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)是免疫性移植物损伤的主要原因。 缩短移植的半衰期，从而缩短移植受者的半衰期。这是由免疫介导的 这一过程依赖于B淋巴细胞的活化和分化为产生抗体的浆细胞(PC) 捐献器官。事实证明，抗体一旦确立，就很难根除。建立一个有效的和 治疗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患者。我们的实验室描述了一种有效的治疗非霍奇金淋巴瘤的方法 人灵长类动物(NHP)致敏肾移植模型降低供体特异性抗体(DSA)和 防止AMR造成的伤害。PC耗竭联合生发中心的治疗 解体共同降低同种异体抗体水平。补体对免疫系统的双重靶向作用 药物是基于NHP和使用蛋白酶体抑制剂和贝拉塔塞特的人体数据。B细胞活化和 在PC耗尽的同时，分化受到抑制。因此，DSA下降，炎症 肾脏消退，肾功能稳定。这种干预措施对感染风险的影响不是很好。 已确定，但预计将增加。我们建议测量治疗对人类白细胞抗原特异性和 病原体特异的B记忆细胞和PC。我们假设对治疗的易感性是有等级的， 保护性免疫比同种异体B细胞记忆更具抵抗力。我们会评估该计划的影响。 以巨细胞病毒(CMV)为主的T细胞功能治疗方案。晚期AMR的治疗性治疗现状 使用或不使用利妥昔单抗的血浆交换(TPE)和静脉免疫球蛋白(IVIG)显示出变量 结果和DSA的频繁反弹。低水平的证据支持这些治疗的有效性，这意味着 非常需要进行良好的临床试验来指导AMR的治疗。我们建议第一阶段/第二阶段 人肾移植患者AMR的随机、对照、前瞻性干预研究 卡非佐米/贝拉坦(C/B)联合TPE+IVIG治疗与单纯TPE/IVIG治疗比较。结果将会 包括使用最近验证的用于AMR评估的iBox评分对AMR的临床影响，以及 使用标准化的感染定义计算感染的数量和类型。我们将衡量 治疗人类白细胞抗原和病原体相关的B记忆和PC以及巨细胞病毒特异性多功能T细胞。我们 将评估计算机数字成像分析的AMR非视觉活检功能，以评估机器 学习算法可以改进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非常差，我们认为 这项试验在伦理上是合理的，并可能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.