Practical Journal of Organ Transplantation(Electronic Version) ›› 2013, Vol. 1 ›› Issue (3): 138-146.

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The role of indoleamine 2,3-dioxygenase in mesenchymal stem cell induced kidney allograft tolerance

JIANG Xue-ming,ZHANG Zhi-xiang,GAO Chao,LIU Tong,TIAN Wei-jun,QI Feng,HAN Hong-qiu,WANG Hao.
  

  1. General Surgery,General Hospital of Tianjin Medical University,Tianjin Institute of General Surgery,Tianjin 300052,China
  • Online:2013-05-20 Published:2021-04-27

吲哚胺 2,3- 双加氧酶在间充质干细胞诱导肾移植免疫耐受中的作用

姜雪明,章志翔,高超,刘彤,田伟军,戚峰,韩洪秋,王浩   

  1. 天津医科大学总医院普通外科,天津普通外科研究所,天津 300052
  • 基金资助:

    国家自然科学基金面上项目(81273257);

    天津市外国专家局引进国外技术、管理人才项目(Y2012087);

    天津医科大学总医院科研启动基金

Abstract:

Objective To determine whether mesenchymal stem cells(MSCs)can induce the establishment of kidney allograft tolerance,as well as indoleamine 2,3-dioxygenase(IDO)contributes to the immunoregulatory functions of MSCs in that process. Methods MSCs(1×106)from wild-type(wt-MSCs)or IDO-knockout (IDO-/--MSCs)C57BL/6 mice were injected intravenously into BALB/c recipients 24 hours after receiving a life-supporting orthotopic C57BL/6 renal graft. Recipients treated with either wt-MSCs or IDO-/--MSCs were used as two study groups(n=6/group). In addition,6 native BALB/c mice were used as controls. Samples were collected at endpoint of graft rejection or on postoperative day(POD)100. Long-term surviving BALB/c kidney allograft recipients received full-thickness skin grafts(1 cm×1 cm)from C57BL/6 donor and C3H mouse strains on POD100 and were monitored daily. The graft pathology,immunohistochemistry,flow cytometry,mixed lymphocyte reaction were used for detecting graft rejection,intragraft Foxp3+ cell infiltration,donor-reactive antibody and cellular phenotypic expression,dendritic cell(DC)and T cell function,respectively. Results wt-MSC-treated recipients achieved allograft tolerance with normal histology and undetectable antidonor antibody levels. Tolerant recipients demonstrated significantly high frequencies of tolerogenic dendritic cells(Tol-DCs). In addition,high frequencies of CD4+CD25+Foxp3+ regulatory T-cells(Tregs)were found in recipient spleens and donor grafts,implying the important role of Tregs in the MSC-induced tolerance. Interestingly,renal allograft recipients treated with IDO-/--MSCs, were unable to achieve allograft tolerance,suggesting that functional IDO was necessary for the immunosuppression observed with wt-MSC treatment. Conclusion IDO secreted by MSCs was responsible for induction of kidney allograft tolerance through generation of Tregs. This study supports the clinical application of MSCs in transplantation

Key words:

Indoleamine 2, 3-dioxygenase Mesenchymal stem cells Regulatory T cells Tolerance Kidney transplantation 

摘要:

目的 研究探讨骨髓间充质干细胞(MSC)是否能够诱导肾脏移植物免疫耐受的产生以及吲 哚胺 2,3- 双加氧酶(IDO)在 MSC 介导免疫调节反应中的作用。方法 BALB/c 小鼠接受 C57BL/6 小 鼠移植肾脏后 24 小时,C57BL/6 小鼠来源的正常(wt)或 IDO 基因敲除(IDO-/-)的 MSC1×106)经静 脉注入到移植受体中,分别作为 wt-MSC 治疗组和 IDO-/--MSC 治疗组,每组 6 只。以 6 只未注射的 BALB/c移植小鼠受体为未治疗组。以移植物排斥反应所致小鼠死亡或术后 100 天设定为研究终点。长期存活的 BALB/c 肾移植受体在移植术后 100 天,接受来自 C57BL/6 供体或第三方移植物供体 C3H(H-2k)小鼠的 皮肤移植,监测移植皮肤情况。对 3 组小鼠进行移植物组织病理学观察,免疫组化评估肾脏组织 Foxp3+ 胞水平。用流式细胞技术进行抗原特异性抗体和细胞表型检测,用混合淋巴细胞反应(MLR)评估树突细 胞(DC)和 T 细胞功能。结果 本研究发现 wt-MSC 治疗可诱导受体产生同种异体移植物免疫耐受,表现 为移植物病理检查结果正常、未发现抗原特异性抗体水平升高、免疫耐受受体中耐受性树突细胞(Tol-DC 数量显著增多等。同时,在免疫耐受的受体脾脏和肾移植物中均可发现大量 CD4+CD25+Foxp3+ 调节性 T 胞(Treg)。这些结果均提示 Treg MSC 诱导免疫耐受中的重要作用。值得关注的是,经 IDO-/--MSC 处理 的移植受体中,MSC 丧失了其诱导同种异体移植物的免疫耐受的能力,肾移植物很快被排斥,同时机体移 植物的排斥反应变化与未治疗组相同。结论 MSC 分泌的 IDO 通过促进 Treg 的生成,在诱导肾脏移植 免疫耐受中起着关键性的作用。本研究将为 MSC 在器官移植中的临床应用提供理论及临床转化依据。

关键词:

吲哚胺 2, 3- 双加氧酶 骨髓间充质干细胞 调节性 T 细胞 免疫耐受 肾移植