Foxp3+ Treg Cells & Primary Graft Dysfunction in Clinical Lung Tx Recipients

Foxp3 Treg 细胞

• 批准号: 8338293
• 负责人: Wayne William Hancock
• 金额: $ 45.62万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338293
• 关键词: Acute Lung Injury; Adult; Affect; Ancillary Study; Asses; Autoimmunity; Biological; Biological Assay; Biology; Blood specimen; Cell Therapy; Cell physiology; Cells; Characteristics; Clinical; Clinical Research; Cohort Studies; Defect; Depressed mood; Development; Diffuse; End stage renal failure; Epigenetic Process; Epithelial; Experimental Models; Functional disorder; Funding; Graft Survival; Heart; Hypoxemia; Immune response; Immune system; Immunology; Implant; Incidence; Indiana; Inflammation; Injury; Knowledge; Lead; Liver; Lung; Lung Transplantation; Lung diseases; Lymphocyte; Methylation; Modification; Morbidity - disease rate; Operative Surgical Procedures; Organ Transplantation; Outcome; Patients; Play; Population; Postoperative Period; Predictive Value; Pulmonary Edema; Recovery of Function; Regulation; Regulatory T-Lymphocyte; Reperfusion Injury; Reporting; Research Infrastructure; Research Personnel; Risk; Risk Factors; Role; Sampling; Severities; Solutions; Staging; Survival Rate; T-Cell Proliferation; T-Lymphocyte; Testing; Time; Transplant Recipients; Transplantation; United States National Institutes of Health; cell type; clinical effect; cost; economic outcome; high risk; improved; lung ischemia; mortality; novel diagnostics; novel therapeutic intervention; novel therapeutics; predictive modeling; prospective; transcription factor

DESCRIPTION (provided by applicant): In the modern era, organ transplantation has proven increasingly important as a solution to severe or end- stage diseases of the kidney, heart and liver, but unfortunately the results of lung transplantation have lagged considerably in terms of patient and graft survival rates. One of the main contributors to this poorer outcome is the development of primary graft dysfunction (PGD) within the first few days of lung transplantation. Dr. Jason Christie at UPenn has been studying the pathophysiology underlying PGD for the past decade, and has NIH- funded clinical studies underway in which blood samples are being collected pre- and post-lung transplantation in adults. An important new concept in immunology is that FOXP3+ T-regulatory (Treg) cells are key to normal regulation of immune responses, and that decreased Treg function likely contributes, clinically, to many forms of autoimmunity and inflammation. We hypothesize that pre-existing defects in Treg numbers or function, or defects in Treg numbers or function as a result of lung transplantation, may contribute to the development of PGD. We propose to test this hypothesis by assessing patients undergoing study in the underlying NIH-funded study of Dr. Christie that will last until 2014, using state-of-the art tests of Treg function that we have developed. Aim 1) of this ancillary study will assess aspects of Treg numbers and/or function pre-operatively and seek to ask whether any changes in Treg function are associated with increased rates or severity of PGD. Aim 2) of this ancillary study will asses whether the development of PGD in the very early post-Tx period is associated with decreased Treg numbers and/or function. Our studies will provide the first information on this clinically highly significant problem in lung Tx. Our findings, using samples obtained from 3 active lung transplant centers (Columbia, Indiana, Penn), may lead to new diagnostic or therapeutic interventions involving Treg cells therapies, or use of agents to enhance Treg function, in the very early post-operative period so as to overcome, or markedly decrease, the incidence and severity of PGD post-lung transplantation. PUBLIC HEALTH RELEVANCE: We will determine whether abnormalities in a key population of circulating lymphocytes called T-regulatory (Treg) cells affects the very early outcomes of lung transplants in patients with severe lung diseases. We will assess whether problems with Tregs occur pre- or post-transplant using blood samples already being collected as part of an NIH-funded clinical study of lung transplant recipients. Our studies may identify new diagnostic or therapeutic options to decrease the high morbidity and mortality rates currently associated with clinical lung transplantation. ! !

描述（由申请人提供）：在现代时代，有机体移植已被证明是解决肾脏，心脏和肝脏严重或末期疾病的解决方案，但不幸的是，肺移植的结果在患者和移植物生存率方面已大大落后。导致这种较差结果的主要因素之一是在肺移植的前几天内发育原发性移植功能障碍（PGD）。在过去的十年中，Upenn的Jason Christie博士一直在研究PGD的病理生理学，并正在进行NIH资助的临床研究，其中正在为成人中收集血液样本前后的血液样本。免疫学方面的一个重要新概念是FOXP3+ T调节（TREG）细胞是正常调节免疫反应的关键，而Treg功能降低可能在临床上可能导致多种形式的自身免疫性和炎症。我们假设在Treg数字或功能中存在的缺陷，或Treg数字中的缺陷或由于肺移植而导致的功能，可能有助于PGD的发展。我们建议通过评估基础NIH资助的Christie博士的研究患者，该研究将持续到2014年，使用我们开发的Treg功能的最先进的测试。目的1）这项辅助研究将评估Treg数字和/或术前功能的各个方面，并试图询问Treg功能的任何变化是否与PGD的率或严重程度增加有关。目的2）这项辅助研究将评估TX早期时期PGD的发展是否与Treg数量和/或功能减少有关。我们的研究将提供有关肺TX中该临床上严重问题的第一个信息。我们的发现使用从3个活跃的肺移植中心（哥伦比亚，印第安纳州，宾夕法尼亚州）获得的样品，可能会导致新的诊断或治疗性干预涉及Treg细胞疗法或使用剂来增强Treg功能，以在术后早期的早期术中，以便越来越多地降低pgd perflund serflunt of Pgd serflund serflunt of Pgd serflung of PGD。 公共卫生相关性：我们将确定称为T调节（TREG）细胞的关键循环淋巴细胞中的异常是否会影响严重肺部疾病患者肺移植的早期结局。我们将使用已经收集的血液样本作为NIH资助的肺移植受者的临床研究的一部分来评估转移前或移植后发生的问题。我们的研究可能确定新的诊断或治疗选择，以降低目前与临床肺移植相关的高发病率和死亡率。呢呢