儿童肝移植免疫耐受相关进展

王凯; 高伟

doi:10.3969/j.issn.1001-5256.2019.11.005

儿童肝移植免疫耐受相关进展

DOI: 10.3969/j.issn.1001-5256.2019.11.005

王凯,
高伟

天津市第一中心医院儿童器官移植科

基金项目:

天津市卫计委攻关项目(16KG107)；天津市自然科学基金项目(17JCYBJC27500)；

详细信息

中图分类号: R726.5
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出版历程
- 收稿日期: 2019-10-07
- 出版日期: 2019-11-20

Research advances in immune tolerance in children receiving liver transplantation

Wang Kai,
Gao Wei

Department of Pediatric Organ Transplantation,Tianjin First Central Hospital

Research funding:

摘要

摘要: 相比于成人受者,儿童肝移植受者对于免疫耐受的需求更为迫切,成功实现免疫耐受的概率更高。但目前,在临床上缺乏有效的实验方案、免疫监测手段以及对长期停用免疫抑制剂后移植物组织学的评估,导致免疫耐受长期停留于理论阶段,尚未在临床上有效、广泛开展。通过对儿童肝移植术后免疫耐受在近年来的进展与面临的困难进行简要综述,以期对临床操控性免疫耐受提供一定的帮助。
- 肝移植 /
- 免疫耐受 /
- 儿童
Abstract: Compared with adult recipients,pediatric liver transplantation recipients have urgent needs for immune tolerance,with a higher probability of successful realization of immune tolerance. However at present,there is still a lack of effective experimental regimens,immune monitoring methods,and graft histological evaluation after long-term discontinuation of immunosuppressive agents in clinical practice,which results in the fact that immune tolerance stays in the theoretic stage and is not effectively implemented in clinical practice. This article reviews the advances and difficulties in immune tolerance in pediatric liver transplantation recipients in recent years,in order to provide help for operational immune tolerance in future.
- liver transplantation /
- immune tolerance /
- child

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参考文献(65)

[1] GAO W,WANG K,MA N,et al. Living donor liver transplantations for pediatric patients withbiliary atresia in a single center:306[J]. Chin J Organ Transplant,2019,41(1):13-17.(in Chinese)高伟，王凯，马楠，等．亲属活体肝移植治疗儿童胆道闭锁306例临床分析[J]．中华器官移植杂志，2019,41(1):13-17.

[2] NEPOM GT,ST CLAIR EW,TURKA LA. Challenges in the pursuit of immune tolerance[J]. Immunol Rev,2011,241(1):49-62.

[3] WALDMANN H. Tolerance:An overview and perspectives[J]. Nat Rev Nephrol,2010,6(10):569-576.

[4] de la GARZA RG,SAROBE P,MERINO J,et al. Trial of complete weaning from immunosuppression for liver transplant recipients:Factors predictive of tolerance[J]. Liver Transpl,2013,19(9):937-944.

[5] STARZL TE,DEMETRIS AJ,TRUCCO M,et al. Cell migration and chimerism after whole-organ transplantation:The basis of graft acceptance[J]. Hepatology,1993,17(6):1127-1152.

[6] MAZARIEGOS GV,REYES J,MARINO IR,et al. Weaning of immunosuppression in liver transplant recipients[J]. Transplantation,1997,63(2):243-249.

[7] ORLANDO G,MANZIA T,BAIOCCHI L,et al. The Tor Vergata weaning off immunosuppression protocol in stable HCV liver transplant patients:The updated follow up at 78 months[J].Transpl Immunol,2008,20(1-2):43-47.

[8] BENSELER V,TAY SS,BOWEN DG,et al. Role of the hepatic parenchyma in liver transplant tolerance:A paradigm revisited[J]. Dig Dis,2011,29(4):391-401.

[9] CRISPE IN. Immune tolerance in liver disease[J]. Hepatology,2014,60(6):2109-2117.

[10] SCHILDBERG FA,SHARPE AH,TURLEY SJ. Hepatic immune regulation by stromal cells[J]. Curr Opin Immunol,2015,32:1-6.

[11] DEMETRIS AJ,BELLAMY CO,GANDHI CR,et al. Functional immune anatomy of the liver-as an allograft[J]. Am J Transplant,2016,16(6):1653-1680.

