bone marrow chimeras, and double KO mice will be employed. In Aim 3, we will determine if the PD-L1/PD-L2L-PD-1 T cell regulatory pathway influences the development of atherosclerosis and associated T cell responses. We hypothesize that PD-L1 and/or PD-L2, expressed on bone marrow derived antigen presenting cells or on endothelial cells bind to PD-1 on T cells and function to limit T cell responses to atheroantigens. We will employ LDLR KO mice deficient in PD-L1 and PD-L2 or PD-1, using bone marrow chimeras, and compound KO mice. Atherosclerosis remains a major cause of morbidity and mortality throughout the world. Successful completion of the Aims in this proposal will lead to a better understanding of how immune responses that aggravate atherosclerotic disease may be therapeutically controlled.

描述（由申请人提供）：慢性炎症是动脉粥样硬化的基本组成部分，并由特定于病变内抗原的T细胞促进。申请人实验室中的工作确定了TH1细胞分化和B7家庭contimulators对亲动构型T细胞反应的重要性。尽管在T细胞调节领域取得了重要的进步，但这种知识几乎没有应用于动脉粥样硬化。我们的初步数据表明，在高胆固醇血症的情况下，调节T细胞（TREG）发生了系统性变化，并且T细胞共刺激分子ICOS和Treg活性之间存在潜在的重要联系。该提案的目的是更好地了解可以限制促进性T细胞反应的调节途径。提出了三个具体目标。在AIM 1中，我们将确定调节性T细胞（TREG）是否以及如何影响促动脉粥样硬化效应T细胞的反应和病变的发展。我们假设高胆固醇血症会增强效应子CD4+ T细胞反应和代偿性全身性Treg反应。 TREG将在淋巴组织中列举，并在LDLR KO小鼠中（包括FOXP3-GFP/LDLR报告小鼠）中列举Treg。将对从LDLR KO小鼠分离的TREG进行功能测定，并将通过体内收养转移和耗竭研究检查对动脉粥样硬化的影响和CD4+ T细胞对动脉粥样硬化剂的影响。在AIM 2中，我们将表征T细胞上ICO调节动脉粥样硬化病变发育和成熟的机制。我们假设ICO通过增强Treg介导的对斑块 - 抗原特异性效应T细胞和/或通过扭曲斑块抗原特异性效应T细胞的效应表型来发挥动脉保护作用。我们将在ICOS和ICOS配体不足的LDLR KO小鼠中分析病变的程度和表型，以及对动脉粥样硬化剂的效应子和Treg反应。将使用骨髓嵌合体和双KO小鼠。在AIM 3中，我们将确定PD-L1/PD-L2L-PD-1 T细胞调节途径是否影响动脉粥样硬化和相关T细胞反应的发展。我们假设Pd-L1和/或PD-L2在骨髓衍生的抗原呈递细胞或内皮细胞上表达，在T细胞上与PD-1结合并限制T细胞对动脉粥样硬化剂的反应。我们将使用骨髓嵌合体和化合物KO小鼠使用缺乏PD-L1和PD-L2或PD-1的LDLR KO小鼠。动脉粥样硬化仍然是全世界发病率和死亡率的主要原因。在该提案中成功完成目标将使您更好地了解如何通过治疗控制动脉粥样硬化疾病的免疫反应。