耐受性树突状细胞在肝移植免疫耐受中应用进展

doi:10.3877/cma.j.issn.2095-3232.2026.03.018

肝移植已经成为挽救终末期肝病的最有效手段。而移植物排斥反应是影响器官移植受者长期存活的主要障碍，尽管免疫抑制剂的普遍应用可以显著改善患者的短期预后生存，但长期应用免疫抑制剂会增加如药物中毒、全身感染、肿瘤复发等不良事件的风险，且在改善移植物总生存率方面作用有限。因此如何诱导肝移植免疫耐受实现并维持移植物无免疫抑制状态长期存活仍然是器官移植领域迫切需要解决的科学问题。近年来，耐受性树突状细胞（tolDC）在肝移植术后免疫耐受方面的机制研究和临床试验初见成效。本文将tolDC的生物学特征、免疫调节作用及在临床肝脏移植中的应用进行综述，总结tolDC在诱导肝移植免疫耐受中的应用价值。

关键词: 肝移植, 免疫耐受, 树突状细胞, 排斥反应, 细胞因子

Liver transplantation has become the most effective therapeutic option for end-stage liver disease. Graft rejection is the main obstacle to the long-term survival of organ transplantation recipients. Although widespread use of immunosuppressants can significantly improve the short-term prognosis and survival of patients, long-term use of immunosuppressants will increase the risk of adverse events, such as drug poisoning, systemic infection and tumor recurrence, and exerts limited effect on improving the overall survival rate of grafts. Therefore, how to induce the immune tolerance of liver transplantation and maintain the long-term survival of grafts without use of immunosuppressants remains an urgent scientific challenge in the field of organ transplantation. In recent years, the mechanism research and clinical trials of tolerogenic dendritic cell (tolDC) in immune tolerance after liver transplantation have achieved initial outcomes. In this article, biological characteristics, immunomodulation and application of tolDC in clinical liver transplantation were reviewed, and the application value of tolDC in inducing immune tolerance in liver transplantation was evaluated.

Key words: Liver transplantation, Immune tolerance, Dendritic cells, Reaction, Cytokines

[1]	Li X, Wang Y, Yang H, et al. Liver and hepatocyte transplantation: what can pigs contribute?[J]. Front Immunol, 2022, 12: 802692. DOI: 10.3389/fimmu.2021.802692.
[2]	Feng S, Bucuvalas J. Tolerance after liver transplantation: where are we?[J]. Liver Transpl, 2017, 23(12): 1601-1614. DOI: 10.1002/lt.24845.
[3]	中华医学会器官移植学分会, 中国医师协会器官移植医师分会. 肝移植术后急性移植物抗宿主病诊疗中国专家共识(2024版)[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(1): 1-12. DOI: 10.3877/cma.j.issn.2095-3232.2024992.
[4]	Cvetkovski F, Hexham JM, Berglund E. Strategies for liver transplantation tolerance[J]. Int J Mol Sci, 2021, 22(5): 2253. DOI: 10.3390/ijms22052253.
[5]	中华医学会器官移植学分会肝移植学组, 中国医师协会器官移植医师分会. 中国自身免疫性肝病肝移植受者免疫抑制方案应用指南[J/OL]. 中华移植杂志(电子版), 2025, 19(2): 76-85. DOI: 10.3877/cma.j.issn.1674-3903.2025.02.002.
[6]	Åberg F, Gissler M, Karlsen TH, et al. Differences in long-term survival among liver transplant recipients and the general population: a population-based Nordic study[J]. Hepatology, 2015, 61(2): 668-677. DOI: 10.1002/hep.27538.
[7]	Benítez C, Londoño 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. DOI: 10.1002/hep.26426.
[8]	Fortunato M, Morali K, Passeri L, et al. Regulatory cell therapy in organ transplantation: achievements and open questions[J]. Front Immunol, 2021, 12: 641596. DOI: 10.3389/fimmu.2021.641596.
[9]	Huang YL, Wang YZ, Chen JB, et al. Prevention of acute and chronic allograft rejection by combinations of tolerogenic dendritic cells[J]. Scand J Immunol, 2011, 73(2): 91-101. DOI: 10.1111/j.1365-3083.2010.02485.x.
[10]	Wang Z, Divito SJ, Shufesky WJ, et al. Dendritic cell therapies in transplantation revisited: deletion of recipient DCs deters the effect of therapeutic DCs[J]. Am J Transplant, 2012, 12(6): 1398-1408. DOI: 10.1111/j.1600-6143.2012.04060.x.
