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

• 批准号: 8119804
• 负责人: Stuart C Sweet
• 金额: $ 15.83万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-29 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119804
• 关键词: Acute; Alloantigen; Allografting; Animal Model; Antibodies; 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; Detection; Development; Early Diagnosis; 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; 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; adverse outcome; alpha Tubulin; autoreactivity; chemokine; clinical decision-making; cohort; cross reactivity; cytokine; design; experience; improved; innovation; isoimmunity; lung allograft; modifiable risk; mortality; new therapeutic target; patient population; programs; prospective; respiratory; response; retransplantation; viral detection

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）：儿童肺移植治疗各种病因的终末期肺部疾病，受者可能具有正常的肺外器官功能和发育。然而，与其他实体器官受者不同，儿童肺移植受者不良后果的频率在过去十年中并没有下降。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）与异体移植物不良结果之间的联系，这是由于病毒诱导的移植物内炎症和移植物定向的同种免疫、自身免疫和先天免疫反应的刺激。最近发展的灵敏、高通量的分子RVI检测方法和免疫监测技术，可以全面、前瞻性地评估RVIs对儿童肺移植受者发病率和死亡率的免疫介导贡献。我们建议通过刺激先天、细胞和体液免疫反应来验证移植后肺呼吸道病毒感染对儿童肺移植受者的预后有负面影响的假设。在我们的观察性临床研究中，我们将使用包括5个核心实验室在内的6个中心儿童肺移植联盟，对首次儿童肺移植受者进行前瞻性观察性研究设计，并采用综合分子病毒检测方法来评估RVIs作为达到闭塞性细支气管炎、死亡和再移植等主要复合临床终点的危险因素。在相关的机制研究中，我们将使用最先进的免疫分析来评估有和没有RVI的儿童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必要的队列规模（N=80），以获得足够的统计能力来检测有RVIs和没有RVIs的儿科肺移植受者之间结果的差异，并且在先天性、细胞和体液免疫反应的时间依赖性分析方面经验丰富，需要确定潜在的机制。这些研究的结果将导致创新的病毒检测和免疫监测方案的设计，可以直接整合到临床决策中，以预测个体化不良后果的风险，并将提出新的治疗靶点，以改善儿童肺移植的预后。儿童肺移植受者的预后（排斥反应、死亡或再移植）在过去十年中没有改善。使用最先进的方法，我们将研究儿童常见的肺部病毒感染引起移植肺排斥的方式。通过确定排斥相关病毒和免疫反应，这些研究将为早期诊断和预防性治疗提供新的策略，从而改善儿童肺移植受者的预后。