PD-1/PD-L1信号通路在肝脏疾病中的功能及作用机制
|
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。
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.
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.
引文
[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.
[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.