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

Foxp3 Treg 细胞

基本信息

批准号：
8469907
负责人：
Wayne William Hancock
金额：
$ 38.59万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
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/8469907
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

项目摘要

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.

描述（由申请人提供）：在现代，器官移植作为治疗严重或终末期肾脏、心脏和肝脏疾病的方法已被证明越来越重要，但不幸的是，肺移植的结果在患者方面远远落后。和移植物成活率。导致这种较差结果的主要原因之一是在肺移植的最初几天内出现原发性移植物功能障碍（PGD）。宾夕法尼亚大学的 Jason Christie 博士在过去十年中一直在研究 PGD 的病理生理学，并正在进行 NIH 资助的临床研究，在成人肺移植前后收集血样。免疫学中一个重要的新概念是，FOXP3+ T 调节 (Treg) 细胞是免疫反应正常调节的关键，并且 Treg 功能下降可能在临床上导致多种形式的自身免疫和炎症。我们假设，预先存在的 Treg 数量或功能缺陷，或者肺移植导致的 Treg 数量或功能缺陷，可能会导致 PGD 的发生。我们建议通过评估接受 NIH 资助的 Christie 博士研究的患者来检验这一假设，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。这项辅助研究的目标 1) 将评估术前 Treg 数量和/或功能的各个方面，并寻求询问 Treg 功能的任何变化是否与 PGD 发生率或严重程度增加相关。这项辅助研究的目标 2) 将评估 Tx 后早期 PGD 的发展是否与 Treg 数量和/或功能减少相关。我们的研究将提供有关肺 Tx 中这一临床高度重要问题的第一手信息。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、宾夕法尼亚州）获得的样本，可能会在术后早期产生新的诊断或治疗干预措施，包括 Treg 细胞疗法，或使用增强 Treg 功能的药物从而克服或显着降低肺移植后PGD的发生率和严重程度。