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：
Scott M Palmer
金额：
$ 46.32万
依托单位：
DUKE UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/8073307
关键词：
Adverse effects Affect Antigens Autoantigens Autoimmune Diseases Autoimmunity Bioinformatics Biological Assay Biological Markers Blood Blood specimen Bronchiolitis Obliterans Cells Chronic Clinical Collagen Type V Collection Commit Computing Methodologies Delayed Hypersensitivity Development Diagnosis Diagnostic Disease Disease Outcome Effectiveness Effector Cell Fibrosis Flow Cytometry Future General Population Goals Graft Rejection Human Immune Immune response Immune system Immunologic Monitoring Immunosuppression Immunosuppressive Agents Incidence Individual Instruction Intervention Liquid substance Lung Lung Inflammation Lung Transplantation Lung diseases Measures Mediating Memory Modeling National Heart, Lung, and Blood Institute Obstruction Outcome Pathogenesis Pathway interactions Patients Pneumonia Population Principal Investigator Production Pulmonology Qualifying Regulatory T-Lymphocyte Research Research Personnel Risk Site Spirometry Statistical Methods Stratification Syndrome T memory cell T-Lymphocyte Testing Therapeutic Intervention Time Toxic effect Transplant Recipients Transplantation Validation alemtuzumab base cytokine design effective intervention experience high risk improved innovation lung injury meetings novel novel diagnostics patient population peripheral blood pre-clinical prevent programs response statistics symposium tool

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）：纤维化肺部疾病是越来越重要的肺部疾病，普通人群发生率上升。我们的应用集中于支气管炎闭塞性综合征（BOS），这是一种在人类肺移植后发生的纤维化疾病，是肺移植受者长期生存不良的主要原因。令人信服的证据表明，涉及调节性T细胞（TREG），效应子/记忆T细胞和自身免疫的免疫失调发生在BOS中。通常在免疫系统中隐藏的Col-V可能在肺损伤或炎症的情况下暴露并成为免疫系统靶标。由于免疫失调和自身免疫性在BOS发病机理中的重要性，要测试的主要假设是Treg或T效应子/记忆群的改变和/或其对Col-V的多功能细胞因子对COL-V的多功能细胞因子反应预测BOS的发展。我们将利用杜克大学的大量临床移植人群，前瞻性地获得和以前的PB样本，以及经验丰富的多学科研究人员的专业知识。我们将通过使用多色流式细胞术来测量外周血（AIM 1）及其Col-V抗原特异性反应（AIM 2）并应用创新统计和生物信息信息来鉴定BOS的精确细胞预测因子（AIM 3）。我们的生物信息学方法旨在使用多变量混合物建模来鉴定新型候选免疫生物标志物，并使用判别性信息测量指标促进将其应用于临床诊断，从而定义了确定预测性细胞子集所需的最小标记组。在Cadet-2中，我们将使用这些方法来识别BOS高风险的个体，并测试特定的临床干预措施（例如免疫抑制的强化）将延迟或阻止其发作。由于免疫失调似乎是许多慢性纤维化肺部疾病的中心主题，因此长期发育目标是使用通过这些通过这些肺移植中的概念证明研究确立的临床，技术和生物信息学专业知识，以在肺部医学中为临床诊断的临床诊断带来晚期免疫特征。相关性（请参阅说明）：尽管肺移植受益于许多患有晚期肺部疾病的患者，但肺移植后的长期结局受到进行性AINWAY纤维化的限制，称为细支气管炎细支气管炎。我们的研究将确定血液中的新型免疫生物标志物，可以鉴定出这种情况高风险的患者，从而允许早期，更有效的干预措施，以改善长期移植结局