From bench to bedside: reversing established antibody responses and desensitization.
From bench to bedside: reversing established antibody responses and desensitization.
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DOI：
10.1097/mot.0000000000001009
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发表时间：
2022-10-01
影响因子：
2.2
通讯作者：
Habal, Marlena, V
中科院分区：
文献类型：
--
作者：
Chong, Anita S.;Habal, Marlena, V
关键词：
基础移植免疫学主要关注机制的定义，但经常提出的一个理想目标是将基础机制研究转化为未来的治疗。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。虽然当代的免疫抑制有效地预防非致敏患者移植后的早期细胞排斥，但它在控制预先存在的 HLA 抗体反应或一旦建立后逆转 DSA 方面效果较差，因此强调需要更好的治疗方法。我们在此回顾了一种从实验室到临床的方法的开发，该方法涉及瞬时蛋白酶体抑制以消耗浆细胞，并结合 CTLA-4Ig 或贝拉西普的维持共刺激阻断，以防止新的抗体分泌细胞 (ASC) 的产生。这篇综述讨论了这种经过合理设计和验证的治疗方案如何逆转小鼠模型中已建立的 DSA 反应，转化为逆转临床中的主动 AMR，以及如何使移植候补名单上的高度敏感患者脱敏。
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. Pre-transplant donor specific antibodies (DSA) mediate hyperacute as well as early antibody-mediated rejection (AMR), while DSA developing late post-transplantation may additionally mediated chronic rejection. While contemporary immunosuppression effectively prevents early cellular rejection after transplant in non-sensitized patients, it is less effective at controlling pre-existing 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 discussed how this a treatment regimen that 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.