[11]	Morelli AE, Thomson AW. Tolerogenic dendritic cells and the quest for transplant tolerance[J]. Nat Rev Immunol, 2007, 7(8): 610-621. DOI: 10.1038/nri2132.
[12]	Schinnerling K, García-González P, Aguillón JC. Gene expression profiling of human monocyte-derived dendritic cells–searching for molecular regulators of tolerogenicity[J]. Front Immunol, 2015, 6: 528. DOI: 10.3389/fimmu.2015.00528.
[13]	Villar J, Segura E. Decoding the heterogeneity of human dendritic cell subsets[J]. Trends Immunol, 2020, 41(12): 1062-1071. DOI: 10.1016/j.it.2020.10.002.
[14]	Bordon Y. Battle scars[J]. Nat Rev Immunol, 2015, 15(11): 668. DOI: 10.1038/nri3932.
[15]	Balasubramani A, Shibata Y, Crawford GE, et al. Modular utilization of distal cis-regulatory elements controls Ifng gene expression in T cells activated by distinct stimuli[J]. Immunity, 2010, 33(1): 35-47. DOI: 10.1016/j.immuni.2010.07.004.
[16]	Nikolic T, Suwandi JS, Wesselius J, et al. Tolerogenic dendritic cells pulsed with islet antigen induce long-term reduction in T-cell autoreactivity in type 1 diabetes patients[J]. Front Immunol, 2022, 13: 1054968. DOI: 10.3389/fimmu.2022.1054968.
[17]	Ma X, Guo S, Liu F, et al. Unveiling the prevalence and impact of silent rhinovirus infection in chronic rhinosinusitis with nasal polyps[J]. Ann Allergy Asthma Immunol, 2025, 134(4): 420-430. e1. DOI: 10.1016/j.anai.2025.01.026.
[18]	Mohammadi B, Saghafi M, Abdulsattar Faraj T, et al. The role of tolerogenic dendritic cells in systematic lupus erythematosus progression and remission[J]. Int Immunopharmacol, 2023, 115: 109601. DOI: 10.1016/j.intimp.2022.109601.
[19]	Liu Q, Umemoto E, Morita N, et al. Pyruvate enhances oral tolerance via GPR31[J]. Int Immunol, 2022, 34(7): 343-352. DOI: 10.1093/intimm/dxac010.
[20]	Fu L, Upadhyay R, Pokrovskii M, et al. PRDM16-dependent antigen-presenting cells induce tolerance to gut antigens[J]. Nature, 2025, 642(8068): 756-765. DOI: 10.1038/s41586-025-08982-4.
[21]	Segovia M, Cuturi MC, Hill M. Preparation of mouse bone marrow-derived dendritic cells with immunoregulatory properties[M]//Suppression and Regulation of Immune Responses. Totowa, NJ: Humana Press, 2010: 161-168. DOI: 10.1007/978-1-60761-869-0_11.
[22]	Takayama T, Tahara H, Thomson AW. Transduction of dendritic cell progenitors with a retroviral vector encoding viral interleukin-10 and enhanced green fluorescent protein allows purification of potentially tolerogenic antigen-presenting cells1, 2[J]. Transplantation, 1999, 68(12): 1903-1909. DOI: 10.1097/00007890-199912270-00015.
[23]	Matsumoto T, Hasegawa H, Onishi S, et al. Protein kinase C inhibitor generates stable human tolerogenic dendritic cells[J]. J Immunol, 2013, 191(5): 2247-2257. DOI: 10.4049/jimmunol.1203053.
[24]	Xie Z, Chen J, Zheng C, et al. 1, 25-dihydroxyvitamin D₃-induced dendritic cells suppress experimental autoimmune encephalomyelitis by increasing proportions of the regulatory lymphocytes and reducing T helper type 1 and type 17 cells[J]. Immunology, 2017, 152(3): 414-424. DOI: 10.1111/imm.12776.
[25]	Trabanelli S, Očadlíková D, Ciciarello M, et al. The SOCS3-independent expression of IDO2 supports the homeostatic generation of T regulatory cells by human dendritic cells[J]. J Immunol, 2014, 192(3): 1231-1240. DOI: 10.4049/jimmunol.1300720.
[26]	Wang H, Li Y, Yu Q, et al. Immunological characteristics of hepatic dendritic cells in patients and mouse model with liver Echinococcus multilocularis infection[J]. Trop Med Infect Dis, 2024, 9(5): 95. DOI: 10.3390/tropicalmed9050095.
