Immune Checkpoints in Acute Respiratory Distress Syndrome (IC-ARDS)

急性呼吸窘迫综合征 (IC-ARDS) 中的免疫检查点

基本信息

批准号：
10254220
负责人：
Carmen R Mikacenic
金额：
$ 71.08万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-05 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10254220
关键词：
Adult Respiratory Distress Syndrome Affect Alveolar Alveolar Macrophages Anti-Inflammatory Agents Antigens Bilateral Binding Biological Biological Markers Bronchoscopy Cell membrane Cell physiology Cell surface Cells Centrifugation Cessation of life Clinical Clinical Trials Cluster Analysis Complication Critical Illness Cytometry Data Defect Enrollment Fright Functional disorder Heterogeneity Hypoxemia IL8 gene Immune Immune checkpoint inhibitor Immune response Immunosuppression Impairment Inflammation Inflammatory Injury Intensive Care Units Interferon Type II Interleukin-17 Interleukin-6 Knowledge Lead Leukocytes Ligands Link Liquid substance Lung Measurement Measures Mechanical ventilation Mediating Medical Medical center Modeling Molecular Morbidity - disease rate Mus Nature Operative Surgical Procedures Outcome Pathogenicity Pathway interactions Patients Pharmacologic Substance Phenotype Plasma Play Production Proteins Proteomics Pulmonary Inflammation RNA Splicing Receptor Signaling Regulatory T-Lymphocyte Resolution Respiratory Failure Risk Risk Factors Role Sepsis Severities Severity of illness Signal Transduction Stains Study Subject Subgroup Surface Syndrome T cell regulation T cell response T-Cell Proliferation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Thoracic Radiography Tissues Trauma United States Validation Variant Ventilator circulating biomarkers cohort cost cytokine differential expression disability experience high dimensionality high risk immune checkpoint immune function immunoregulation inhibitor/antagonist lung injury macrophage microvesicles monocyte mortality mortality risk novel patient subsets peripheral blood personalized approach prognostic programmed cell death ligand 1 programmed cell death protein 1 protein expression receptor recruit response side effect tissue injury ventilation

项目摘要

PROJECT SUMMARY/ABSTRACT Acute respiratory distress syndrome (ARDS) is an important cause of morbidity and mortality resulting in over 74,000 intensive care unit deaths per year in the United States. Patients often present with rapidly progressive respiratory failure requiring prolonged mechanical ventilation which is costly and associated with long term disability. A more refined understanding of the pathophysiologic mechanisms of ARDS may guide more personalized approaches for prognostication and therapy. The immune “checkpoint” pathway includes the receptor Programmed cell death protein 1 (PD-1) and its ligand Programmed death-ligand 1 (PD-L1). The binding of PD-L1 to PD-1 leads to negative regulation of T cell receptor signaling. PD-1 and PD-L1 have been associated with defects in immune function in patients with sepsis which is a major risk factor for ARDS. For example, high PD-1 expression on circulating T cells in patients with sepsis is associated with decreased T cell interferon-gamma production. However, other studies suggest a role for this pathway in limiting tissue inflammation. Preliminary data in this proposal shows that patients with ARDS who have prolonged mechanical ventilation have lower expression of PD-L1 on alveolar macrophages. Further, a serious side effect of pharmaceutical inhibitors of this pathway termed “checkpoint inhibitors” is immune mediated tissue injury such as an ARDS-like pneumonitis. Thus the role of this pathway in modulating immune responses may be critical to our understanding of ARDS. The hypothesis of this study is that immune checkpoint proteins are protective against poor outcomes in ARDS by limiting tissue injury. This study will also investigate potential mechanisms of this association through promotion of regulatory T cell responses or limiting inflammatory T cell responses. Study subjects will be enrolled into a discovery cohort where measurements will be performed using novel high dimensional mass cytometry to identify expression of these proteins on a single cell basis. A validation cohort will be recruited externally to confirm these findings. Aim 1 will identify whether cell surface immune checkpoint protein expression is associated with severity of ARDS, Aim 2 will focus on mechanisms behind the association in modulating T cell responses, and Aim 3 will identify potential soluble measures of this pathway. This study aims to identify a biologically relevant immune signature of patients at risk for prolonged mechanical ventilation and death from ARDS.

项目概要/摘要急性呼吸窘迫综合征（ARDS）是导致发病率和死亡率的重要原因美国每年有 74,000 名重症监护病房患者死亡，且病情进展迅速。呼吸衰竭需要长时间机械通气，成本高昂且与长期相关对 ARDS 病理生理机制的更深入的了解可能会指导更多的工作。免疫“检查点”途径包括个性化的预后和治疗方法。受体程序性细胞死亡蛋白 1 (PD-1) 及其配体程序性死亡配体 1 (PD-L1)。 PD-L1 与 PD-1 的结合导致 T 细胞受体信号传导的负调节。脓毒症患者的免疫功能缺陷与ARDS的主要危险因素有关。例如，脓毒症患者循环 T 细胞上 PD-1 的高表达与 T 细胞减少相关然而，其他研究表明该途径在限制组织中发挥作用。该提案的初步数据显示，患有长期机械性炎症的 ARDS 患者。通气会降低肺泡巨噬细胞上PD-L1的表达，此外还有严重的副作用。该途径的药物抑制剂称为“检查点抑制剂”，是免疫介导的组织损伤，例如因此，该途径在调节免疫反应中的作用可能对于 ARDS 样肺炎至关重要。我们对 ARDS 的理解是，这项研究的假设是免疫检查点蛋白具有保护作用。通过限制组织损伤来对抗 ARDS 的不良后果这项研究还将调查潜在的机制。通过促进调节性 T 细胞反应或限制炎症性 T 细胞反应来增强这种关联。研究对象将被纳入一个发现队列，其中将使用新型高多维质谱流式细胞仪在单细胞基础上鉴定这些蛋白质的表达。将外部招募来确认这些发现，目标 1 将确定细胞表面免疫检查点是否存在。蛋白质表达与 ARDS 的严重程度相关，目标 2 将重点关注其背后的机制调节 T 细胞反应中的关联，目标 3 将确定该途径的潜在可溶性措施。本研究旨在确定存在长期机械损伤风险的患者的生物学相关免疫特征。通气和 ARDS 导致的死亡。