Resolution of inflammation after cardiac arrest

心脏骤停后炎症的消退

• 批准号: 10566655
• 负责人: Edy Yong Kim
• 金额: $ 84.41万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566655
• 关键词: Address; Agonist; Anti-Inflammatory Agents; Bioinformatics; Brain; Brain Injuries; Cardiac; Cardiopulmonary Resuscitation; Cause of Death; Cells; Chest; Circulation; Clinical; Collaborations; Critical Care; Cryopreservation; Data; Enrollment; Goals; Heart; Heart Arrest; Hospitalization; Immune; Immune Targeting; Immune response; Immune system; Immunology; Immunophenotyping; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Interferon Type II; Interleukin-10; Intervention; Mediating; Methods; Monoclonal Antibodies; Mus; Natural Killer Cells; Nervous System Trauma; Neurologic; Neurological outcome; Outcome; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Production; Reaction; Recombinants; Resolution; Resources; Resuscitation; Sepsis; Site; Testing; Therapeutic; Therapeutic Intervention; Time; Validation; biobank; checkpoint receptors; clinically relevant; cohort; cytokine; immune checkpoint; immune function; immunoregulation; improved; monocyte; mortality; mouse model; multidisciplinary; nectin; novel therapeutic intervention; out-of-hospital cardiac arrest; prevent; prospective; response; single-cell RNA sequencing; systemic inflammatory response; therapeutic candidate; therapeutic target

Abstract Out of hospital cardiac arrest (OHCA) produces an early systemic inflammatory response associated with significant neurological injury and mortality. Unlike sepsis, OHCA offers an opportunity to intervene at the earliest stages of the immune response. However, the immunology of cardiac arrest is understudied. To address this, we started the multi-center Immunology of Cardiac Arrest Network (I-CAN), a collaboration applying single-cell approaches to a unique biobank of cryopreserved, viable peripheral blood mononuclear cells (PBMC) from OHCA patients. Our premise is that cardiac arrest triggers endogenous, compensatory mechanisms that promote the resolution of inflammation, limit injury and improve survival. Our preliminary studies identified that monocyte and NK cell states expressing immune checkpoints were expanded in patients with poor neurological outcomes. Interactome analysis identified cytokines (IFNγ, IL-10) that mediate cross-talk between Nectin-2+ monocytes and Tim-3+ TIGIT+ NK cells. Subsequent ex vivo studies on PBMC from OHCA patients demonstrated that Nectin-2 is a brake on production of IFNγ by NK cells. IFNγ-deficient mice in experimental cardiac arrest and resuscitation had reduced neurological injury and mortality. These findings suggest our hypothesis that Nectin-2 monocytes are a protective response to ameliorate inflammation and neurological injury after OHCA. Here, we propose to define the mechanisms that resolve inflammation after cardiac arrest. In Aim 1, we perform deep immunophenotyping of OHCA patients at single-cell resolution. In Aim 2, we define the immune checkpoint profile of OHCA and its association with neurological outcomes. We then define the function of immune checkpoints in OHCA, with a focus on Nectin-2+ monocytes. In Aim 3, we test targeting of immune checkpoint receptors as a therapeutic strategy in a mouse model of cardiac arrest and resuscitation. Together, these aims define a new therapeutic approach: augmentation of endogenous, protective mechanisms to reduce inflammation after cardiac arrest. Further, our multi-center and multi- disciplinary team in the Immunology of Cardiac Arrest Network (I-CAN) establishes the resource of a two-site biorepository of clinical cardiac arrest with deep immunophenotyping of the subjects.

摘要 院外心脏骤停（OHCA）会产生早期全身炎症反应， 严重的神经损伤和死亡率。与脓毒症不同，OHCA提供了一个机会， 免疫反应的最早阶段。然而，心脏骤停的免疫学尚未得到充分研究。到 为了解决这个问题，我们启动了多中心心脏骤停免疫学网络（I-CAN）， 将单细胞方法应用于冷冻保存的活外周血单核细胞的独特生物库， 细胞（PBMC）。我们的前提是心脏骤停触发了内源性代偿性 促进炎症消退、限制损伤和提高存活率的机制。我们的初步 研究发现，表达免疫检查点的单核细胞和NK细胞状态在患者中扩增， 神经功能不佳相互作用组分析鉴定了介导串扰的细胞因子（IFNγ，IL-10）。 在Nectin-2+单核细胞和Tim-3+ TIGIT+ NK细胞之间。对来自OHCA的PBMC的后续离体研究 患者证实Nectin-2是NK细胞产生IFNγ的制动器。IFNγ缺陷小鼠 实验性心脏骤停和复苏降低了神经损伤和死亡率。这些发现 提示我们假设Nectin-2单核细胞是改善炎症的保护性反应， OHCA后的神经损伤在这里，我们建议定义炎症后解决炎症的机制， 心脏骤停在目标1中，我们以单细胞分辨率对OHCA患者进行深度免疫表型分析。在 目的2，我们定义了OHCA的免疫检查点特征及其与神经系统结局的相关性。我们 然后定义免疫检查点在OHCA中的功能，重点是Nectin-2+单核细胞。在目标3中，我们 在心脏骤停的小鼠模型中测试免疫检查点受体作为治疗策略的靶向， 复苏术总之，这些目标定义了一种新的治疗方法：增强内源性， 保护机制，以减少心脏骤停后的炎症。此外，我们的多中心和多- 心脏骤停免疫学网络（I-CAN）的一个学科小组建立了一个两个站点的资源， 临床心脏骤停的生物储存与受试者的深层免疫表型。