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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：
10655533
负责人：
Carmen R Mikacenic
金额：
$ 54.26万
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/10655533
关键词：
Acute 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 IL17 gene IL8 gene Immune Immune checkpoint inhibitor Immune response Immunosuppression Impairment Infiltration Inflammation Inflammatory Injury Intensive Care Units Interferon Type II Interleukin-6 Knowledge Lead Leukocytes Ligands Link Liquid substance Lung Macrophage 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 Proliferating 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 lung injury microvesicles monocyte mortality mortality risk novel participant enrollment patient subsets peripheral blood personalized approach prognostication programmed cell death ligand 1 programmed cell death protein 1 protein expression receptor recruit response side effect tissue injury ventilation vesicular release

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.

项目总结/文摘