Prevention of allograft rejection in heart transplantation through concurrent gene silencing of TLR and Kinase signaling pathways.
Prevention of allograft rejection in heart transplantation through concurrent gene silencing of TLR and Kinase signaling pathways.
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通过同时沉默 TLR 和激酶信号通路基因来预防心脏移植中的同种异体移植排斥
DOI：
10.1038/srep33869
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发表时间：
2016-09-23
影响因子：
4.6
通讯作者：
Min W
中科院分区：
文献类型：
--
作者：
Wang H;Zhang X;Zheng X;Lan Z;Shi J;Jiang J;Zwiep T;Li Q;Quan D;Zhang ZX;Min W
Toll样受体（TLR）作为引发剂和导体，负责器官移植中的先天性和适应性免疫应答。哺乳动物雷帕霉素靶蛋白（mTOR）是影响细胞功能包括代谢、生长和存活的广泛方面的最关键的信号传导激酶之一。在心脏移植前3天和7天以及移植后7天、14天和21天，用MyD 88、TRIF和mTOR siRNA载体处理受体（BALB/c）。siRNA治疗后，受体接受完全MHC错配的C57 BL/6心脏。用mTOR siRNA治疗显著延长了心脏移植中的同种异体移植物存活。此外，mTOR siRNA与MyD 88和TRIF siRNA的组合进一步延长了同种异体移植物存活;流式细胞术分析显示，在MyD 88、TRIF和mTOR处理的小鼠中，脾淋巴细胞中FoxP 3表达上调，同时脾树突状细胞中CD 40、CD 86表达下调，PD-L1表达上调。在从耐受受体分离的T细胞中存在显著上调的T细胞耗竭。这项研究是通过TLR和激酶信号通路的同时基因沉默来预防同种异体心脏移植物的免疫排斥反应的首次证明，突出了siRNA在临床移植中的治疗潜力。
Toll-like receptors (TLRs) act as initiators and conductors responsible for both innate and adaptive immune responses in organ transplantation. The mammalian target of rapamycin (mTOR) is one of the most critical signaling kinases that affects broad aspects of cellular functions including metabolism, growth and survival. Recipients (BALB/c) were treated with MyD88, TRIF and mTOR siRNA vectors, 3 and 7 days prior to heart transplantation and 7, 14 and 21 days after transplantation. After siRNA treatment, recipients received a fully MHC-mismatched C57BL/6 heart. Treatment with mTOR siRNA significantly prolonged allograft survival in heart transplantation. Moreover, the combination of mTOR siRNA with MyD88 and TRIF siRNA further extended the allograft survival; Flow cytometric analysis showed an upregulation of FoxP3 expression in spleen lymphocytes and a concurrent downregulation of CD40, CD86 expression, upregulation of PD-L1 expression in splenic dendritic cells in MyD88, TRIF and mTOR treated mice. There is significantly upregulated T cell exhaustion in T cells isolated from tolerant recipients. This study is the first demonstration of preventing immune rejection of allogeneic heart grafts through concurrent gene silencing of TLR and kinase signaling pathways, highlighting the therapeutic potential of siRNA in clinical transplantation.
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DOI：
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