PD-1/PD-L1信号通路在肝脏疾病中的功能及作用机制

潘思宇; 王志鑫; 周灜; 王涛; 尹杰; 王强; 樊海宁

doi:10.3969/j.issn.1001-5256.2019.03.050

PD-1/PD-L1信号通路在肝脏疾病中的功能及作用机制

DOI: 10.3969/j.issn.1001-5256.2019.03.050

青海大学附属医院肝胆胰外科

基金项目:

青海省卫计委重点课题(2016-wjzd-04)；青海省科技厅项目(2017-SF-L2)；

详细信息

中图分类号: R575
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出版历程
- 出版日期: 2019-03-20

Function and mechanism of action of the PD-1/PD-L1 pathway in liver diseases

Department of Hepatopancreatobiliary Surgery, Qinghai University Affiliated Hospital

Research funding:

摘要

摘要: 程序性死亡受体（PD） 1是一种重要的免疫抑制分子,与其配体PD-L1相互作用后,在中枢及外周免疫耐受、移植免疫、肿瘤免疫逃逸、自身免疫性疾病中发挥至关重要的作用。目前,关于PD-1/PD-L1信号通路参与肝脏疾病的发生发展尚无系统性认识。归纳了PD-1/PD-L1信号通路参与肝脏疾病进展的相关研究文献,对PD-1/PD-L1信号通路免疫调节功能及其在肝脏疾病中的作用进行阐述。认为PD-1/PD-L1信号通路参与了肝脏免疫调节功能,对肝脏炎症、自身免疫性肝病、病毒性肝病、肿瘤免疫逃逸、移植排斥反应、诱导免疫应答及自身免疫耐受等疾病的发生发展发挥重要作用,对PD-1/PD-L1信号通路的干预可能为肝脏疾病的防治提供新的策略和方向。
- 肝疾病 /
- 胞间信号肽类和蛋白质类 /
- 程序性死亡受体1 /
- 综述
Abstract: Programmed death-1 ( PD-1) is an important immunosuppressive molecule which interacts with its ligand programmed death-ligand 1 ( PD-L1) and plays an important role in central/peripheral immune tolerance, transplantation immunity, tumor immune escape, and autoimmune disease. At present, there is still no systematic understanding of the role of the PD-1/PD-L1 pathway in the developmentand progression of liver diseases. This article summarizes related studies on the role of the PD-1/PD-L1 pathway in the progression of liverdiseases and reviews the immunoregulatory function of the PD-1/PD-L1 pathway and its role in liver diseases. It is pointed out that thePD-1/PD-L1 pathway is involved in immunoregulatory function of the liver and plays an important role in the development and progressionof liver inflammation, autoimmune liver diseases, viral liver diseases, tumor immune escape, transplantation rejection reaction, induced im-mune response, and autoimmune tolerance. Intervention of the PD-1/PD-L1 pathway may provide new strategies and directions for theprevention and treatment of liver disease.
- liver diseases /
- intercellular signaling peptides and proteins /
- programmed death 1 /
- review

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参考文献(43)

[1] CHEN L, HAN X. Anti-PD-1/PD-L1 therapy of humancancer:Past, present, and future[J]. J Clin Invest, 2015, 125 (9) :3384-3391.

[2] KIM JW, EDER JP. Prospects for targeting PD-1 and PD-L1in various tumor types[J]. Oncology, 2014, 3 (11 Suppl 3) :15-28.

[3] REBELATTO MC, MIDHA A, MISTRY A, et al. Development ofa programmed cell death ligand-1 immunohistochemical as-say validated for analysis of non-small cell lung cancer andhead and neck squamous cell carcinoma[J]. Diagn Pathol, 2016, 11 (1) :95-97.

[4] ROZALI EN, HATO SV, ROBINSON BW, et al. Programmeddeath ligand 2 in cancer-induced immune suppression[J].Clin Dev Immunol, 2012, 2012 (2) :656340.

