Targeting the B Cell Response to Treat Antibody-Mediated Rejection

摘要 实体器官移植的抗体介导的排斥反应（AMR）是免疫移植物损伤的主要原因， 缩短移植物的半衰期，从而缩短移植受体的半衰期。这种免疫介导的 这一过程依赖于B淋巴细胞活化，分化为浆细胞（PC），产生抗 捐赠器官。一旦建立，抗体已被证明难以根除。建立一个有效和 治疗已确定AMR患者的安全方法可能会延长移植器官的半衰期， 延长患者的生命，减少再次移植的需要，最终增加 可以接受救命器官移植的病人我们的实验室已经描述了一种有效的治疗方法， 人灵长类动物（NHP）致敏肾移植模型用于降低供体特异性抗体（DSA）， 防止AMR的伤害。治疗依赖于PC耗竭结合生发中心 这会降低同种抗体水平。免疫系统的双重靶向， 药物是基于NHP和人类数据使用蛋白酶体抑制剂和贝拉西普。B细胞活化和 在PC耗尽的同时，分化被抑制。因此，DSA下降， 肾脏恢复正常，肾功能稳定。这种干预对感染风险的影响并不好 已确定，但预计会增加。我们建议测量治疗对HLA特异性和 病原体特异性B记忆细胞和PC。我们假设对治疗的敏感性有一个等级， 保护性免疫比同种异体B细胞记忆更有抵抗力。我们将评估 针对巨细胞病毒（CMV）的T细胞功能方案。目前使用治疗药物治疗晚期AMR 血浆置换（TPE）和静脉注射免疫球蛋白（IVIG）联合或不联合利妥昔单抗显示出可变的 DSA结果及频繁反弹。低水平的证据支持这些治疗的有效性，这意味着 对指导AMR治疗的良好临床试验的巨大需求。我们建议第一/第二阶段 在人肾移植患者中进行的AMR随机、对照、前瞻性干预性研究， 与TPE/IVIG单独治疗相比，卡非佐米/贝拉西普（C/B）联合TPE和IVIG治疗。成果将 包括使用最近验证的iBox评分进行AMR评估的治疗对AMR的临床影响， 感染的数量和类型使用感染的标准化定义。我们将衡量 对HLA和病原体相关的B记忆和PC以及CMV特异性多功能T细胞的治疗。我们 将评估AMR非视觉活检特征的计算数字成像分析，以评估机器是否 学习算法可以改善AMR的Banff标准，以更好地指导治疗和预测临床结果。 由于晚期活动性和慢性活动性AMR对肾移植患者的预后很差，我们认为， 该试验在伦理上是合理的，可能会产生重要的安全性和初步疗效数据， 可能会改善移植患者的免疫管理。

ABSTRACT Antibody-mediated rejection (AMR) of solid organ transplants is the leading cause of immunologic graft injury, shortening the half-life of transplants and consequently of transplant recipients. This immunologically mediated process depends on B lymphocyte activation with differentiation to plasma cells (PC) that produce antibodies to the donor organ. Once established, antibodies have proven difficult to eradicate. Establishing an effective and safe way to treat patients with established AMR would potentially increase the half-life of transplanted organs, extend the lives of patients, and reduce the need for re-transplantation, ultimately increasing the number of patients who could receive life-saving organ transplants. Our lab has described an effective therapy in a non- human primate (NHP) sensitized model of kidney transplantation for lowering donor-specific antibody (DSA) and preventing injury from AMR. The treatment depends on PC depletion in combination with germinal center disorganization which together lower alloantibody levels. Dual targeting of the immune system by complementary drugs is based on NHP and human data using a proteasome inhibitor and belatacept. B cell activation and differentiation is inhibited at the same time that PC are depleted. Consequently, DSA declines, inflammation in the kidney resolves, and renal function stabilizes. The impact of this intervention on infection risk is not well defined but is anticipated to increase. We propose to measure the impact of therapy on both HLA-specific and pathogen-specific B memory cells and PC. We hypothesize that there is a hierarchy of susceptibility to therapy, with protective immunity being more resistant than allogeneic B cell memory. We will evaluate the impact of the regimen on T-cell function focusing on cytomegalovirus (CMV). Current therapy of late AMR using therapeutic plasma exchange (TPE) and intravenous immune globulin (IVIG) with or without rituximab has shown variable results and frequent rebound of DSA. A low level of evidence supports the efficacy of these treatments, implying a tremendous need for well-conducted clinical trials to guide treatment of AMR. We propose a Phase I/II randomized, controlled, prospective interventional study of AMR in human kidney transplant patients using combined carfilzomib/belatacept (C/B) therapy with TPE and IVIG compared to TPE/IVIG alone. Outcomes will include the clinical impact of therapy on AMR using the recently validated iBox score for AMR assessment and the number and type of infections using standardized definitions of infection. We will measure the impact of therapy on HLA and pathogen-associated B memory and PC as well as CMV-specific polyfunctional T-cells. We will assess computational digital imaging analysis of AMR non-visual biopsy features to assess whether machine learning algorithms can improve on Banff criteria of AMR to better guide treatment and predict clinical outcome. Since late active and chronic active AMR have such a poor prognosis for kidney transplant patients, we believe that this trial is ethically justified and would potentially yield important safety and preliminary efficacy data that may lead to improved immune management of transplant patients.