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

基本信息

批准号：
8750156
负责人：
Maria Pilar Alcaide Alonso
金额：
$ 41.25万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/8750156
关键词：
Adhesions Affect Anti-Inflammatory Agents Anti-inflammatory Biological Assay Blood Blood Vessels CD4 Positive T Lymphocytes Cardiac Cardiac Myocytes Cardiovascular system Cell Adhesion Molecules Cell Communication Cessation of life Chest Chronic Clinical Trials 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 Lymphoid Mediating Modeling Molecular Mus Organ Pathway interactions Patients Peripheral Pharmaceutical Preparations Physiological Physiology Pilot Projects Play Process Recruitment Activity Regulation Regulatory T-Lymphocyte Research Role Sampling Selectins Source Staging Staining method Stains Stress Syndrome System T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Time Translating Vascular Endothelial Cell Vascular Endothelium Ventricular Video Microscopy Western Blotting Work base cell mediated immune response chemokine receptor constriction cytokine hemodynamics immune activation improved in vivo innovation migration mortality new therapeutic target novel outcome forecast pressure prevent public health relevance reconstitution response ventricular assist device

项目摘要

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（由适用提供）：心力衰竭（HF）是一种渐进综合征，影响了全世界近2000万人，通常是由于对病理压力的响应而对心脏进行重塑引起的。新兴证据将全身感染与左心室（LV）功能障碍和HF相关，但是观察到的全身感染的机制在很大程度上是意外的。我们使用胸腔主动脉收缩（TAC）的初步数据（TAC）是一种明确的HF模型，表明T细胞被募集到心脏，随着LV功能恶化，局部激活了心脏血管座室。有趣的是，我们发现，经历HF的小鼠的T细胞与在体外物理流条件下与对照小鼠的T细胞的活化小鼠心脏森林细胞相互作用。值得注意的是，在我们的初步研究中，T细胞缺乏小鼠（TCR¿-/ - ）显示出生存期的增加，保留的LV功能以及改善的纤维化。基于这些数据，在此提案中，我们将测试中心假设，即T细胞介导的免疫复杂会影响压力超负荷引起的HF的心脏重塑。我们提出了3个特定旨在检验这一假设的特定旨在，其中我们将在HF过程中获得有关调节小鼠和人类T细胞在心脏中募集的机制，涉及的T细胞子群的机制，以及它们在调节HF中心脏重塑的机制中的影响。在目标1中，我们将使用视频显微镜研究在TAC诱导的HF进展过程中调节小鼠T细胞与心脏内皮细胞之间的相互作用，从而确定HF的小鼠的T细胞是否利用Selectin和/或Inteplin/intectin/intectin/Ig超级家族途径，以介导滚动，停滞，降压，降级，降低了滚动，降低物理迁移，并迁移了范围。来自HF小鼠的T细胞中粘合分子和趋化因子受体的表达和功能也将以流式细胞仪为特征。 AIM 2将表征由TAC诱导的T细胞介导的免疫调节，定义T细胞亚群在HF进展过程中的作用，以及它们在体外的心肌细胞和心脏成纤维细胞功能中的作用。将进行TAC研究在wt和tcr¿-/ - 小鼠和不同的T细胞子集中，将适当地转移到TCR知识中 - / - 接受者小鼠进行TAC。 LV功能将通过超声心动图和血液动力学研究，果皮红色染色以及流式细胞仪，QPCR，Western blot和免疫组织化学方法来确定，以确定T细胞子群及其细胞因子在心脏肌细胞和成纤维细胞功能中的作用。 AIM 3将使用类似的方法将我们的发现在AIM 1和2中转化为人类生物学，通过探索调节HF中人类T细胞募集的机制。这些目标的完成将使人们更深入地了解如何最好地调节T细胞介导的感染，以改善失败心脏的结构，功能和分子定义，并将确定基于我们对控制T细胞免疫反应的新型机制的基本理解，以控制HF的替代治疗方法来治疗HF。