Protection of the Heart by PD-1 and PD-L1

PD-1 和 PD-L1 保护心脏

基本信息

批准号：
8612207
负责人：
ANDREW H LICHTMAN
金额：
$ 44.26万
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：
2014
资助国家：
美国
起止时间：
2014-02-17 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8612207
关键词：
Address Affect Antigens Attention Autoantigens Autoimmune Process CD28 gene CD4 Positive T Lymphocytes CD8B1 gene Cardiac Cardiomyopathies Cell surface Cells Chronic Clinical Clinical Research Cytoprotection Data Dendritic Cells Development Dilated Cardiomyopathy Disease Endothelial Cells Ensure Family Fibrosis Gene Expression Goals Graft Rejection Heart Heart Diseases Heart Transplantation Heart failure Immune Immune response Immunotherapy Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Knowledge Ligands Lymphocyte Malignant Neoplasms Mediating Methods Modality Modeling Molecular Mus Muscle Cells Myelogenous Myeloid Cells Myocardial Myocardial Infarction Myocardial Reperfusion Injury Myocarditis Myocardium Pathogenesis Pathway interactions Phenotype Play Predisposition Regulation Regulatory T-Lymphocyte Risk Role Signal Transduction Sirolimus T cell regulation T cell response T-Lymphocyte Testing Therapeutic Time Viral Virus Diseases Work allograft rejection cancer risk cell type cytokine therapy design gene function heart allograft heart function insight macrophage microbial monocyte prevent public health relevance regenerative response therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Myocardial inflammation occurs in in response to ischemic injury, infections, and activation of autoreactive or alloreactive lymphocytes. Myocardial function is impaired by inflammatory mediators, and inflammation contributes to chronic myocardial injury, fibrosis, and heart failure. Innate and adaptive immune responses are tightly regulated in the heart, which serves to prevent maladaptive inflammation. Nonetheless, these mechanisms are poorly understood, and when they fail, inflammatory responses are central to the pathogenesis of myocardial disease. A better understanding of the normal mechanisms that suppress myocardial inflammation is key to the design of therapeutic strategies to limit inflammatory damage in the setting of several cardiac diseases. Extensive preliminary work has demonstrated that the molecules PD-1 and its ligand PD-L1 are important regulators of adaptive immune responses to microbial, alloreactive and self- antigens. In particular, the PD 1/PD L1 pathway appears to be a central negative regulatory checkpoint in controlling immune responses in the heart. However, because of the complexities of the cellular expression of PD-1 and PD-L1, it is still unclear how the pathway is actually engaged to suppress myocardial inflammation. The broad objectives of this project are to discover how cardiac inflammation is regulated by endothelial, myocyte, and dendritic cell PD-L1, and by myeloid PD-1. The work will take advantage of newly developed mouse lines with lineage specific deficiencies of PD-L1 and PD-1, which will be used in the context of models of innate and adaptive immune mediated myocardial inflammation. These approaches will be organized into the following three Specific Aims: Aim 1. Determine which cell types mediate PD-L1-dependent protection against T cells in the heart, the mechanisms of protection, and the feasibility of therapeutically engaging these mechanisms. Aim 2. Test the hypothesis that the PD-1-PD-L1 pathway directly regulates myeloid cell inflammatory responses in the heart. Aim 3. Develop PD-1:PD-L1 dependent methods to therapeutically induced T cell tolerance to myocardial antigens The data generated by the completion of these Aims will define for the first time the regulation of cardiac inflammation by endothelial, myocyte, and DC PD-L1, and by myeloid PD-1. The findings will be important for development of therapeutic modalities to treat myocardial inflammation and for an understanding of the risks of therapeutic approaches to block PD-1 and PD-L1, which are actively being developed in cancer and chronic viral infection.

描述（由申请人提供）：心肌炎症发生在响应缺血性损伤，感染和自动反应性或同种异体淋巴细胞的激活中。心肌功能受到炎症介质的损害，炎症会导致慢性心肌损伤，纤维化和心力衰竭。先天和适应性免疫反应在心脏中受到严格调节，这有助于防止适应不良的炎症。尽管如此，这些机制知之甚少，当它们失败时，炎症反应对于心肌疾病的发病机理至关重要。更好地理解抑制心肌炎症的正常机制是设计治疗策略以限制在几种心脏病的情况下限制炎症损害的关键。广泛的初步工作表明，分子PD-1及其配体PD-L1是对微生物，同种异体反应性和自我抗原的适应性免疫反应的重要调节剂。特别是，PD 1/PD L1途径似乎是控制心脏免疫反应的中心负调节检查点。但是，由于PD-1和PD-L1的细胞表达的复杂性，目前尚不清楚该途径实际上是如何接合以抑制心肌炎症的。该项目的广泛目的是发现心脏炎症如何受到内皮，肌细胞和树突状细胞PD-L1的调节，以及髓样PD-1。这项工作将利用新开发的小鼠线，具有PD-L1和PD-1的谱系特异性缺陷，这些缺陷将用于先天和适应性免疫介导的心肌炎症模型的背景下。这些方法将被组织到以下三个特定目的中：目标1。确定哪些细胞类型介导了针对心脏中T细胞的PD-L1依赖性保护，保护机制以及治疗性参与这些机制的可行性。 AIM 2。检验PD-1-PD-L1途径直接调节心脏中髓样细胞炎症反应的假设。 AIM 3。开发PD-1：PD-L1依赖性方法，以治疗诱导的T细胞耐受性对心肌抗原的耐受性，通过这些目标完成产生的数据将首次定义通过内皮，心肌细胞和DC PD-L1和DC-L1和Myeloid PD-1来调节心脏炎症。这些发现对于开发治疗心肌炎症的治疗方式和理解阻断PD-1和PD-L1的治疗方法的风险将很重要，这些方法在癌症和慢性病毒感染中积极发展。