留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

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

李先亮 白纯 杨龙 李瀚 吕少诚 朱继巧 马军 寇建涛 贺强

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
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

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

doi: 10.3969/j.issn.1674-7445.2019.04.011
基金项目: 

国家自然科学基金 81571554

国家自然科学基金 81471590

国家自然科学基金 81273270

详细信息
    通讯作者:

    李先亮,男,1971年生,博士,副主任医师,研究方向为器官移植诱导免疫耐受,Email:lixianliangbjcy@126.com

  • 中图分类号: R617, R322.1+1

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

More Information
  • 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。

     

  • 图  1  各组大鼠的肝功能比较

    与手术对照组比较,aP < 0.05

    Figure  1.  Comparison of liver function in rats among each group

    图  2  各组大鼠肝组织细胞因子表达水平的比较

    与手术对照组比较,aP < 0.05

    Figure  2.  Comparision of cytokine expression levels of liver tissues in rats among each group

    图  3  各组大鼠血清细胞因子表达水平的比较

    Figure  3.  Comparision of serum cytokine expression levels in rats among each group

    图  4  各组大鼠的蛋白芯片分析

    A图为手术对照组和短期组的基因差异分析;B图为手术对照组和耐受组的基因差异分析;C图为手术对照组和短期组的GO生物过程分析;D图为手术对照组和耐受组的GO生物过程分析;E图为手术对照组和短期组的GO分子功能分析;F图为手术对照组和耐受组的GO分子功能分析

    Figure  4.  Protein microarray analysis in rats among each group

  • [1] 李坤, 孔伟浩, 张俊斌, 等.MiR-155在大鼠肝移植术后排斥反应中作用机制的研究[J].器官移植, 2018, 9(3):194-199.DOI: 10.3969/j.issn.1674-7445.2018.03.005.

    LI K, KONG WH, ZHANG JB, et al. Study of miR-155 in the mechanism of rejection after liver transplantation in rats[J]. Organ Transplant, 2018, 9(3):194-199. DOI: 10.3969/j.issn.1674-7445.2018.03.005.
    [2] 叶林森, 张英才, 唐晖, 等.长期生存的肝移植受者外周血免疫细胞分析[J].中华普通外科杂志, 2017, 32(6):508-511.DOI: 10.3760/cma.j.issn.1007-631X.2017.06.014.

