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

基本信息

批准号：
8607881
负责人：
Stuart C Sweet
金额：
$ 145.78万
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 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607881
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 High-Throughput Nucleotide Sequencing 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

项目摘要

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）：尽管小儿肺移植是一种接受终末期肺和肺血管疾病的接受疗法，与其他固体器官受益者不同，具有正常肺外器官功能和发育潜力的儿童的各种病因，但在过去的十年中，晚期并发症的过度频率没有得到显着改善。几条证据，包括我们小儿肺移植联盟的初步数据，表明针对供体组织抗原（DSA）（DSA）和隐秘自我抗原（AutoAB）的抗体的发展与长期存活率不佳相关。我们建议测试以下假设：添加旨在去除B细胞的诱导策略（利妥昔单抗）将通过减少DSA和自身抗体的发展并限制T细胞同种异体免疫性，而无需损害患者的安全。在我们的随机控制的II期临床试验中，我们将使用一个六个中心的小儿肺移植联盟，其中包括在定义基本机制所需的先天性，细胞和体液免疫反应的时间依赖性分析中经历的核心实验室。我们的临床部位具有足够的体积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支气管炎的复合临床终点，死亡和再移植。在随附的机械研究中，使用最先进的免疫测定来评估儿科肺移植受者中移植损伤的机制，我们将测试以下假设：利妥昔单抗诱导将减少供体特定的同种抗体和自身抗体的发展，并在移植后限制B-cell抗原抗原疗法，并限制抗原抗原疗法。我们预计这些研究将导致治疗策略，以改善小儿肺移植的预后，并确定可预测肺同种异体功能障碍的新型生物标志物。