[27]	Du J, Que Z, Aihaiti A, et al. Co-delivery of SN38 and MEF2D-siRNA via tLyp-1-modified liposomes reverses PD-L1 expression induced by STING activation in hepatocellular carcinoma[J]. Colloids Surf B Biointerfaces, 2025, 245: 114318. DOI: 10.1016/j.colsurfb.2024.114318.
[28]	Bamboat ZM, Stableford JA, Plitas G, et al. Human liver dendritic cells promote T cell hyporesponsiveness[J]. J Immunol, 2009, 182(4): 1901-1911. DOI: 10.4049/jimmunol.0803404.
[29]	Dart SJ, Prosser AC, Huang WH, et al. Subset-specific retention of donor myeloid cells after major histocompatibility complex-matched and mismatched liver transplantation[J]. Transplantation, 2023, 107(7): 1502-1512. DOI: 10.1097/tp.0000000000004481.
[30]	Johnstone BH, Messner F, Brandacher G, et al. A large-scale bank of organ donor bone marrow and matched mesenchymal stem cells for promoting immunomodulation and transplant tolerance[J]. Front Immunol, 2021, 12: 622604. DOI: 10.3389/fimmu.2021.622604.
[31]	Chaudhry S, Kato Y, Weiner J, et al. Transient-mixed chimerism with nonmyeloablative conditioning does not induce liver allograft tolerance in nonhuman primates[J]. Transplantation, 2020, 104(8): 1580-1590. DOI: 10.1097/tp.0000000000003263.
[32]	Huang Y, Wu X, Tang S, et al. Donor programmed cell death 1 ligand 1 is required for organ transplant tolerance in major histocompatibility complex-mismatched mixed chimeras although programmed cell death 1 ligand 1 and major histocompatibility complex class Ⅱ are not required for inducing chimerism[J]. Am J Transplant, 2023, 23(8): 1116-1129. DOI: 10.1016/j.ajt.2023.04.022.
[33]	Morante-Palacios O, Fondelli F, Ballestar E, et al. Tolerogenic dendritic cells in autoimmunity and inflammatory diseases[J]. Trends Immunol, 2021, 42(1): 59-75. DOI: 10.1016/j.it.2020.11.001.
[34]	Lu L, Qian S, Hershberger PA, et al. Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation[J]. J Immunol, 1997, 158(12): 5676-5684. DOI: 10.4049/jimmunol.158.12.5676.
[35]	Mellor AL, Baban B, Chandler P, et al. Cutting edge: induced indoleamine 2, 3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion[J]. J Immunol, 2003, 171(4): 1652-1655. DOI: 10.4049/jimmunol.171.4.1652.
[36]	Sage PT, Schildberg FA, Sobel RA, et al. Dendritic cell PD-L1 limits autoimmunity and follicular T cell differentiation and function[J]. J Immunol, 2018, 200(8): 2592-2602. DOI: 10.4049/jimmunol.1701231.
[37]	Ju F, Wang D, Huang L, et al. Progress of PD-1/PD-L1 signaling in immune response to liver transplantation for hepatocellular carcinoma[J]. Front Immunol, 2023, 14: 1227756. DOI: 10.3389/fimmu.2023.1227756.
[38]	Nakano R, Yoshida O, Kimura S, et al. Donor plasmacytoid dendritic cells modulate effector and regulatory T cell responses in mouse spontaneous liver transplant tolerance[J]. Am J Transplant, 2021, 21(6): 2040-2055. DOI: 10.1111/ajt.16412.
[39]	Hill M, Thebault P, Segovia M, et al. Cell therapy with autologous tolerogenic dendritic cells induces allograft tolerance through interferon-gamma and Epstein-Barr virus-induced gene 3[J]. Am J Transplant, 2011, 11(10): 2036-2045. DOI: 10.1111/j.1600-6143.2011.03651.x.
[40]	Huang H, Dawicki W, Zhang X, et al. Tolerogenic dendritic cells induce CD4⁺CD25^hiFoxp3⁺ regulatory T cell differentiation from CD4⁺CD25^-/ ^loFoxp3^- effector T cells[J]. J Immunol, 2010, 185(9): 5003-5010. DOI: 10.4049/jimmunol.0903446.
[41]	Hsu SM, Mathew R, Taylor AW, et al. Ex-vivo tolerogenic F4/80+ antigen-presenting cells (APC) induce efferent CD8⁺ regulatory T cell-dependent suppression of experimental autoimmune uveitis[J]. Clin Exp Immunol, 2014, 176(1): 37-48. DOI: 10.1111/cei.12243.
