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

描述（由申请人提供）：心肌炎症发生于对缺血性损伤、感染和自身反应性或同种异体反应性淋巴细胞活化的反应。炎症介质可损害心肌功能，炎症可导致慢性心肌损伤、纤维化和心力衰竭。先天性和适应性免疫反应在心脏中受到严格调节，这有助于防止适应性不良的炎症。然而，这些机制尚不清楚，当它们失效时，炎症反应是心肌疾病发病机制的核心。更好地了解抑制心肌炎症的正常机制是设计治疗策略以限制几种心脏病炎症损伤的关键。大量的初步研究表明，PD-1分子及其配体PD-L1是对微生物、同种异体反应和自身抗原的适应性免疫反应的重要调节因子。特别是，PD 1/PD L1通路似乎是控制心脏免疫反应的中心负性调节检查点。然而，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抑制心肌炎症的。这个项目的主要目标是发现心脏炎症是如何被内皮细胞、肌细胞、树突状细胞PD-L1和髓细胞PD-1调节的。这项工作将利用新开发的具有PD-L1和PD-1谱系特异性缺陷的小鼠系，这将用于先天性和适应性免疫介导的心肌炎症模型。这些方法将被组织成以下三个具体目标：确定哪些细胞类型介导pd - l1依赖的心脏对T细胞的保护，保护机制，以及治疗上参与这些机制的可行性。目标2。验证PD-1-PD-L1通路直接调节心脏髓细胞炎症反应的假说。目标3。开发PD-1:PD-L1依赖的方法来治疗诱导T细胞对心肌抗原的耐受性。完成这些目标所产生的数据将首次确定内皮细胞、肌细胞和DC细胞PD-L1以及髓细胞PD-1对心脏炎症的调节。这些发现对于开发治疗心肌炎症的治疗方式以及了解阻断PD-1和PD-L1的治疗方法的风险具有重要意义，PD-1和PD-L1正在癌症和慢性病毒感染中积极发展。

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.