B-CELL TARGETED INDUCTION TO IMPROVE OUTCOMES IN PEDIATRIC LUNG TRANSPLANTATION

描述（由申请人提供）：尽管儿童肺移植是治疗各种病因的终末期肺和肺血管病变的一种公认的治疗方法，但与其他实体器官受体不同，晚期并发症的发生率在过去十年中没有显著改善。包括我们的儿科肺移植联盟的初步数据在内的几条证据表明，针对供体组织抗原（DSA）和隐性自身抗原（autoAb）的抗体的发展与较差的长期生存率相关。我们建议验证这样一种假设，即添加一种旨在去除b细胞的诱导策略（利妥昔单抗）将通过减少DSA和自身抗体的产生以及限制T细胞同种免疫来改善儿童肺移植的结果，而不会影响患者的安全性。在我们的随机对照II期临床试验中，我们将使用6个中心的儿童肺移植联盟，包括在先天性、细胞和体液免疫反应的时间依赖性分析方面经验丰富的核心实验室，以确定潜在的机制。我们的临床站点有足够的容量来提供足够的临床队列（N=50）来测试利妥昔单抗诱导是否会改善闭塞性细支气管炎、死亡和再移植的复合临床终点。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儿童肺移植受者移植损伤的机制，我们将检验利妥昔单抗诱导会减少移植后供者特异性同种异体抗体和自身抗体的产生，并限制b细胞抗原呈递，从而减少同种异体免疫和自身免疫细胞反应的假设。我们预计这些研究将为改善儿童肺移植的预后提供治疗策略，并确定预测同种异体肺移植功能障碍的新生物标志物。

DESCRIPTION (provided by applicant): Although pediatric lung transplantation is an accepted therapy for end-stage lung and pulmonary vascular diseased of diverse etiologies in children with potential for normal extrapulmonary organ function and development, unlike other solid organ recipients, the over frequency of late complications has not improved significantly during the past decade. Several lines of evidence, including preliminary data from our Pediatric Lung Transplant Consortium, indicate that the development of antibodies directed against donor tissue antigens (DSA) and cryptic self-antigens (autoAb) correlate with poor long term survival. We propose to test the hypothesis that addition of an induction strategy designed to remove B-cells (rituximab) will improve pediatric lung transplant outcome by reducing the development of DSA and autoantibodies and by limiting T cell alloimmunity, without compromising patient safety. In our randomized, controlled phase II clinical trial, we will use a six center Pediatric Lung Transplant Consortium that includes core laboratories experienced in performance of time-dependent analyses of innate, cellular, and humoral immune responses necessary to define underlying mechanisms. Our clinical sites have sufficient volume to provide an adequate clinical cohort (N=50) to test whether rituximab induction will improve a composite clinical endpoint of bronchiolitis obliterans, death, and re-transplantation. In the accompanying mechanistic study, using state-of- the-art immune assays to assess mechanisms of graft injury in pediatric lung transplant recipients we will test the hypothesis that rituximab induction will reduce the development of donor specific alloantibodies and autoantibodies after transplantation and also limit B-cell antigen presentation that will reduce alloimmune and autoimmune cellular responses. We anticipate that these studies will lead to treatment strategies for improved outcomes in pediatric lung transplantation as well as identifying novel biomarkers predictive of lung allograft dysfunction.