T Cell mediated immune responses as a regulator of heart failure

T 细胞介导的免疫反应作为心力衰竭的调节剂

• 批准号: 9307971
• 负责人: Maria Pilar Alcaide Alonso
• 金额: $ 41.25万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307971
• 关键词: Adhesions; Adoptive Transfer; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Biological Assay; Blood; Blood Vessels; CD4 Positive T Lymphocytes; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Adhesion Molecules; Cell Communication; Cessation of life; Chest; Clinical Trials; Congestive Heart Failure; Data; Disease; Echocardiography; Endothelial Cells; Fibroblasts; Fibrosis; Flow Cytometry; Goals; Heart; Heart failure; Hospitalization; Human; Human Biology; Immune response; Immunohistochemistry; Immunology; In Vitro; Inflammation; Inflammatory; Integrins; Left; Left Ventricular Dysfunction; Left Ventricular Function; Left Ventricular Hypertrophy; Lymphoid; Mediating; Modeling; Molecular; Mus; Organ; Pathologic; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Physiology; Pilot Projects; Play; Process; Recruitment Activity; Regulatory T-Lymphocyte; Research; Role; Sampling; Selectins; Source; Staining method; Stains; Stress; Syndrome; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Time; Translating; Vascular Endothelium; Ventricular; Video Microscopy; Western Blotting; Work; adaptive immune response; base; cell mediated immune response; chemokine receptor; constriction; cytokine; hemodynamics; immune activation; immunoregulation; improved; in vivo; innovation; left ventricular assist device; migration; mortality; new therapeutic target; novel; outcome forecast; pressure; prevent; public health relevance; reconstitution; response; targeted treatment

DESCRIPTION (provided by applicant): Heart failure (HF) is a progressive syndrome affecting nearly 20 million people worldwide and is generally caused by remodeling of the heart in response to pathological stress. Emerging evidence associates systemic inflammation with left ventricular (LV) dysfunction and HF, but the mechanisms for the observed systemic inflammation are largely unexplored. Our preliminary data using Thoracic aortic constriction (TAC), a well-defined model of HF, indicates that T cells are recruited to the heart and the heart vascular endothelium is activated locally as LV function worsens. Interestingly, we found that T cells from mice undergoing HF interact with activated mouse heart endothelial cells in significant higher numbers than T cells from control mice under physiological flow conditions in vitro. Remarkably, T cell deficient mice (TCR�-) showed increased survival, preserved LV function, and decreased fibrosis in our pilot studies. Based on these data, in this proposal we will test the central hypothesis that T cell mediated immune responses influence cardiac remodeling in pressure overload induced HF. We propose 3 specific aims to test this hypothesis, in which we will obtain novel information about the mechanisms regulating mouse and human T cell recruitment in the heart during the course of HF, the T cell subsets involved, and their influence in the mechanisms regulating cardiac remodeling in HF. In Aim 1 we will use videomicroscopy to study the adhesion mechanisms regulating interactions between mouse T cells and heart endothelial cells during the progression of HF induced by TAC, determining if T cells from mice with HF utilize selectin and/or integrin/Ig superfamily pathways, to mediate rolling, arrest and transendothelial migration under physiological flow conditions in vitro. The expression and functionality of adhesion molecules and chemokine receptors in T cells from mice with HF will also be characterized by flow cytometry. Aim 2 will characterize the T cell mediated immune response induced by TAC, define the role of T cell subsets during the progression of HF, and their role in cardiomyocyte and cardiac fibroblast function in vitro. TAC studies will be performed in WT and TCR�- mice and different T cell subsets will be adoptively transferred into TCR�- recipient mice undergoing TAC. LV function will be determined by echocardiography and hemodynamic studies, fibrosis by picosirious red staining, and flow cytometry, qPCR, western blot and Immunohistochemistry approaches will be used to determine the effect of T cell subsets and their cytokines in cardiac myocyte and fibroblast function. Similar approaches will be used in Aim 3 to translate our findings in Aims 1 and 2 to human biology by exploring the mechanisms regulating human T cell recruitment in HF. Completion of these aims will result in a deeper understanding of how best to regulate T cell mediated inflammation to improve the structural, functional and molecular deficits of the failing heart, and will identify alternative therapeutic approaches to treat HF based on our basic understanding of novel mechanisms that control the timing, type and progression of the T cell immune response in pathological remodeling of the heart.

描述(申请人提供)：心力衰竭(HF)是一种进行性综合征，影响着全球近2000万人，通常是由心脏重塑引起的，以应对病理性压力。越来越多的证据表明，全身炎症与左心功能不全和心力衰竭有关，但所观察到的全身炎症的机制在很大程度上尚不清楚。我们使用胸主动脉缩窄(TAC)的初步数据表明，随着左心功能的恶化，T细胞被招募到心脏，心脏血管内皮细胞被局部激活。有趣的是，我们发现，在体外生理流动条件下，接受心衰治疗的小鼠的T细胞与激活的小鼠心脏内皮细胞相互作用的数量显著高于来自对照小鼠的T细胞。值得注意的是，在我们的初步研究中，T细胞缺陷小鼠(TCR�-)显示出延长存活率、保存左心功能和减少纤维化。基于这些数据，在这份提案中，我们将测试 中心假设T细胞介导的免疫反应影响压力超负荷所致心力衰竭的心脏重构。我们提出了三个特定的目标来验证这一假说，在这三个目标中，我们将获得关于在心力衰竭过程中调节小鼠和人类T细胞在心脏中募集的机制、涉及的T细胞亚群以及它们在调控心力衰竭心脏重构机制中的影响的新信息。在目标1中，我们将利用视频显微镜研究在TAC诱导的心衰过程中小鼠T细胞与心脏内皮细胞之间的黏附机制，以确定来自心衰小鼠的T细胞是否利用选择素和/或整合素/Ig超家族通路，在体外生理流动条件下介导滚动、阻止和跨内皮细胞迁移。此外，还将通过流式细胞术对心衰小鼠T细胞中黏附分子和趋化因子受体的表达和功能进行研究。目的2研究TAC诱导的T细胞免疫应答，明确T细胞亚群在心力衰竭发病过程中的作用，以及它们在体外心肌细胞和心肌成纤维细胞功能中的作用。交通谘询委员会将会进行研究 在WT和TCR�小鼠中，不同的T细胞亚群将被过继地转移到TCR�受体小鼠中进行TAC。超声心动图和血流动力学检测左心功能，微红染色检测心肌纤维化，流式细胞术、定量聚合酶链式反应、免疫印迹和免疫组织化学方法检测T细胞亚群及其细胞因子对心肌细胞和成纤维细胞功能的影响。类似的方法将在AIM 3中使用，通过探索调节人T细胞在HF中招募的机制，将我们在AIMS 1和2中的发现转化为人类生物学。这些目标的完成将使我们更深入地了解如何最好地调节T细胞介导的炎症，以改善衰竭心脏的结构、功能和分子缺陷，并将根据我们对心脏病理重塑中控制T细胞免疫反应的时间、类型和进展的新机制的基本理解，找到治疗心衰的替代治疗方法。