[5] YOKOSUKA T, TAKAMATSU M, KOBAYASHIIMANISHI W, etal. Programmed cell death 1 forms negative costimulatory mi-croclusters that directly inhibit T cell receptor signaling by re-cruiting phosphatase SHP2[J]. J Exp Med, 2012, 209 (6) :1201-1217.

[6] HUI E, CHEUNG J, ZHU J, et al. T cell costimulatory receptorCD28 is a primary target for PD-1-mediated inhibition[J].Science, 2017, 355 (6332) :1428-1432.

[7] PATSOUKIS N, BROWN J, PETKOVA V, et al. Selective effectsof PD-1 on Akt and Ras pathways regulate molecular compo-nents of the cell cycle and inhibit T cell proliferation[J]. Sci Sig-nal, 2012, 5 (230) :46-50.

[8] CHAMOTO K, CHOWDHURY PS, KUMAR A, et al. Mitochon-drial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity[J]. ProcNatl Acad Sci U S A, 2017, 114 (5) :e761-e770.

[9] CHANG CH, QIU J, O'SULLIVAN D, et al. Metabolic competi-tion in the tumor microenvironment is a driver of cancer pro-gression[J]. Cell, 2015, 162 (6) :1229-1241.

[10] SPRANGER S, KOBLISH HK, HORTON B, et al. Mechanismof tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and prolif-eration of CD8 (+) T cells directly within the tumor microenvi-ronment[J]. J Immunother Cancer, 2014, 2 (1) :3-6.

[11] TAO LL, LAI X, WEI J. PD-1/PD-L signaling pathway inchronic hepatitis B[J]. J Clin Hepatol, 2016, 32 (12) :2373-2378. (in Chinese) 陶丽琳, 赖欣, 韦嘉. PD-1/PD-L信号通路在慢性HBV感染免疫反应中的作用[J].临床肝胆病杂志, 2016, 32 (12) :2373-2378.

[12] AHN J, BISHOP JA, RODEN RBS, et al. The PD-1 and PD-L1 pathway in recurrent respiratory papillomatosis[J]. La-ryngoscope, 2017, 128 (1) :e27-e32.

[13] TREHANPATI N, VYAS AK. Immune regulation by T regulatorycells in hepatitis B virus-related inflammation and cancer[J].Scand J Immunol, 2017, 85 (3) :175-181.

[14] PENG JP, SUN KW, WU YN, et al. Programmed cell death 1expression on HBV-specific CTLs induced by dendritic cellsin chronic hepatitis B patients[J]. J Clin Hepatol, 2012, 28 (12) :926-929. (in Chinese) 彭建平, 孙克伟, 伍玉南, 等.慢性乙型肝炎患者树突状细胞诱导的HBV特异性细胞毒性T淋巴细胞PD-1的表达[J].临床肝胆病杂志, 2012, 28 (12) :926-929.

[15] ZHU Q, CHENG BQ, LIN WG, et al. Study on relationship be-tween chronic hepatitis B HBVDNA and pd-1/pd-L1[J].Fujian Med J, 2018, 40 (1) :8-10. (in Chinese) 朱琪, 程变巧, 林伟国, 等.慢性乙型肝炎HBV DNA载量与PD-1/PD-L1表达相关性研究[J].福建医药杂志, 2018, 40 (1) :8-10.

[16] BUKH J. The history of hepatitis C virus (HCV) :Basic re-search reveals unique features in phylogeny, evolution and theviral life cycle with new perspectives for epidemic control[J].J Hepatol, 2016, 65 (1) :s2-s21.

[17] KONG LB, NAN YM, ZHANG YG, et al. Association of pro-grammed cell death-1 gene polymorphisms with chronic hep-atitis C virus infection and antiviral effect[J]. J Clin Hepatol, 2016, 32 (9) :1721-1724. (in Chinese) 孔令波, 南月敏, 张玉果, 等.程序性细胞死亡受体1基因多态性与慢性HCV感染及抗病毒疗效的关系[J].临床肝胆病杂志, 2016, 32 (9) :1721-1724.

