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

项目总结/摘要 急性呼吸窘迫综合征（ARDS）是导致严重急性呼吸窘迫综合征（ARDS）的重要原因之一。 在美国，每年有74，000人在重症监护室死亡。患者通常表现为快速进展的 需要长时间机械通气的呼吸衰竭，这是昂贵的，并且与长期 残疾。对ARDS病理生理机制的更深入了解可能会指导更多的研究。 个性化的治疗方法。免疫“检查点”途径包括： 受体程序性细胞死亡蛋白1（PD-1）及其配体程序性死亡配体1（PD-L1）。的 PD-L1与PD-1的结合导致T细胞受体信号传导的负调节。PD-1和PD-L1已被 与脓毒症患者的免疫功能缺陷相关，脓毒症是ARDS的主要危险因素。为 例如，脓毒症患者循环T细胞上的高PD-1表达与T细胞减少相关。 干扰素-γ的产生。然而，其他研究表明，这一途径在限制组织 炎症该提案的初步数据显示，长期机械通气的ARDS患者 通气组肺泡巨噬细胞PD-L1表达降低。此外，一个严重的副作用， 称为“检查点抑制剂”的该途径的药物抑制剂是免疫介导的组织损伤， 类似于急性呼吸窘迫综合征的肺炎因此，该途径在调节免疫应答中的作用可能是至关重要的， 我们对ARDS的理解这项研究的假设是免疫检查点蛋白具有保护性 通过限制组织损伤来对抗ARDS的不良结局。这项研究还将探讨潜在的机制 通过促进调节性T细胞反应或限制炎症性T细胞反应来抑制这种关联。 研究受试者将入组发现队列，在该队列中，将使用新的高剂量标准进行测量。 三维质谱细胞术以在单细胞基础上鉴定这些蛋白质的表达。验证队列 将从外部招聘人员来证实这些发现。目的1将确定细胞表面是否存在免疫检查点 蛋白表达与ARDS的严重程度相关，Aim 2将关注蛋白表达背后的机制。 Aim 3将确定该途径的潜在可溶性措施。 本研究的目的是确定有长期机械性心脏病风险的患者的生物学相关免疫特征， 通气和死于ARDS。

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.