[12] DEMETRIS AJ,MURASE N,NAKAMURA K,et al. Immunopathology of antibodies as effectors of orthotopic liver allograft rejection[J]. Semin Liver Dis,1992,12(1):51-59.

[13] FENG S,EKONG UD,LOBRITTO SJ,et al. Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants[J]. JAMA,2012,307(3):283-293.

[14] TAKATSUKI M,UEMOTO S,INOMATA Y,et al. Weaning of immunosuppression in living donor liver transplant recipients[J]. Transplantation,2001,72(3):449-454.

[15] DIJKE IE,HOEPPLI RE,ELLIS T,et al. Discarded human thymus is a novel source of stable and long-lived therapeutic regulatory T cells[J]. Am J Transplant,2016,16(1):58-71.

[16] FOOTE JB,KOK M,LEATHERMAN JM,et al. A sting agonist given with OX40 receptor and PD-L1 modulators primes immunity and reduces tumor growth in tolerized mice[J]. Cancer Immunol Res,2017,5(6):468-479.

[17] KUMAR P,ALHARSHAWI K,BHATTACHARYA P,et al. Soluble OX40L and JAG1 induce selective proliferation of functional regulatory Tcells independent of canonical TCR signaling[J].Sci Rep,2017,7:39751.

[18] BAEYENS A,SAADOUN D,BILLIARD F,et al. Effector T cells boost regulatory T cell expansion by IL-2,TNF,OX40,and plasmacytoid dendritic cells depending on the immune context[J]. J Immunol,2015,194(3):999-1010.

[19] FEHR T,SYKES M. Clinical experience with mixed chimerism to induce transplantation tolerance[J]. Transpl Int,2008,21(12):1118-1135.

[20] MATHEW JM,LEVENTHAL JR,MILLER J. Microchimerism in promoting graft acceptance in clinical transplantation[J]. Curr Opin Organ Transplant,2011,16(4):345-352.

[21] SCANDLING JD,BUSQUE S,SHIZURU JA,et al. Induced immune tolerance for kidney transplantation[J]. N Engl J Med,2011,365(14):1359-1360.

[22] MORRIS H,DEWOLF S,ROBINS H,et al. Tracking donorreactive T cells:Evidence for clonal deletion in tolerant kidney transplantpatients[J]. Sci Transl Med, 2015, 7(272):272ra10.

[23] HUTCHINSON JA,RIQUELME P,SAWITZKI B,et al. Cutting edge:Immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients[J]. J Immunol,2011,187(5):2072-2078.

[24] BEZIE S,PICARDA E,OSSART J,et al. Compensatory regulatory networks between CD8 T,B,and myeloid cells in organ transplantation tolerance[J]. J Immunol,2015,195(12):5805-5815.

[25] WANG K,LIU K,ZHOU CL,et al. Expressions of Treg/Th17cells in post liver transplantation acute rejection in pediatric recipients diagnosed with biliary atresia[J]. Chin J Hepatobiliary Surg,2019,25(1):5-9.(in Chinese)王凯，刘凯，周春雷，等．Treg/Th17细胞在胆道闭锁儿童肝移植术后急性排斥反应中的变化[J]．中华肝胆外科杂志，2019,25(1):5-9.

[26] TAUBERT R,DANGER R,LONDONO MC,et al. Hepatic infiltrates in operational tolerant patients after liver transplantation show enrichment of regulatory T cells before proinflammatory genes are downregulated[J]. Am J Transplant,2016,16(4):1285-1293.

[27] HAJKOVA M,HERMANKOVA B,JAVORKOVA E,et al. Mesenchymal stem cells attenuate the adverse effects of immunosuppressive drugs on distinct T cell subopulations[J]. Stem Cell Rev,2017,13(1):104-115.

[28] WHITEHOUSE G,GRAY E,MASTORIDIS S,et al. IL-2 therapy restores the impaired function of regulatory T cells induced by calcineurin inhibitors[J]. Proc Natl Acad Sci U S A,2017,114(27):7083-7088.

[29] KIM N,CHO SG. Overcoming immunoregulatory plasticity of mesenchymal stem cells for accelerated clinical applicationsTracking donor-reactive T cells:Evidence for clonal deletion in tolerant kidney transplantpatients[J]. Int J Hematol,2016,103(2):129-137.