    YE LS, ZHANG YC, TANG H, et al. Peripheral blood immune cells in long-term survival patients after liver transplantation[J]. Chin J Gen Surg, 2017, 32(6):508-511. DOI: 10.3760/cma.j.issn.1007-631X.2017.06.014.
    [3] HWANG W, LEE J. Pathophysiologic implications of cytokines secretion during liver transplantation surgery[J]. Int J Med Sci, 2018, 15(14):1737-1745. DOI: 10.7150/ijms.28382.
    [4] LÓPEZ-ABENTE J, BERNALDO-DE-QUIRÓS E, CAMINO M, et al. Immune dysregulation and Th2 polarization are associated with atopic dermatitis in heart-transplant children: a delicate balance between risk of rejection or atopic symptoms[J]. Am J Transplant, 2019, 19(5):1536-1544. DOI: 10.1111/ajt.15245.
    [5] ETEGHADI A, PAK F, AHMADPOOR P, et al. Th1, Th2, Th17 cell subsets in two different immunosuppressive protocols in renal allograft recipients (sirolimus vs mycophenolate mofetil): a cohort study[J]. Int Immunopharmacol, 2019, 67:319-325. DOI: 10.1016/j.intimp.2018.12.033.
    [6] LIU M, LI S, LI MO. TGF-β control of adaptive immune tolerance: a break from Treg cells[J]. Bioessays, 2018, 40(11):e1800063. DOI: 10.1002/bies.201800063.
    [7] HOE E, ANDERSON J, NATHANIELSZ J, et al. The contrasting roles of Th17 immunity in human health and disease[J]. Microbiol Immunol, 2017, 61(2):49-56. DOI: 10.1111/1348-0421.12471.
    [8] NOACK M, MIOSSEC P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases[J]. Autoimmun Rev, 2014, 13(6):668-677. DOI: 10.1016/j.autrev.2013.12.004.
    [9] ZHENG L, LI Z, LING W, et al. Exosomes derived from dendritic cells attenuate liver injury by modulating the balance of Treg and Th17 cells after ischemia reperfusion[J]. Cell Physiol Biochem, 2018, 46(2):740-756. DOI: 10.1159/000488733.
    [10] ZHANG A, WANG K, ZHOU C, et al. Knockout of microRNA-155 ameliorates the Th1/Th17 immune response and tissue injury in chronic rejection[J]. J Heart Lung Transplant, 2017, 36(2):175-184. DOI: 10.1016/j.healun.2016.04.018.
    [11] LU L, LI G, RAO J, et al. In vitro induced CD4(+)CD25(+)Foxp3(+) Tregs attenuate hepatic ischemia-reperfusion injury[J]. Int Immunopharmacol, 2009, 9(5):549-552. DOI: 10.1016/j.intimp.2009.01.020.
    [12] PERUCHA E, MELCHIOTTI R, BIBBY JA, et al. The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells[J]. Nat Commun, 2019, 10(1):498. DOI: 10.1038/s41467-019-08332-9.
    [13] PILAT N, MAHR B, GATTRINGER M, et al. CTLA4Ig improves murine iTreg induction via TGFβ and suppressor function in vitro[J]. J Immunol Res, 2018:2484825. DOI: 10.1155/2018/2484825.
    [14] TEIJEIRA A, HUNTER MC, RUSSO E, et al. T cell migration from inflamed skin to draining lymph nodes requires intralymphatic crawling supported by ICAM-1/LFA-1 interactions[J]. Cell Rep, 2017, 18(4):857-865. DOI: 10.1016/j.celrep.2016.12.078.
    [15] SILVA PDE M, BIER J, PAIATTO LN, et al. Tolerogenic dendritic cells on transplantation: immunotherapy based on second signal blockage[J]. J Immunol Res, 2015:856707. DOI: 10.1155/2015/856707.
    [16] SCHELLENBURG S, SCHULZ A, POITZ DM, et al. Role of neuropilin-2 in the immune system[J]. Mol Immunol, 2017, 90:239-244. DOI: 10.1016/j.molimm.2017.08.010.
    [17] BURGHARDT S, CLAASS B, ERHARDT A, et al. Hepatocytes induce Foxp3+ regulatory T cells by notch signaling[J]. J Leukoc Biol, 2014, 96(4):571-577. DOI: 10.1189/jlb.2AB0613-342RR.
    [18] FINSTERBUSCH M, NORMAN MU, HALL P, et al. Platelet retention in inflamed glomeruli occurs via selective prolongation of interactions with immune cells[J]. Kidney Int, 2019, 95(2):363-374. DOI: 10.1016/j.kint.2018.08.042.
    [19] REN J, ZHOU T, PILLI VSS, et al. Novel paracrine functions of smooth muscle cells in supporting endothelial regeneration following arterial injury[J]. Circ Res, 2019, 124(8):1253-1265. DOI: 10.1161/CIRCRESAHA.118.314567.
    [20] SHARPE AH, FREEMAN GJ. The B7-CD28 superfamily[J]. Nat Rev Immunol, 2002, 2(2):116-126. doi: 10.1038/nri727
    [21] SHEN H, WU N, NANAYAKKARA G, et al. Co-signaling receptors regulate T-cell plasticity and immune tolerance[J]. Front Biosci (Landmark Ed), 2019, 24:96-132. doi: 10.2741/4710
    [22] LI K, CHENG X, TILEVIK A, et al. In situ and in silico kinetic analyses of programmed cell death-1 (PD-1) receptor, programmed cell death ligands, and B7-1 protein interaction network[J]. J Biol Chem, 2017, 292(16):6799-6809. DOI: 10.1074/jbc.M116.763888.
    [23] WATANABE M, FUJIHARA C, RADTKE AJ, et al. Co-stimulatory function in primary germinal center responses: CD40 and B7 are required on distinct antigen-presenting cells[J]. J Exp Med, 2017, 214(9):2795-2810. DOI: 10.1084/jem.20161955.
    [24] KANG S, ZHANG C, OHNO T, et al. Unique B7-H1 expression on masticatory mucosae in the oral cavity and trans-coinhibition by B7-H1-expressing keratinocytes regulating CD4+ T cell-mediated mucosal tissue inflammation[J]. Mucosal Immunol, 2017, 10(3):650-660. DOI: 10.1038/mi.2016.89.
  • 加载中
图(4)
计量
  • 文章访问数:  139
  • HTML全文浏览量:  82
  • PDF下载量:  15
  • 被引次数: 0
出版历程
  • 收稿日期:  2019-04-25
  • 网络出版日期:  2021-01-19
  • 刊出日期:  2019-07-15

目录

    /

    返回文章
    返回