Indoleamine 2, 3-Dioxgenase Transfected Mesenchymal Stem Cells Induce Kidney Allograft Tolerance by Increasing the Production and Function of Regulatory T Cells
Indoleamine 2, 3-Dioxgenase Transfected Mesenchymal Stem Cells Induce Kidney Allograft Tolerance by Increasing the Production and Function of Regulatory T Cells
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DOI：
10.1097/tp.0000000000000856
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发表时间：
2015-09-01
期刊：
影响因子：
6.2
通讯作者：
Wu, Xiongfei
中科院分区：
文献类型：
--
作者：
He, Yue;Zhou, Shan;Wu, Xiongfei
背景。间充质干细胞（MSC）的免疫调节特性已在体外得到很好的表征。然而，间充质干细胞在器官移植中的作用仍不清楚。本研究的目的是检查吲哚胺 2, 3-双加酶 (IDO) 转染的 MSC 在体外和体内免疫调节中的作用。方法。将野生型（WT）MSCs、空慢病毒转染的MSCs（Lenti-MSCs）或IDO慢病毒转染的MSCs（IDO-MSCs）与外周血单核细胞（PBMCs）或CD4（+）CD25（+）调节性T（Treg）细胞共培养，以体外研究IDO对MSCs免疫调节特性的影响。术后立即将WT-MSCs、Lenti-MSCs或IDO-MSCs（2×10(6)/kg）静脉注射给兔肾移植受者，以检测IDO-MSCs在体内耐受诱导中的作用。结果。 MSCs的慢病毒感染导致IDO的稳定表达。 IDO-MSCs比WT-MSCs更能抑制CD4(+)CD25(-)效应T细胞的增殖。 PBMCs和IDO-MSCs的共培养诱导PBMCs中CD4(+)CD25(+)Foxp3(+) Treg细胞的比例更高。此外，这些CD4(+)CD25(+) Treg细胞的抗原特异性抑制功能也增强。 IDO-MSC 处理的 Treg 细胞显示细胞毒性 T 淋巴细胞相关抗原 4 的表达上调，并且 IL-10 和 TGF-β 的分泌增加。低剂量的IDO-MSCs通过诱导抗原特异性CD4(+)CD25(+) Treg细胞延长移植物存活并诱导耐受性，这一点通过IDO-MSCs治疗的肾移植受者接受供者特异性皮肤移植物但拒绝第三方移植物的发现得到证明。结论。 IDO 增加了 MSC 的直接免疫调节特性。 IDO-MSCs增强CD4(+)CD25(+)Foxp3(+) Treg细胞的表达和功能并诱导同种异体移植物耐受。
Background. The immunoregulatory properties of mesenchymal stem cells (MSCs) have been well characterized in vitro. However, the role of MSCs in organ transplantation remains unclear. The purpose of this study was to examine the role of indoleamine 2, 3-dioxgenase (IDO)-transfected MSCs in immunoregulation both in vitro and in vivo. Methods. Wild-type (WT) MSCs, empty lentivirus-transfected MSCs (Lenti-MSCs) or IDO-lentivirus-transfected MSCs (IDO-MSCs) were cocultured with peripheral blood mononuclear cells (PBMCs) or CD4(+)CD25(+) regulatory T (Treg) cells to examine the impact of IDO on the immunoregulatory properties of MSCs in vitro. WT-MSCs, Lenti-MSCs or IDO-MSCs (2 x 10(6)/kg) were intravenously injected into rabbit renal transplant recipients immediately after surgery to examine the role of IDO-MSCs in tolerance induction in vivo. Results. Lentivirus infection of MSCs resulted in stable expression of IDO. The IDO-MSCs inhibited the proliferation of CD4(+)CD25(-) effector T cells to a greater extent than WT-MSCs. Coculture of PBMCs and IDO-MSCs induced a higher percentage of CD4(+)CD25(+)Foxp3(+) Treg cells in PBMCs. Additionally, the antigen-specific suppressive function of these CD4(+)CD25(+) Treg cells was increased. The IDO-MSC-streated Treg cells showed upregulated expression of cytotoxic T-lymphocyte-associated antigen 4 and increased secretion of IL-10 and TGF-beta. Low doses of IDO-MSCs prolonged graft survival and induced tolerance by inducing antigen-specific CD4(+)CD25(+) Treg cells, as evidenced by the finding that IDO-MSCs-treated kidney transplant recipients accepted donor-specific skin grafts but rejected third-party grafts. Conclusions. The IDO increased the direct immunoregulatory properties of MSCs. The IDO-MSCs enhanced the expression and function of CD4(+)CD25(+)Foxp3(+) Treg cells and induced allograft tolerance.