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

描述（由申请人提供）：慢性排斥反应或闭塞性细支气管炎综合征（BOS）已成为肺移植术后长期生存的主要障碍。尽管肺移植后BOS的病因尚不清楚，但已确定的临床危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）和对供体人白细胞抗原（DSA）产生抗体。初步数据显示，大约50%的肺移植受者在移植后的第一年发生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。研究已经确定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DSA与肾移植中抗体介导的排斥反应（AMR）存在关联。为了验证在排斥反应发生前治疗诱导的DSA耗竭降低慢性排斥反应或BOS发生率的假设，本研究将采用双盲随机安慰剂对照试验来评估IVIG和抗cd20抗体的疗效和安全性。该研究的主要终点包括DSA的清除，次要终点包括无bos生存、急性排斥反应、淋巴细胞性细支气管炎、慢性排斥反应、感染、生存和生活质量。作为本研究的主要次要目的，研究者将(1)标准化肺移植受者的DSA检测，(2)利用本研究的数据，基于DSA的存在和组织学发现，提出肺移植后AMR的标准化临床病理定义。该项目还将建立标准化临床标本收集的基础设施，包括血液、唾液、肺活检和肺液，以供未来研究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地验证DSA监测方案和技术、AMR的定义以及这种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并改善移植受者的预后。（摘要结束）

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.