Preclinical and clinical studies for transplant tolerance via the mixed chimerism approach.
Preclinical and clinical studies for transplant tolerance via the mixed chimerism approach.
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DOI：
10.1016/j.humimm.2017.11.008
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发表时间：
2018-05
期刊：
影响因子：
2.7
通讯作者：
Kawai T
中科院分区：
文献类型：
--
作者：
Sasaki H;Oura T;Spitzer TR;Chen YB;Madsen JC;Allan J;Sachs DH;Cosimi AB;Kawai T
基于对小鼠模型的观察，我们开发了在非人类灵长类动物(NHP)和人类中通过联合肾和骨髓移植(CKBMT)诱导同种异体肾移植耐受的方案。在主要组织相容性复合体(MHC)不匹配的灵长类动物中，诱导持久的混合嵌合体已被证明是极其困难的，可检测到的嵌合体通常在30-60天内消失。然而，在MHC不匹配的NHP中，使用非清髓性条件处理方法已经成功地实现了移植肾的长期无免疫抑制存活，该方法也已成功推广到人类肾移植受者。CKBMT也被应用于终末期肾病合并血液系统恶性肿瘤患者。肾移植耐受和骨髓瘤的长期缓解是通过短暂的混合或持续的完全嵌合来实现的。本文综述了CKBMT诱导肾移植和非肾移植耐受的临床前和临床研究现状。提高耐受诱导的一致性和较低的发病率，将这一方法推广到已故供者移植和诱导非肾移植耐受，是将这一策略推广到更广泛的临床应用的关键下一步。
Based upon observations in murine models, we have developed protocols to induce renal allograft tolerance by combined kidney and bone marrow transplantation (CKBMT) in non-human primates (NHP) and in humans. Induction of persistent mixed chimerism has proved to be extremely difficult in major histocompatibility complex (MHC)-mismatched primates, with detectable chimerism typically disappearing within 30–60 days. Nevertheless, in MHC mismatched NHP, long-term immunosuppression-free renal allograft survival has been achieved reproducibly, using a non-myeloablative conditioning approach that has also been successfully extended to human kidney transplant recipients. CKBMT has also been applied to the patients with end stage renal disease with hematologic malignancies. Renal allograft tolerance and long-term remission of myeloma have been achieved by transient mixed or persistent full chimerism. This review summarizes the current status of pre-clinical and clinical studies for renal and non-renal allograft tolerance induction by CKBMT. Improving the consistency of tolerance induction with less morbidity, extending this approach to deceased donor transplantation and inducing tolerance of non-renal transplants, are critical next steps for bringing this strategy to a wider range of clinical applications.
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