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，器官移植作为肾脏、心脏和肝脏的严重或终末期疾病的解决方案已被证明越来越重要，但不幸的是，肺移植的结果在患者和移植物存活率方面相当滞后.这种较差结果的主要原因之一是肺移植最初几天内发生原发性移植物功能障碍（PGD）。在过去的十年里，宾夕法尼亚大学的Jason Christie博士一直在研究PGD的病理生理学基础，并且正在进行NIH资助的临床研究，其中在成人肺移植前后收集血液样本。免疫学中一个重要的新概念是FOXP 3 + T调节（Treg）细胞是免疫应答正常调节的关键，并且Treg功能降低可能在临床上导致许多形式的自身免疫和炎症。我们推测，预先存在的Treg数量或功能缺陷，或肺移植导致的Treg数量或功能缺陷，可能有助于PGD的发展。我们建议通过评估在NIH资助的克里斯蒂博士的基础研究中接受研究的患者来测试这一假设，该研究将持续到2014年，使用我们开发的最先进的Treg功能测试。本辅助研究的目的1）将评估术前Treg数量和/或功能的各个方面，并试图询问Treg功能的任何变化是否与PGD的发生率或严重程度增加相关。该辅助研究的目的2）将评估在非常早期的Tx后时期中PGD的发展是否与Treg数量和/或功能降低相关。我们的研究将提供关于肺Tx中这一临床上高度显著的问题的第一信息。我们的研究结果，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）获得的样本，可能会导致新的诊断或治疗干预措施，涉及Treg细胞疗法，或使用药物来增强Treg功能，在手术后的早期阶段，以克服或显着降低肺移植后PGD的发病率和严重程度。 公共卫生相关性：我们将确定被称为T调节（Treg）细胞的循环淋巴细胞的关键群体的异常是否会影响严重肺部疾病患者肺移植的早期结果。我们将使用已经作为NIH资助的肺移植受者临床研究的一部分收集的血液样本来评估TclO问题是否发生在移植前或移植后。我们的研究可能会发现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。! !