Viral Triggers of Alloimmunity and Autoimmunity in Pediatric Lung Transplantation

小儿肺移植中同种免疫和自身免疫的病毒触发因素

基本信息

批准号：
7452649
负责人：
Stuart C Sweet
金额：
$ 89.15万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7452649
关键词：
Acute Alloantigen Allografting Animal Model Antibodies Appendix Arts Autoimmune Process Autoimmunity B-Lymphocytes Biological Assay Biopsy Bronchiolitis Obliterans Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid Cessation of life Child Childhood Chronic Clinical Clinical Research Collagen Communities Complement Cytomegalovirus Data Decision Making Detection Development Early Diagnosis End Point Enrollment Etiology Evaluation Frequencies Gene Expression Goals Graft Rejection Guidelines Human Immune Immune response Immune system Immunity Immunologic Monitoring Incidence Infection Inflammation Injury International Laboratories Lead Link Lung Lung Transplantation Lung diseases Mediating Mediator of activation protein Methods Molecular Monitor Morbidity - disease rate Natural Immunity Observational Study Organ Organ Transplantation Outcome Patients Performance Peripheral Blood Mononuclear Cell Polymerase Chain Reaction Population Proteins RNA Research Design Research Personnel Risk Risk Factors Satellite Viruses Serum Solid Staging Structure of parenchyma of lung Surrogate Markers Swab Syndrome T-Lymphocyte Techniques Testing Time Transplant Recipients Transplantation Viral Virus Virus Diseases alpha Tubulin autoreactivity chemokine cohort cross reactivity cytokine design experience improved innovation isoimmunity lung allograft modifiable risk mortality novel therapeutics programs prospective respiratory response retransplantation size therapeutic target viral detection

项目摘要

DESCRIPTION (provided by applicant): Pediatric lung transplantation treats end-stage lung disease of diverse etiologies in recipients with potential for normal extrapulmonary organ function and development. However, unlike other solid organ recipients, frequencies of adverse outcomes in pediatric lung transplant recipients have not declined over the last decade. Evidence from animal models and limited data in humans support a link between respiratory viral infection (RVI) and adverse allograft outcome due to virus-induced intragraft inflammation and to stimulation of graft-directed alloimmune, autoimmune, and innate immune responses. The recent development of sensitive, high throughput molecular RVI detection methods and immune monitoring techniques permits comprehensive, prospective evaluation of the immune-mediated contribution of RVIs to morbidity and mortality in pediatric lung transplant recipients. We propose to test the hypothesis that post transplant pulmonary respiratory viral infections negatively impact outcomes in pediatric lung transplant recipients by stimulation of innate, cellular, and humoral immune responses. In our observational clinical study, we will use a 6 center Pediatric Lung Transplant Consortium that includes 5 core laboratories, a prospective observational study design of first pediatric lung transplant recipients, and comprehensive molecular viral detection methods to assess RVIs as a risk factor for reaching a primary, composite clinical endpoint of bronchiolitis obliterans, death, and re-transplantation. In the accompanying mechanistic study, we will use state-of-the-art immune assays to assess mechanisms of graft injury in pediatric lung transplant recipients with and without RVI. Our Pediatric Lung Transplant Consortium provides access to a cohort size (N=80) necessary to achieve sufficient statistical power to detect differences in outcome between pediatric lung transplant recipients with and without RVIs and is experienced in performance of time-dependent analyses of innate, cellular, and humoral immune responses necessary to define underlying mechanisms. The results of these studies will lead to the design of innovative viral detection and immune monitoring schema that can be directly integrated into clinical decision-making to predict individualized risk of adverse outcomes and will suggest novel therapeutic targets to improve pediatric lung transplant outcomes. Outcomes of pediatric lung transplant recipients (rejection, death, or re-transplantation) have not improved over the last decade. Using state of the art methods, we will study the ways that common lung viral infections in children cause rejection of transplanted lungs. By determining the rejection-associated viruses and immune responses, these studies will provide new strategies for early diagnosis and preventative treatment that will improve outcomes in pediatric lung transplant recipients.

描述（由申请人提供）：小儿肺移植治疗受体正常肺外器官功能和发育潜力的受体中各种病因的终末期肺病。但是，与其他固体器官受体不同，在过去的十年中，小儿肺移植受者的不良结局频率尚未下降。动物模型和人类数据有限的证据支持呼吸道病毒感染（RVI）和由于病毒引起的授课内炎症而导致的不良同种异体结果之间的联系，并刺激了移植物指导的同种免疫，自身免疫和先天免疫反应。敏感，高吞吐量分子RVI检测方法和免疫监测技术的最新发展允许对儿科肺移植受者的免疫介导的RVI对发病率和死亡率的免疫介导的贡献进行全面，前瞻性评估。我们建议检验以下假设：移植后肺呼吸道病毒感染会通过刺激先天，细胞和体液免疫反应来对小儿肺移植受者的结局产生负面影响。在我们的观察临床研究中，我们将使用6个中心的小儿肺移植联盟，其中包括5个核心实验室，对第一小儿肺移植受者的前瞻性观察性研究设计以及全面的分子病毒检测方法，以评估RVIS作为主要的临床，临床临床终点的危险因素，以供临床剂的命中率命中术和重复症。在随附的机械研究中，我们将使用最先进的免疫测定法评估有或没有RVI的小儿肺移植受者的移植机制。我们的儿科肺移植联盟提供了需要获得足够的统计能力来检测有或没有RVI的小儿肺移植接受者的预后差异的必要差异，并且在适用于定义机制下必要的适用性的必要时间来依赖于时间依赖的分析时，需要进行统计差异。这些研究的结果将导致设计创新的病毒检测和免疫监测模式，这些模式可以直接整合到临床决策中，以预测个性化的不良后果风险，并将提出新的治疗靶标，以改善儿科肺移植结果。在过去的十年中，小儿肺移植受者的结局（排斥，死亡或再移植）尚未改善。使用最先进的方法，我们将研究儿童常见的肺病毒感染引起移植肺部的方式。通过确定与排斥相关的病毒和免疫反应，这些研究将为早期诊断和预防治疗提供新的策略，以改善小儿肺移植受者的预后。