Novel Cellular Immune Profiles to Predict Lung Disease Outcomes

预测肺部疾病结果的新型细胞免疫特征

基本信息

  • 批准号:
    8073307
  • 负责人:
  • 金额:
    $ 46.32万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-05-01 至 2013-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Fibrotic lung diseases are increasingly important lung conditions, with a rising incidence in the general population. Our application focuses on bronchiolitis obliterans syndrome (BOS), a fibrotic disease that occurs after human lung transplantation and is the primary reason for poor long-term survival among lung transplant recipients. Compelling evidence suggests that immune dysregulation involving regulatory T cells (Tregs), effector/memory T cells, and autoimmunity to type V collagen (Col-V) occurs in BOS. Normally hidden from the immune system, Col-V may be exposed in the setting of lung injury or inflammation and become an immune system target. Because ofthe importance of immune dysregulation and autoimmunity in the pathogenesis of BOS, the primary hypothesis to be tested is that alterations in Treg or T effector/memory populations and/or their polyfunctional cytokine response to Col-V predict the development of BOS. We will leverage the large clinical transplant population at Duke, prospectively obtained and previously banked PB samples, and the expertise of a highly experienced multi-disciplinary team of investigators. We will test this hypothesis through complementary aims that use polychromatic flow cytometry to measure T subsets in the peripheral blood (Aim 1) and their Col-V antigen specific responses (Aim 2) and apply innovative statistics and bioinformatics to identify precise cellular predictors of BOS (Aim 3). Our bioinformatics approach is designed to identify novel candidate immune biomarkers using multivariate mixture modeling and to facilitate application into clinical diagnostics using discriminative information measures that define the minimal group of markers necessary to identify predictive cellular subsets. In CADET-2, we will use these approaches to identify individual at high risk for BOS and test the idea that specific clinical interventions, such as intensification of immunosuppression, will delay or prevent its onset. As immune dysregulation appears a central theme across many chronic fibrotic lung diseases, a long-term development goal is to use the clinical, technical and bioinformatics expertise established through these proof-of-concept studies in lung transplant to bring advanced immune profiling to the forefront of clinical diagnostics in pulmonary medicine. RELEVANCE (See instructions): Although lung transplantation benefits many patients with advanced lung disease, long-term outcomes after lung transplantation are limited by progressive ainway fibrosis called bronchiolitis obliterans. Our research will identify novel immune biomarkers in the blood that can identify patients at high risk for this condition, thereby allowing for early and more effective interventions that will improve long-term transplant outcomes
描述(由申请人提供):纤维化肺病是越来越重要的肺部疾病,在普通人群中的发病率不断上升。我们的应用重点关注闭塞性细支气管炎综合征 (BOS),这是一种人类肺移植后发生的纤维化疾病,也是肺移植受者长期生存不佳的主要原因。令人信服的证据表明,BOS 中发生了涉及调节性 T 细胞 (Treg)、效应/记忆 T 细胞和 V 型胶原 (Col-V) 自身免疫的免疫失调。 Col-V 通常对免疫系统隐藏,但在肺损伤或炎症的情况下可能会暴露并成为免疫系统的目标。由于免疫失调和自身免疫在 BOS 发病机制中的重要性,要测试的主要假设是 Treg 或 T 效应器/记忆群体的改变和/或其对 Col-V 的多功能细胞因子反应可预测 BOS 的发展。我们将利用杜克大学庞大的临床移植群体、前瞻性获得的和之前储存的 PB 样本,以及经验丰富的多学科研究团队的专业知识。我们将通过互补的目标来检验这一假设,即使用多色流式细胞术测量外周血中的 T 亚群(目标 1)及其 Col-V 抗原特异性反应(目标 2),并应用创新的统计学和生物信息学来识别 BOS 的精确细胞预测因子(目标 3)。我们的生物信息学方法旨在使用多变量混合模型来识别新型候选免疫生物标志物,并使用判别性信息测量来促进临床诊断的应用,这些判别性信息测量定义了识别预测细胞亚群所需的最小标志物组。在 CADET-2 中,我们将使用这些方法来识别 BOS 高风险个体,并测试特定的临床干预措施(例如强化免疫抑制)将延迟或预防其发作的想法。由于免疫失调似乎是许多慢性纤维化肺病的中心主题,长期发展目标是利用通过肺移植概念验证研究建立的临床、技术和生物信息学专业知识,将先进的免疫分析带到肺医学临床诊断的最前沿。相关性(参见说明):虽然肺移植使许多患有晚期肺病的患者受益,但肺移植后的长期结果受到称为闭塞性细支气管炎的进行性纤维化的限制。我们的研究将识别血液中的新型免疫生物标志物,这些标志物可以识别患有这种疾病的高风险患者,从而可以进行早期和更有效的干预措施,从而改善长期移植结果

项目成果

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Scott M Palmer其他文献

Scott M Palmer的其他文献

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{{ truncateString('Scott M Palmer', 18)}}的其他基金

Proof of concept treatment interventions in a rodent model of the rare disease bronchiolitis obliterans
在罕见疾病闭塞性细支气管炎的啮齿动物模型中进行概念治疗干预的验证
  • 批准号:
    10040120
  • 财政年份:
    2020
  • 资助金额:
    $ 46.32万
  • 项目类别:
Proof of concept treatment interventions in a rodent model of the rare disease bronchiolitis obliterans
在罕见疾病闭塞性细支气管炎的啮齿动物模型中进行概念治疗干预的验证
  • 批准号:
    10206315
  • 财政年份:
    2020
  • 资助金额:
    $ 46.32万
  • 项目类别:
Improving Lung Transplant Outcomes with Coping Skills and Physical Activity
通过应对技巧和体力活动改善肺移植结果
  • 批准号:
    10579871
  • 财政年份:
    2019
  • 资助金额:
    $ 46.32万
  • 项目类别:
The Lung Transplant Clinical Trials Network (LT-CTN)
肺移植临床试验网络 (LT-CTN)
  • 批准号:
    8771920
  • 财政年份:
    2014
  • 资助金额:
    $ 46.32万
  • 项目类别:
The Lung Transplant Clinical Trials Network (LT-CTN)
肺移植临床试验网络 (LT-CTN)
  • 批准号:
    9100633
  • 财政年份:
    2014
  • 资助金额:
    $ 46.32万
  • 项目类别:
The Lung Transplant Clinical Trials Network (LT-CTN)
肺移植临床试验网络 (LT-CTN)
  • 批准号:
    8880119
  • 财政年份:
    2014
  • 资助金额:
    $ 46.32万
  • 项目类别:
Lung Repair and Regeneration Consortium Administrative Coordinating Center
肺修复与再生联盟行政协调中心
  • 批准号:
    8403667
  • 财政年份:
    2012
  • 资助金额:
    $ 46.32万
  • 项目类别:
Lung Repair and Regeneration Consortium Administrative Coordinating Center
肺修复与再生联盟行政协调中心
  • 批准号:
    8788546
  • 财政年份:
    2012
  • 资助金额:
    $ 46.32万
  • 项目类别:
Lung Repair and Regeneration Consortium Administrative Coordinating Center
肺修复与再生联盟行政协调中心
  • 批准号:
    8223487
  • 财政年份:
    2012
  • 资助金额:
    $ 46.32万
  • 项目类别:
Lung Repair and Regeneration Consortium Administrative Coordinating Center
肺修复与再生联盟行政协调中心
  • 批准号:
    8616781
  • 财政年份:
    2012
  • 资助金额:
    $ 46.32万
  • 项目类别:

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