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

• 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
• 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

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.

项目摘要/摘要 急性呼吸窘迫综合征（ARDS）是发病率和死亡率的重要原因，导致过度 美国每年74,000例重症监护病房死亡。患者经常出现迅速进行的 呼吸衰竭需要长时间的机械通气，这是昂贵且与长期相关的 残疾。对ARDS的病理生理机制的更精致的了解可能指导更多 提示和治疗的个性化方法。免疫“检查点”途径包括 受体程序性细胞死亡蛋白1（PD-1）及其配体编程的死亡配体1（PD-L1）。这 PD-L1与PD-1的结合导致T细胞受体信号传导负调控。 PD-1和PD-L1已经 与败血症患者的免疫功能缺陷有关，这是ARDS的主要危险因素。为了 例如，败血症患者的循环T细胞上的高PD-1表达与T细胞降低有关 干扰素 - 伽马生产。但是，其他研究表明该途径在限制组织中的作用 炎。该提案中的初步数据表明，机械延长的ARDS患者 通风在肺泡巨噬细胞上的PD-L1表达较低。此外，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 作为ARDS样肺炎。该途径在调节免疫反应中的作用可能对 我们对ards的理解。这项研究的假设是免疫切解点蛋白受到保护 通过限制组织损伤，反对ARD的不良预后。这项研究还将研究潜在的机制 通过促进调节性T细胞反应或限制炎症T细胞反应的关联。 研究对象将被招募到一个发现队列中，其中将使用新颖的高高进行测量 尺寸质量细胞术以鉴定单个细胞的表达。验证队列 将在外部招募以确认这些发现。 AIM 1将确定细胞表面免疫检查点是否 蛋白质表达与ARDS的严重程度有关，AIM 2将重点放在背后的机制上 调节T细胞反应的关联和AIM 3将确定该途径的潜在固体度量。 这项研究旨在确定具有长时间机械风险的患者的生物学相关免疫特征 ARDS的通风和死亡。