TREATMENT OF ANTI-HLA ANTIBODIES TO PREVENT BOS AFTER LUNG TRANSPLANTATION

描述（申请人提供）：慢性排斥反应或闭塞性细支气管炎综合征（BOS）已成为肺移植后长期生存的主要障碍。尽管肺移植后BOS的原因尚不清楚，但已确定的临床风险因素包括急性排斥反应、淋巴细胞性细支气管炎、原发性移植物功能障碍（PGD）、胃食管疾病（GERD）和供体人类白细胞抗原（DSA）抗体的产生。初步数据表明，大约50%的肺移植受者在移植后第一年发生DSA。实验数据表明DSA可能对移植肺有直接的致病作用。在动物模型中，DSA可引起类似于人肺移植后慢性排斥反应的气道病变。研究发现DSA是急性排斥反应和淋巴细胞性细支气管炎的独立危险因素，并且在肾移植中DSA与抗体介导的排斥反应（AMR）之间存在关联。 为了检验在排斥反应发生之前治疗诱导的DSA消耗降低慢性排斥反应或BOS的发生率的假设，本研究将使用双盲随机安慰剂对照试验来评价IVIG和抗CD 20抗体的疗效和安全性。该研究的主要终点包括DSA清除率，次要终点包括无BOS生存率、急性排斥反应、淋巴细胞性细支气管炎、慢性排斥反应、感染、生存率和生活质量。作为研究的关键次要目的，研究者将（1）标准化肺移植受者的DSA检查，（2）根据DSA和组织学结果，使用研究数据提出肺移植后AMR的标准化临床病理学定义。该项目还将建立标准化收集临床标本的基础设施，包括血液，唾液，肺活检和肺液，用于未来的研究，重点是抗体介导的移植物损伤的发病机制。研究人员计划在未来的大型多中心随机对照试验中前瞻性验证DSA监测方案和技术，AMR的定义以及此类治疗的有效性和安全性。总之，该项目解决了肺移植领域的一个重要问题，并有可能改变临床实践和改善移植受者的预后。(End摘要） 公共卫生相关性：在美国每年接受肺移植的近1,500人中，肺的排斥限制了长期存活。这项拟议中的研究使用新技术来监测和治疗肺移植后一种不寻常的排斥反应。这项研究的结果有可能改变肺移植受者的常规护理，提高他们的生活质量和生存率。

DESCRIPTION (provided by applicant): Chronic rejection or bronchiolitis obliterans syndrome (BOS) has emerged as the primary obstacle to long- term survival after lung transplantation. Though the cause of BOS after lung transplantation remains unclear, identified clinical risk factors include episodes of acute rejection, lymphocytic bronchiolitis, primary graft dysfunction (PGD), gastroesophageal disease (GERD), and the development of antibodies to donor human leukocyte antigens (DSA). Preliminary data suggest that approximately 50% of lung transplant recipients develop DSA in the first year after transplantation. Experimental data suggest that DSA may have a direct pathogenic effect on the transplanted lung. In animal models, DSA can cause an airway lesion similar to chronic rejection after human lung transplantation. Studies have identified DSA as an independent risk factor for acute rejection and lymphocytic bronchiolitis, and an association between DSA and antibody-mediated rejection (AMR) exists in kidney transplantation. To test the hypothesis that treatment-induced depletion of DSA, before the onset of rejection, reduces the incidence of chronic rejection or BOS, the study will use a double blind randomized placebo controlled trial to evaluate the efficacy and safety of IVIG and anti-CD20 antibody. The study's primary endpoint consists of clearance of DSA, and the secondary endpoints include BOS-free survival, acute rejection, lymphocytic bronchiolitis, chronic rejection, infections, survival, and quality of life. As key secondary aims of the study, investigators will (1) standardize DSA testing in lung transplant recipients, and (2) use the data from the study to propose a standardized clinicopathological definition of AMR after lung transplantation based on the presence of DSA and histologic findings. The project will also establish the infrastructure for standardized collection of clinical specimens including blood, saliva, lung biopsies, and lung fluid for future studies that focus on the pathogenesis of antibody-mediated graft injury. The investigators plan to prospectively validate the DSA monitoring protocol and techniques, the definition of AMR, and the efficacy and safety of such therapy in a future large multicenter randomized controlled trial. In summary, this project addresses an important problem in the field of lung transplantation, and has the potential to change clinical practice and improve outcomes for transplant recipients. (End of Abstract) PUBLIC HEALTH RELEVANCE: In the almost 1,500 people that undergo lung transplantation each year in the U.S., rejection of the lung limits long-term survival. The proposed study uses novel techniques to monitor and treat an unusual form of rejection after lung transplantation. Findings from the study have the potential to change the routine care of lung transplant recipients and improve their quality of life and survival.