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:
- 金额:$ 54.26万
- 依托单位:
- 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:
- 关键词:Acute Respiratory Distress SyndromeAffectAlveolarAlveolar MacrophagesAnti-Inflammatory AgentsAntigensBilateralBindingBiologicalBiological MarkersBronchoscopyCell membraneCell physiologyCell surfaceCellsCentrifugationCessation of lifeClinicalClinical TrialsCluster AnalysisComplicationCritical IllnessCytometryDataDefectEnrollmentFrightFunctional disorderHeterogeneityHypoxemiaIL17 geneIL8 geneImmuneImmune checkpoint inhibitorImmune responseImmunosuppressionImpairmentInfiltrationInflammationInflammatoryInjuryIntensive Care UnitsInterferon Type IIInterleukin-6KnowledgeLeadLeukocytesLigandsLinkLiquid substanceLungMacrophageMeasurementMeasuresMechanical ventilationMediatingMedicalMedical centerModelingMolecularMorbidity - disease rateMusNatureOperative Surgical ProceduresOutcomePathogenicityPathway interactionsPatientsPharmacologic SubstancePhenotypePlasmaPlayProductionProliferatingProteinsProteomicsPulmonary InflammationRNA SplicingReceptor SignalingRegulatory T-LymphocyteResolutionRespiratory FailureRiskRisk FactorsRoleSepsisSeveritiesSeverity of illnessSignal TransductionStainsStudy SubjectSubgroupSurfaceSyndromeT cell regulationT cell responseT-Cell ProliferationT-Cell ReceptorT-LymphocyteT-Lymphocyte SubsetsThoracic RadiographyTissuesTraumaUnited StatesValidationVariantVentilatorcirculating biomarkerscohortcostcytokinedifferential expressiondisabilityexperiencehigh dimensionalityhigh riskimmune checkpointimmune functionimmunoregulationinhibitorlung injurymicrovesiclesmonocytemortalitymortality risknovelparticipant enrollmentpatient subsetsperipheral bloodpersonalized approachprognosticationprogrammed cell death ligand 1programmed cell death protein 1protein expressionreceptorrecruitresponseside effecttissue injuryventilationvesicular 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.
项目摘要/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。
在美国,每年有7.4万人死于重症监护病房。患者通常表现为进展迅速
需要长时间机械通气的呼吸衰竭,成本高昂,且与长期相关
残疾。对ARDS的病理生理机制有更深入的了解可能会指导更多
个人化的预测和治疗方法。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)。这个
PD-L1与PD-1的结合导致T细胞受体信号的负调控。PD-1和PD-L1已经
与脓毒症患者的免疫功能缺陷有关,这是ARDS的主要危险因素。为
例如,脓毒症患者循环T细胞上PD-1的高表达与T细胞减少有关
干扰素-伽马的产生。然而,其他研究表明,这一途径在限制组织方面发挥了作用。
发炎。该提案中的初步数据显示,患有ARDS的患者机械活动时间延长
机械通气组肺泡巨噬细胞上PD-L1表达降低。此外,一个严重的副作用是
这一途径的药物抑制物称为“检查点抑制物”,是免疫介导的组织损伤。
一种类似ARDS的肺炎。因此,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细胞反应来抑制这种联系。
研究对象将被登记到发现队列中,在那里将使用新颖的HIGH进行测量
用多维质量细胞术在单细胞基础上鉴定这些蛋白质的表达。一个有效的队列
将从外部招聘以证实这些调查结果。目标1将确定细胞表面免疫检查点
蛋白表达与ARDS的严重程度相关,AIM 2将重点介绍
在调节T细胞反应中的关联,目标3将确定这一途径的潜在可溶措施。
这项研究的目的是确定长期机械性疾病风险患者的生物相关免疫特征。
通风和ARDS死亡。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Carmen R Mikacenic其他文献
Carmen R Mikacenic的其他文献
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{{ truncateString('Carmen R Mikacenic', 18)}}的其他基金
Systems Immunology profiling of respiratory viral infections in vulnerable populations
易感人群呼吸道病毒感染的系统免疫学分析
- 批准号:
10420949 - 财政年份:2022
- 资助金额:
$ 54.26万 - 项目类别:
Systems Immunology profiling of respiratory viral infections in vulnerable populations
易感人群呼吸道病毒感染的系统免疫学分析
- 批准号:
10598132 - 财政年份:2022
- 资助金额:
$ 54.26万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 54.26万 - 项目类别:
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:
10434143 - 财政年份:2020
- 资助金额:
$ 54.26万 - 项目类别:
Influence of TLR1 Polymorphisms on T-Regulatory Cells in ARDS
TLR1 多态性对 ARDS 调节性 T 细胞的影响
- 批准号:
8865672 - 财政年份:2014
- 资助金额:
$ 54.26万 - 项目类别:
Influence of TLR1 Polymorphisms on T-Regulatory Cells in ARDS
TLR1 多态性对 ARDS 调节性 T 细胞的影响
- 批准号:
8616243 - 财政年份:2014
- 资助金额:
$ 54.26万 - 项目类别:
Influence of TLR1 Polymorphisms on T-Regulatory Cells in ARDS
TLR1 多态性对 ARDS 调节性 T 细胞的影响
- 批准号:
9271218 - 财政年份:2014
- 资助金额:
$ 54.26万 - 项目类别:
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