Viral Triggers of Alloimmunity and Autoimmunity in Pediatric Lung Transplantation

描述（由申请人提供）：小儿肺移植可治疗具有正常肺外器官功能和发育潜力的受者的多种病因的终末期肺病。然而，与其他实体器官受者不同，儿科肺移植受者的不良后果发生频率在过去十年中并未下降。来自动物模型的证据和有限的人类数据支持呼吸道病毒感染（RVI）与病毒引起的移植物内炎症以及刺激移植物定向同种免疫、自身免疫和先天免疫反应导致的不良同种异体移植结果之间的联系。最近开发的灵敏、高通量分子 RVI 检测方法和免疫监测技术可以对 RVI 的免疫介导对儿科肺移植受者的发病率和死亡率的影响进行全面、前瞻性的评估。我们建议检验以下假设：移植后肺呼吸道病毒感染通过刺激先天、细胞和体液免疫反应对儿科肺移植受者的结果产生负面影响。在我们的观察性临床研究中，我们将使用一个由 6 个中心组成的儿科肺移植联盟，其中包括 5 个核心实验室，对首例儿科肺移植受者进行前瞻性观察性研究设计，并采用全面的分子病毒检测方法来评估 RVI 作为达到闭塞性细支气管炎、死亡和再移植的主要复合临床终点的危险因素。在随附的机制研究中，我们将使用最先进的免疫测定来评估患有或不患有 RVI 的儿科肺移植受者的移植物损伤机制。我们的儿科肺移植联盟提供了获得足够统计能力所需的队列规模 (N=80)，以检测有或没有 RVI 的儿科肺移植受者之间的结果差异，并且在对确定潜在机制所需的先天、细胞和体液免疫反应进行时间依赖性分析方面经验丰富。这些研究的结果将导致创新病毒检测和免疫监测方案的设计，这些方案可以直接整合到临床决策中，以预测不良结果的个体化风险，并将提出新的治疗靶点以改善儿科肺移植结果。在过去的十年中，儿科肺移植受者的结果（排斥、死亡或再次移植）没有改善。我们将使用最先进的方法，研究儿童常见肺部病毒感染导致移植肺排斥的方式。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性治疗提供新策略，从而改善儿科肺移植受者的预后。

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.