[18] WEN X, LONG FJ, XIAO ZD, et al. PD-1/PD-L1 signalpathway participates in HCV F protein-induced T cell dys-function in chronic HCV infection[J]. Immunol Res, 2016, 64 (2) :412-423.

[19] ZHANG M, ZHANG L, LI H, et al. Circulating T follicular help-er cells are associated with rapid virological response in chron-ic hepatitis C patients undergoing peginterferon therapy[J].Int Immunopharmacol, 2016, 34:235-243.

[20] XIAO W, PEI JP, JI XW, et al. An overview of immunoregula-tory roles of PD-1/PD-L1 in HCV treatment[J]. Chin J DisControl Prev, 2017, 21 (2) :200-205. (in Chinese) 肖雯, 裴家平, 季晓伟, 等. HCV治疗中PD-1/PD-L1信号免疫调控作用的研究概况[J].中华疾病控制杂志, 2017, 21 (2) :200-205.

[21] ZHAI N, LI H, SONG H, et al. Hepatitis C virus induces MD-SCs-like monocytes through TLR2/PI3K/AKT/STAT3 signa-ling[J]. PLos One, 2017, 12 (1) :e0170516.

[22] SAAB S, RHEEM J, JIMENEZ M, et al. Curing hepatitis C in livertransplant recipients is associated with changes in immunosup-pressant use[J]. J Clin Transl Hepatol, 2016, 4 (1) :32-38.

[23] THAN NN, WIEGARD C, WEILER-NORMANN C, et al. Long-term follow-up of patients with difficult to treat type 1 auto-immune hepatitis on tacrolimus therapy[J]. Scand J Gastro-enterol, 2016, 51 (3) :329-336.

[24] LEONARDI GC, GAINOR JF, ALTAN M, et al. Safety of pro-grammed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disor-ders[J]. J Clin Oncol, 2018, 36 (19) :1905-1908.

[25] RUI ZL. Programmed cell death-1 and programmed celldeath-1 receptor on peripheral blood CD8+T lymphocytes inpatients with autoimmune hepatitis[J]. J Prac Hepatol, 2017, 20 (3) :352-353. (in Chinese) 芮志莲.自身免疫性肝炎患者外周血CD8+T淋巴细胞PD-1表达水平变化[J].实用肝脏病杂志, 2017, 20 (3) :352-353.

[26] ZHANG B, CHIKUMA S, HORI S, et al. Nonoverlapping rolesof PD-1 and FoxP3 in maintaining immune tolerance in a no-vel autoimmune pancreatitis mouse model[J]. Proc Natl AcadSci U S A, 2016, 113 (30) :8490-8495.

[27] AARSLEV K, DIGE A, GREISEN SR, et al. Soluble programmeddeath-1 levels are associated with disease activity and treatmentresponse in patients with autoimmune hepatitis[J]. Scand J Gas-troenterol, 2017, 52 (1) :93-99.

[28] GUTZMER R, KOOP A, MEIER F, et al. Programmed celldeath protein-1 (PD-1) inhibitor therapy in patients withadvanced melanoma and preexisting autoimmunity or ipili-mumab-triggered autoimmunity[J]. Eur J Cancer, 2017, 75 (1) :24-32.

[29] FU J, WANG H. Precision diagnosis and treatment of livercancer in China[J]. Cancer Lett, 2017, 41 (2) :78-83.

[30] CALDERARO J, ROUSSEAU B, AMADDEO G, et al. PD-L1expression in hepatocellular carcinoma:Relationship with clini-cal and pathological features[J]. Hepatology, 2016, 64 (6) :2038-2041.