[30] YOUNG JS,YIN D,VANNIER AGL,et al. Equal expansion of endogenous transplant-specific regulatory T cell and recruitment into the allograft during rejection and tolerance[J]. Front Immunol,2018,9:1385.

[31] TODO S,YAMASHITA K,GOTO R,et al. A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation[J]. Hepatology,2016,64(2):632-643.

[32] BRUNSTEIN CG,MILLER JS,MCKENNA DH,et al. Umbilical cord blood-derived T regulatory cells to prevent GVHD:Kinetics,toxicity profile,and clinical effect[J]. Blood,2016,127(8):1044-1051.

[33] WANG K,JIAGN WT,GAO W,et al. Effects of different immunosuppressants on peripheral CD4+CD25+FoxP3+regulatory T cells in post liver transplant patients[J]. Chin J Gen Surg,2015,30(2):135-139.(in Chinese)王凯，蒋文涛，高伟，等．不同免疫抑制剂对肝移植术后CD4+CD25+FoxP3+调节性T细胞的影响[J]．中华普通外科杂志，2015,30(2):135-139.

[34] HULL CM,NICKOLAY LE,ESTORNINHO M,et al. Generation of human islet-specific regulatory T cells by TCR gene transfer[J]. J Autoimmun,2017,79:63-73.

[35] BOARDMAN D,MAHER J,LECHLER R,et al. Antigen-specificity using chimeric antigen receptors:the future of regulatory T-cell therapy?[J]. Biochem Soc Trans,2016,42(2):342-348.

[36] ZHANG Q,LU W,LIANG CL,et al. Chimeric Antigen Receptor(CAR)Treg:A promising approach to inducing immunological tolerance[J]. Front Immunol,2018,9:2359.

[37] BOURDEAUX C,PIRE A,JANSSEN M,et al. Prope tolerance after pediatric liver transplantation[J]. Pediatr Transplant,2013,17(1):59-64.

[38] Banff Working Group on Liver Allograft Pathology. Importance of liver biopsy findings in immunosuppression management:Biopsy monitoring and working criteria for patients with operational tolerance[J]. Liver Transpl,2012,18(10):1154-1170.

[39] BENITEZ C,LONDONO MC,MIQUEL R,et al. Prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients[J]. Hepatology,2013,58(5):1824-1835

[40] DEMETRIS AJ,ISSE K. Tissue biopsy monitoring of operational Tolerance in liver allograft recipients[J]. Curr Opin Organ Transplant,2013,18(3):345-353.

[41] FENG S,DEMETRIS AJ,SPAIN KM,et al. Five-year histological and serological follow-up of operationally tolerant pediatric liver transplant recipients enrolled in WISP-R[J]. Hepatology,2017,65(2):647-660.

[42] WAKI K,SUGAWARA Y,MIZUTA K,et al. Predicting operational tolerance in pediatric living-donor liver transplantation by absence of HLA antibodies[J]. Transplantation,2013,95(1):177-183.

[43] OHE H,WAKI K,YOSHITOMI M,et al. Factors affecting operational tolerance after pediatric living-donor liver transplantation:Impact of early post-transplant events and HLA match[J]. Transpl Int,2012,25(1):97-106.

[44] YOSHITOMI M,KOSHIBA T,HAGA H,et al. Requirement of protocol biopsy before and after complete cessation of immunosuppression after liver transplantation[J]. Transplantation,2009,87(4):606-614.

[45] LEE JH,LEE SK,LEE HJ,et al. Withdrawal of immunosuppression in pediatric liver transplant recipients in Korea[J].Yonsei Med J,2009,50(6):784-788.

[46] LIN NC,WANG HK,YEH YC,et al. Minimization or withdrawal of immunosuppressants in pediatric liver transplant recipients[J]. J Pediatr Surg,2015,50(12):2128-2133.

[47] KIM JJ,MARKS SD. Long-term outcomes of children after solid organ transplantation[J]. Clinics(Sao Paulo),2014,69(Suppl 1):28-38.

[48] JHUN J,LEE SH,LEE SK,et al. Serial monitoring of immune markers being represented regulatory T Cell/T helper 17 cell ratio:Indicating tolerance for tapering immunosuppression after liver transplantation[J]. Front Immunol,2018,9:352.

