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

B 细胞定向诱导可改善儿科肺移植的结果

• 批准号: 8466657
• 负责人: Stuart C Sweet
• 金额: $ 111.68万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466657
• 关键词: Accounting; Address; Adrenal Cortex Hormones; Adult; Algorithms; Antibodies; Antibody Formation; Antibody-Producing Cells; Antigen Presentation; Antigens; Antithymoglobulin; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmunity; B cell repertoire; B-Lymphocytes; Biological Assay; Biological Markers; Blood; Blood Vessels; Bronchiolitis Obliterans; Bronchoalveolar Lavage; Bronchoscopy; Cessation of life; Child; Childhood; Clinical; Clinical Trials; Collagen; Cytomegalovirus; Data; Development; Diagnostic; Double-Blind Method; Early Diagnosis; Enrollment; Etiology; Evaluation; Event; Frequencies; Functional disorder; Graft Rejection; Human Herpesvirus 4; Immune; Immune response; Immunity; Immunosuppression; Incidence; Infection; Infiltration; Injury; International; Intervention; Intervention Trial; Isoantibodies; Laboratories; Lead; Lung; Lung Transplantation; MS4A1 gene; Mediating; Molecular; Monitor; Neoadjuvant Therapy; Organ; Outcome; Parents; Pathogenicity; Patients; Performance; Peripheral; Phase II Clinical Trials; Phenotype; Placebos; Play; Population; Prevention; Prophylactic treatment; Protocols documentation; Publishing; Randomized; Regulation; Research Infrastructure; Research Personnel; Role; Safety; Sampling; Solid; Staging; Syndrome; T-Lymphocyte; Tacrolimus; Techniques; Testing; Time; Tissue Donors; Tissue Sample; Transplant Recipients; Transplantation; Tubulin; United States; Update; Viral; Whole Blood; Work; arm; base; clinical research site; cohort; cytokine; design; double-blind placebo controlled trial; experience; improved; insight; isoimmunity; lung allograft; mycobacterial; mycophenolate mofetil; novel; patient safety; placebo controlled study; public health relevance; reconstitution; response; rituximab; standard of care; therapy development; treatment strategy; trial comparing

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.

描述（由申请人提供）：尽管儿科肺移植是一种可接受的治疗具有正常肺外器官功能和发育潜力的儿童各种病因的终末期肺和肺血管疾病的疗法，但与其他实体器官接受者不同，在过去十年中，晚期并发症的过度发生率没有显著改善。包括我们儿科肺移植联盟的初步数据在内的多项证据表明，针对供体组织抗原（DSA）和隐性自身抗原（autoAb）的抗体的产生与长期生存率低相关。我们建议测试的假设，增加诱导策略，旨在消除B细胞（利妥昔单抗）将改善儿科肺移植的结果，减少DSA和自身抗体的发展，并通过限制T细胞同种免疫，而不影响患者的安全性。在我们的随机对照II期临床试验中，我们将使用六个中心的儿科肺移植联盟，其中包括在先天性、细胞和体液免疫应答的时间依赖性分析方面经验丰富的核心实验室，这些分析是确定潜在机制所必需的。我们的临床研究中心有足够的容量来提供足够的临床队列（N=50），以测试利妥昔单抗诱导是否会改善闭塞性细支气管炎、死亡和再次移植的复合临床终点。在随附的机制研究中，使用最先进的免疫测定来评估儿科肺移植受者中移植物损伤的机制，我们将检验利妥昔单抗诱导将减少移植后供体特异性同种抗体和自身抗体的发展以及限制B细胞抗原呈递的假设，所述B细胞抗原呈递将减少同种免疫和自身免疫细胞应答。我们预计这些研究将导致治疗策略，以改善儿童肺移植的结果，以及确定新的生物标志物预测肺移植功能障碍。