[31] SHI S, RAO Q, ZHANG C, et al. Dendritic cells pulsed withexosomes in combination with PD-1 antibody increase the ef-ficacy of sorafenib in hepatocellular carcinoma model 1, 2[J].Transl Oncol, 2018, 11 (2) :250-258.

[32] LICHTENEGGER FS, ROTHE M, SCHNORFEIL FM, et al. Targe-ting LAG-3 and PD-1 to enhance T cell activation by antigen-presenting cells[J]. Front Immunol, 2018, 9 (3) :85-90.

[33] HUANG A, ZHANG B, YAN W, et al. Myeloid-derived sup-pressor cells regulate immune response in patients with chron-ic hepatitis B virus infection through PD-1-induced IL-10[J]. J Immunol, 2014, 193 (11) :5461-5469.

[34] YANG L, ZHU XL, LI G. Expression of programmed death--ligand 1 in hepatocellular carcinoma and its clinical signifi-cance[J]. J Clin Hepatol, 2016, 32 (8) :1630-1634. (inChinese) 杨柳, 朱曦龄, 黎功.程序性死亡因子配体1在肝细胞癌中的表达及意义[J].临床肝胆病杂志, 2016, 32 (8) :1630-1634.

[35] HUANG F, WANG B, ZENG J, et al. MicroRNA-374b inhibitsliver cancer progression via down regulating programmed celldeath-1 expression on cytokine-induced killer cells[J]. On-col Lett, 2018, 15 (4) :66-69.

[36] FANG D, CHEN ZY. Diagnosis and treatment of hepatic alveo-lar echinococcosis[J]. J Clin Hepatol, 2017, 33 (5) :990-993. (in Chinese) 方丹, 陈哲宇.肝泡状棘球蚴病的诊断和治疗[J].临床肝胆病杂志, 2017, 33 (5) :990-993.

[37] HUANG SB, MI YY, LIU AQ, et al. The status and progres-sion in the diagnosis of hepatic echinococcosis[J]. Prog ModBiomed, 2016, 16 (4) :797-800. (in Chinese) 黄士波, 米圆圆, 刘爱琴, 等.肝包虫病的诊断现状及进展[J].现代生物医学进展, 2016, 16 (4) :797-800.

[38] ZHANG F, PANG N, ZHU Y, et al. CCR7 (lo) PD-1 (hi) CX-CR5 (+) CD4 (+) T cells are positively correlated with levelsof IL-21 in active and transitional cystic echinococcosis pa-tients[J]. BMC Infect Dis, 2015, 15 (1) :457-461.

[39] LI Y, XIAO Y, SU M, et al. Role of soluble programmed death-1 (sPD-1) and sPD-ligand 1 in patients with cystic echi-nococcosis[J]. Exp Ther Med, 2016, 11 (1) :251-256.

[40] LA X, ZHANG F, LI Y, et al. Upregulation of PD-1 on CD4+CD25+T cells is associated with immunosuppression in liver ofmice infected with Echinococcus multilocularis[J]. Int Immu-nopharmacol, 2015, 26 (2) :357-366.

[41] SONG ZP, GUO D, CAI ZM, et al. Research progress of im-munobiology in organ xenotransplantation[J]. Ogran Trans-plantation, 2018, 9 (3) :236-238. (in Chinese) 宋宗培, 郭蝶, 蔡志明, 等.异种器官移植免疫生物学研究进展[J].器官移植, 2018, 9 (3) :236-238.

[42] de MARE-BREDEMEIJER EL, MANCHAM S, VERSTEGENMM, et al. Human graft-derived mesenchymal stromal cellspotently suppress alloreactive T-cell responses[J]. StemCells Dev, 2015, 24 (12) :1436-1447.

[43] SHI XL, MANCHAM S, HANSEN BE, et al. Counter-regula-tion of rejection activity against human liver grafts by donor PD-L1 and recipient PD-1 interaction[J]. J Hepatol, 2016, 64 (6) :1274-1282.

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