骨髓间充质干细胞诱导调节性 T 细胞生成和肾移植耐受与吲哚胺 2,3-双加氧酶表达相关。
Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression.
机构信息
Department of Surgery, University of Western Ontario, London, ON, Canada.
出版信息
Transplantation. 2010 Dec 27;90(12):1312-20. doi: 10.1097/TP.0b013e3181fed001.
BACKGROUND
The immunoregulatory properties of mesenchymal stem cells (MSCs) have been observed in vitro and in vivo. However, the underlying mechanisms of this immunomodulation remain undefined. Recent research demonstrated that MSCs express the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO), known to suppress T-cell responses. This study was designed to address whether MSCs induce kidney allograft tolerance and whether IDO contributes to the immunoregulatory functions of MSCs in vivo.
METHODS
MSCs (1×10(6), intravenously) from wild-type (WT-MSCs) or IDO knockout (IDO(-/-)-MSCs) C57BL/6 mice were injected into BALB/c recipients 24 hr after receiving a life-supporting orthotopic C57BL/6 renal graft.
RESULTS
WT-MSC-treated recipients achieved allograft tolerance with normal histology and undetectable antidonor antibody levels. Tolerant recipients demonstrated increased circulating kynurenine levels and significantly high frequencies of tolerogenic dendritic cells. They also exhibited significantly impaired CD4+ T-cell responses consisting of decreased donor-specific proliferative ability and a Th2-dominant cytokine shift. In addition, high frequencies of CD4+CD25+Foxp3+ regulatory T cells (Tregs) were found in recipient spleens and donor grafts, with antibody-induced CD25+ cell depletion confirming the critical role of Tregs in the MSC-induced tolerance. Interestingly, renal allograft recipients treated with WT MSCs concomitant with the IDO inhibitor 1-methyl-tryptophan, or those treated with IDO(-/-)-MSCs alone, were unable to achieve allograft tolerance--revealing that functional IDO was necessary for the immunosuppression observed with WT-MSC treatment.
CONCLUSIONS
IDO secreted by MSCs was responsible, at least in part, for induction of kidney allograft tolerance through generation of Tregs. This study supports the clinical application of MSCs in transplantation.
背景
间充质干细胞（MSCs）的免疫调节特性已在体外和体内得到观察。然而，这种免疫调节的潜在机制仍未确定。最近的研究表明，MSCs 表达色氨酸分解酶吲哚胺 2,3-双加氧酶（IDO），已知其抑制 T 细胞反应。本研究旨在探讨 MSCs 是否诱导肾移植耐受，以及 IDO 是否有助于 MSCs 在体内的免疫调节功能。
方法
在接受支持生命的同种异体 C57BL/6 肾移植后 24 小时，将来自野生型（WT-MSCs）或 IDO 敲除（IDO(-/-)-MSCs）C57BL/6 小鼠的 MSCs（1×10(6)，静脉内）注射到 BALB/c 受者体内。
结果
WT-MSC 治疗的受者实现了移植物耐受，组织学正常，抗供体抗体水平无法检测。耐受受者表现出循环犬尿氨酸水平升高和明显高频率的耐受性树突状细胞。它们还表现出明显受损的 CD4+T 细胞反应，包括降低的供体特异性增殖能力和 Th2 优势细胞因子转移。此外，在受者脾脏和供体移植物中发现了高频率的 CD4+CD25+Foxp3+调节性 T 细胞（Tregs），抗体诱导的 CD25+细胞耗竭证实了 Tregs 在 MSC 诱导的耐受中的关键作用。有趣的是，同时接受 WT MSCs 和 IDO 抑制剂 1-甲基色氨酸治疗的肾移植受者，或单独接受 IDO(-/-)-MSCs 治疗的受者，均无法实现移植物耐受——这表明 WT-MSC 治疗中观察到的免疫抑制作用需要功能性 IDO。
结论
MSCs 分泌的 IDO 通过产生 Tregs 对诱导肾移植耐受起作用，至少部分起作用。这项研究支持 MSC 在移植中的临床应用。
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