Induction of chimerism in rhesus macaques through stem cell transplant and costimulation blockade-based immunosuppression
Induction of chimerism in rhesus macaques through stem cell transplant and costimulation blockade-based immunosuppression
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DOI：
10.1111/j.1600-6143.2006.01622.x
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发表时间：
2007-02-01
影响因子：
8.8
通讯作者：
Larsen, C. P.
中科院分区：
文献类型：
--
作者：
Kean, L. S.;Adams, A. B.;Larsen, C. P.
在恒河猴中已经建立了一种在非清髓性条件作用后产生高水平造血细胞嵌合体的策略。这一策略依赖于在非清髓性剂量的白花丹诱导后进行造血干细胞移植，并在用西罗莫司抑制mTOR的情况下阻断IL2受体，并联合使用CD28/CD154共刺激阻断。来自骨髓的造血干细胞和白细胞采集产品都被发现成功地诱导了高水平的嵌合体。供者外周血平均嵌合率为81%，中位嵌合持续时间为145天。其他免疫调节策略，如移植前CD8耗尽、供者特异性输血、受者胸腺切除或移植周围脱氧精原鸟苷治疗，并不能改善嵌合体的水平或持久性。受体免疫学评估表明，嵌合体发生在供者特异性的同种异体反应性T细胞下调中，并在移植排斥反应中重现强烈的T介导同种异体反应性。此外，病毒的重新激活构成了与移植相关的重大毒性，并可能对实现移植干细胞无限期存活的能力产生负面影响。然而，这种嵌合体诱导方案是迄今为止报告的非人类灵长类动物中寿命最长的干细胞嵌合体之一，因此代表了一个评估新出现的耐受诱导策略的平台。
A strategy for producing high-level hematopoietic chimerism after non-myeloablative conditioning has been established in the rhesus macaque. This strategy relies on hematopoietic stem cell transplantation after induction with a non-myeloablative dose of busulfan and blockade of the IL2-receptor in the setting of mTOR inhibition with sirolimus and combined CD28/CD154 costimulation blockade. Hematopoietic stem cells derived from bone marrow and leukopheresis products both were found to be successful in inducing high-level chimerism. Mean peripheral blood peak donor chimerism was 81% with a median chimerism duration of 145 days. Additional immune modulation strategies, such as pre-transplant CD8 depletion, donor-specific transfusion, recipient thymectomy or peritransplant deoxyspergualin treatment did not improve the level or durability of chimerism. Recipient immunologic assessment suggested that chimerism occurred amidst donor-specific down-regulation of alloreactive T cells, and the reappearance of vigorous T-mediated alloreactivity accompanied rejection of the transplants. Furthermore, viral reactivation constituted a significant transplant-related toxicity and may have negatively impacted the ability to achieve indefinite survival of transplanted stem cells. Nevertheless, this chimerism-induction regimen induced amongst the longest-lived stem cell chimerism reported to date for non-human primates and thus represents a platform upon which to evaluate emerging tolerance-induction strategies.