Department of Surgery, University of Chicago, Chicago, Illinois.
Department of Medicine, Columbia University College of Medicine, New York, New York, USA.
Curr Opin Organ Transplant. 2022 Oct 1;27(5):376-384. doi: 10.1097/MOT.0000000000001009. Epub 2022 Aug 3.
Basic transplant immunology has primarily focused on the definition of mechanisms, but an often-stated aspirational goal is to translate basic mechanistic research into future therapy. Pretransplant donor-specific antibodies (DSA) mediate hyperacute as well as early antibody-mediated rejection (AMR), whereas DSA developing late posttransplantation may additionally mediate chronic rejection. Although contemporary immunosuppression effectively prevents early cellular rejection after transplant in nonsensitized patients, it is less effective at controlling preexisting HLA antibody responses or reversing DSA once established, thus underscoring a need for better therapies.
We here review the development of a bench-to-bedside approach involving transient proteasome inhibition to deplete plasma cells, combined with maintenance co-stimulation blockade, with CTLA-4Ig or belatacept, to prevent the generation of new antibody-secreting cells (ASCs).
This review discusses how this treatment regimen, which was rationally designed and validated to reverse established DSA responses in mouse models, translated into reversing active AMR in the clinic, as well as desensitizing highly sensitized patients on the transplant waitlist.
基础移植免疫学主要集中在机制的定义上，但一个常被提及的理想目标是将基础的机制研究转化为未来的治疗方法。移植前供体特异性抗体（DSA）介导超急性和早期抗体介导的排斥反应（AMR），而移植后晚期出现的 DSA 可能另外介导慢性排斥反应。尽管当代免疫抑制在无致敏患者中有效地预防移植后早期的细胞排斥反应，但它在控制预先存在的 HLA 抗体反应或逆转 DSA 方面效果较差，因此强调了需要更好的治疗方法。
我们在这里回顾了一种从实验室到临床的方法的发展，该方法涉及短暂的蛋白酶体抑制以耗尽浆细胞，结合维持共刺激阻断，使用 CTLA-4Ig 或 belatacept，以防止新的抗体分泌细胞（ASC）的产生。
本综述讨论了这种治疗方案如何在小鼠模型中合理设计和验证以逆转已建立的 DSA 反应，并转化为在临床中逆转活跃的 AMR，以及使移植等待名单上高度致敏的患者脱敏。
