李先亮, 白纯, 杨龙, 等. 大鼠肝移植免疫耐受过程Th细胞和Treg细胞因子及信号通路蛋白的变化研究[J]. 器官移植, 2019, 10(4): 416-422. DOI: 10.3969/j.issn.1674-7445.2019.04.011
引用本文: 李先亮, 白纯, 杨龙, 等. 大鼠肝移植免疫耐受过程Th细胞和Treg细胞因子及信号通路蛋白的变化研究[J]. 器官移植, 2019, 10(4): 416-422. DOI: 10.3969/j.issn.1674-7445.2019.04.011
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Li Xianliang, Bai Chun, Yang Long, et al. Changes of Th, Treg cytokines and signaling pathway proteins during immune tolerance process in rat models of liver transplantation[J]. ORGAN TRANSPLANTATION, 2019, 10(4): 416-422. DOI: 10.3969/j.issn.1674-7445.2019.04.011
Citation: Li Xianliang, Bai Chun, Yang Long, et al. Changes of Th, Treg cytokines and signaling pathway proteins during immune tolerance process in rat models of liver transplantation[J]. ORGAN TRANSPLANTATION, 2019, 10(4): 416-422. DOI: 10.3969/j.issn.1674-7445.2019.04.011
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大鼠肝移植免疫耐受过程Th细胞和Treg细胞因子及信号通路蛋白的变化研究

Changes of Th, Treg cytokines and signaling pathway proteins during immune tolerance process in rat models of liver transplantation

    摘要
  • 摘要:
      目的  探讨大鼠肝移植免疫耐受过程中，辅助性T细胞（Th）和调节性T细胞（Treg）细胞因子及相关信号通路蛋白的变化与免疫耐受的关系。
      方法  双袖套法建立原位肝移植模型，将大鼠分为3组：手术对照组（6只），假手术不进行肝移植；短期组（10只），术后存活10 d；耐受组（10只），术后存活100 d，移植肝功能恢复正常。检测各组大鼠肝功能指标如丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST），Th1细胞因子干扰素（IFN）-γ、白细胞介素（IL）-2、肿瘤坏死因子（TNF）-α，Th2细胞因子（IL-4、IL-5、IL-6、IL-13），Th17细胞因子粒细胞-巨噬细胞集落刺激因子（GM-CSF）、IL-17A，Treg细胞因子IL-10、转化生长因子（TGF）-β、IL-12p表达水平。对各组大鼠血清进行蛋白芯片检测。
      结果  与手术对照组比较，短期组AST明显降低，ALT明显升高（P < 0.05）。而耐受组与手术对照组的AST、ALT水平比较，差异均无统计学意义（均为P > 0.05）。各组大鼠的肝组织中，与手术对照组比较，短期组Th1细胞因子IFN-γ、IL-2表达水平明显升高（均为P < 0.05）；耐受组Th2细胞因子IL-4的表达水平明显低于手术对照组（P < 0.05）；短期组Th2细胞因子IL-5、IL-6、IL-13的表达水平明显低于手术对照组（P < 0.05）；耐受组IL-17A的表达水平明显高于手术对照组（P < 0.05）。耐受组IL-10、IL-12p的表达水平明显高于手术对照组（均为P < 0.05），短期组TGF-β的表达水平明显高于手术对照组（P < 0.05）。与手术对照组比较，短期组细胞间黏附分子（ICAM）-1、前血小板碱性蛋白（Ppbp）、神经纤毛蛋白（Neuropilin）-2、Notch-2蛋白的表达水平明显升高（均为P < 0.05）；耐受组趋化因子配基17（CXCL17）、ICAM-1、Neuropilin-2蛋白的表达水平明显升高（均为P < 0.05），而B7-1蛋白的表达水平显著减低（P < 0.05）。
      结论  在大鼠肝移植自然免疫耐受过程中，Treg类细胞因子（IL-10、TGF-β、IL-12p），IL-6，IL-17以及细胞表面的跨膜信号通路分子（ICAM-1、Neuropilin-2、B7-1蛋白）在其中起到了重要的作用。

     

    Abstract:
      Objective  To investigate the relationship between immune tolerance and the changes of helper T cell (Th), regulatory T cell (Treg) cytokines, related signaling pathway proteins during immune tolerance process in rat models of liver transplantation.
      Methods  The orthotopic liver transplantation rat models were established by double-cuff technique. All rats were divided into 3 groups. In the operative control group (n=6), sham operation was performed without liver transplantation. In the short-term group (n=10), the rats survived for 10 d after liver transplantation. In the immune tolerance group (n=10), the rats survived for 100 d after operation and the function of the transplanted liver was restored to normal. The expression levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), Th1 cytokines interferon (IFN)-γ, interleukin (IL)-2 and tumor necrosis factor (TNF)-α, Th2 cytokines (IL-4, IL-5, IL-6 and IL-13), Th17 cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-17A, Treg cytokines IL-10, transforming growth factor (TGF)-β and IL-12p were quantitatively measured. The serum sample of rats in each group was detected by protein chip analysis.
      Results  Compared with the operative control group, the AST level in the short-term group was significantly down-regulated, whereas the ALT level was significantly up-regulated (both P < 0.05). However, the AST and ALT levels did not significantly differ between the immune tolerance group and operative control group (both P > 0.05). In the liver tissues of rats in each group, the expression levels of Th1 cytokines IFN-γ and IL-2 in the short-term group were significantly higher than those in the operative control group (both P < 0.05). The expression level of Th2 cytokine IL-4 in the immune tolerance group was significantly lower than that in the operative control group (P < 0.05). The expression levels of Th2 cytokines IL-5, IL-6 and IL-13 in the short-term group were significantly lower than those in the operative control group (all P < 0.05). The expression level of IL-17A in the immune tolerance group was significantly higher than that in the operative control group (P < 0.05). In the immune tolerance group, the expression levels of IL-10and IL-12p were significantly higher than those in the operative control group (both P < 0.05). The expression level of TGF-β in the short-term group was significantly higher than that in the operative control group (P < 0.05). Compared with the operative control group, the expression levels of intercellular adhesion molecule (ICAM)-1, pro-platelet basic protein (Ppbp), Neuropilin-2, Notch-2 protein in the short-term group were significantly up-regulated (all P < 0.05). The expression levels of CXC chemokine ligand 17 (CXCL17), ICAM-1 and Neuroleptin-2 protein were markedly up-regulated (all P < 0.05), whereas that of B7-1 protein was significantly down-regulated (P < 0.05) in the immune tolerance group.
      Conclusions  Treg cytokines (IL-10, TGF-β and IL-12p), IL-6, IL-17 and trans-membrane signaling pathway molecules (ICAM-1, Neuropilin-2, B7-1 proteins) play a pivotal role in the natural immune tolerance process of rat models of liver transplantation.

     

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