[49] LAU AH,VITALONE MJ,HAAS K,et al. Mass cytometry reveals a distinct immunoprofile of operational tolerance in pediatric liver transplantation[J]. Pediatr Transplant,2016,20(8):1072-1080.

[50] KONG X,SUN R,CHEN Y,et al．γδT cells drive myeloidderived suppressor cell-mediated CD8+T cell exhaustion in hepatitis B virus-induced immunotolerance[J]. J Immunol,2014,193(4):1645-1653.

[51] ZHAO X,LI Y,OHE H,et al. Intragraft Vδ1γδT cells with a unique T-cell receptor are closely associated with pediatricsemiallogeneic liver transplant tolerance[J]. Transplantation,2013,95(1):192-202.

[52] PUIG-PEY I,BOHNE F,BENITEZ C,et al. Characterization ofγδT cell subsets in organ transplantation[J]. Transpl Int,2010,23(10):1045-1055.

[53] GOLDSCHMIDT I,KARCH A,MIKOLAJCZYK R,et al. Immune monitoring after pediatric liver transplantation-the prospective Chil SFree cohort study[J]. BMC Gastroenterol,2018,18(1):63.

[54] LI L,WOZNIAK LJ,RODDER S,et al. A common peripheral blood gene set for diagnosis of operational tolerance in pediatric and adult liver transplantation[J]. Am J Transplant,2012,12(5):1218-1228.

[55] ZHONG KB,ZHANG P,HE XS,et al. Immune parameters to serve as biomarkers and clinical significance in tolerant patients after liver transplantations[J]. Chin J Hepatobiliary Surg,2016,22(2):78-81.(in Chinese)钟克波，张鹏，何晓顺，等．肝移植术后免疫耐受患者相关指标的变化及其临床意义[J]．中华肝胆外科杂志，2016,22(2):78-81.

[56] KOSHIBA T,LI Y,TAKEMURA M,et al. Clinical,immunological,and pathological aspects of operational tolerance after pediatric living-donor liver transplantation[J]. Transpl Immunol,2007,17(2):94-97.

[57] LIU XQ,HU ZQ,PEI YF,et al. Clinical operational tolerance in liver transplantation:state-of-the-art perspective and future prospects[J]. Hepatobiliary Pancreat Dis Int,2013,12(1):12-33.

[58] DEMETRIS AJ,LUNZ JG,RANDHAWA P,et al. Monitoring of human liver and kidney allograft tolerance:A tissue/histopathology perspective[J]. Transpl Int,2009,22(1):120-141.

[59] MIYAGAWA-HAYASHINO A,YOSHIZAWA A,UCHIDA Y,et al. Progressive graft fibrosis and donor-specific human leukocyte antigen antibodies in pediatric late liver allografts[J].Liver Transpl,2012,18(11):1333-1342.

[60] SANADA Y,MATSUMOTO K,URAHASHI T,et al. Protocol liver biopsy is the only examination that can detect mid-term graft fibrosis after pediatric liver transplantation[J]. World J Gastroenterol,2014,20(21):6638-6650.

[61] VENTURI C,SEMPOUX C,QUINONES JA,et al. Dynamics of allograft fibrosis in pediatric liver transplantation[J]. Am J Transplant,2014,14(7):1648-1656.

[62] PONS JA,RAMIREZ P,REVILLA-NUIN B,et al. Immunosuppression withdrawal improves long-term metabolic parameters,cardiovascular risk factors and renal function in liver transplant patients[J]. Clin Transplant,2009,23(3):329-336.

[63] PERITO ER,MOHAMMAD S,ROSENTHAL P,et al. Posttransplant metabolic syndrome in the withdrawal of immunosuppression in Pediatric Liver Transplant Recipients(WISPR)pilot trial[J]. Am J Transplant,2015,15(3):779-785.

[64] ZHENG HB,WATKINS B,TKACHEV V,et al. The knife’s edge of tolerance:Inducing stable multilineage mixed chimerism but with a significant risk of CMV reactivation and disease in rhesus macaques[J]. Am J Transplant,2017,17(3):657-670.

[65] FENG S,BUCUVALAS J. Tolerance after liver transplantation:Where are we?[J]. Liver Transpl,2017,23(12):1601-1614.

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