[42]	Chauveau C, Rémy S, Royer PJ, et al. Heme oxygenase-1 expression inhibits dendritic cell maturation and proinflammatory function but conserves IL-10 expression[J]. Blood, 2005, 106(5): 1694-1702. DOI: 10.1182/blood-2005-02-0494.
[43]	Moreau A, Hill M, Thébault P, et al. Tolerogenic dendritic cells actively inhibit T cells through heme oxygenase-1 in rodents and in nonhuman Primates[J]. FASEB J, 2009, 23(9): 3070-3077. DOI: 10.1096/fj.08-128173.
[44]	Rémy S, Blancou P, Tesson L, et al. Carbon monoxide inhibits TLR-induced dendritic cell immunogenicity[J]. J Immunol, 2009, 182(4): 1877-1884. DOI: 10.4049/jimmunol.0802436.
[45]	Huang H, Chen R, Lin Y, et al. Decoding single-cell landscape and intercellular crosstalk in the transplanted liver[J]. Transplantation, 2023, 107(4): 890-902. DOI: 10.1097/tp.0000000000004365.
[46]	Li SP, Zhang JM, Chen XJ, et al. Characteristics of changes in double positive CD4⁺CD8⁺ T cells in liver transplantation[J]. Int Immunopharmacol, 2022, 110: 109028. DOI: 10.1016/j.intimp.2022.109028.
[47]	Knoedler L, Knoedler S, Panayi AC, et al. Cellular activation pathways and interaction networks in vascularized composite allotransplantation[J]. Front Immunol, 2023, 14: 1179355. DOI: 10.3389/fimmu.2023.1179355.
[48]	Li H, Shi B. Tolerogenic dendritic cells and their applications in transplantation[J]. Cell Mol Immunol, 2015, 12(1): 24-30. DOI: 10.1038/cmi.2014.52.
[49]	Xia MJ, Shan J, Li YP, et al. Adoptive transfusion of tolerogenic dendritic cells prolongs the survival of liver allograft: a systematic review[J]. J Evidence Based Medicine, 2014, 7(2): 135-146. DOI: 10.1111/jebm.12094.
[50]	Macedo C, Tran LM, Zahorchak AF, et al. Donor-derived regulatory dendritic cell infusion results in host cell cross-dressing and T cell subset changes in prospective living donor liver transplant recipients[J]. Am J Transplant, 2021, 21(7): 2372-2386. DOI: 10.1111/ajt.16393.
[51]	Tran LM, Macedo C, Zahorchak AF, et al. Donor-derived regulatory dendritic cell infusion modulates effector CD8⁺T cell and NK cell responses after liver transplantation[J]. Sci Transl Med, 2023, 15(717): eadf4287. DOI: 10.1126/scitranslmed.adf4287.
[52]	Zhou L, Li H, Zhang XX, et al. Rapamycin treated tol-dendritic cells derived from BM-MSCs reversed graft rejection in a rat liver transplantation model by inducing CD8⁺CD45RC–Treg[J]. Mol Immunol, 2021, 137: 11-19. DOI: 10.1016/j.molimm.2021.03.018.
[53]	Ezzelarab MB, Zahorchak AF, Lu L, et al. Regulatory dendritic cell infusion prolongs kidney allograft survival in nonhuman Primates[J]. Am J Transplant, 2013, 13(8): 1989-2005. DOI: 10.1111/ajt.12310.
[54]	Levitsky J, Burrell BE, Kanaparthi S, et al. Immunosuppression withdrawal in liver transplant recipients on sirolimus[J]. Hepatology, 2020, 72(2): 569-583. DOI: 10.1002/hep.31036.
[55]	Dahlqvist G, Renaud S, Barjon C, et al. Modulatory effect of rapamycin and tacrolimus on monocyte-derived dendritic cells phenotype and function[J]. Immunobiology, 2021, 226(1): 152031. DOI: 10.1016/j.imbio.2020.152031.
[56]	Machcińska M, Kotur M, Jankowska A, et al. Cyclosporine A, in contrast to rapamycin, affects the ability of dendritic cells to induce immune tolerance mechanisms[J]. Arch Immunol Ther Exp, 2021, 69: 27. DOI: 10.1007/s00005-021-00632-7.
[57]	Lu X, Han YD, Zu XR, et al. Rapamycin-modified CD169low /-tolDC promotes skin graft survival in mice via IL-10+Breg[J]. Transpl Immunol, 2025, 91: 102244. DOI: 10.1016/j.trim.2025.102244.
[58]	Wang J, Yang K, Yang X, et al. HHLA2 promotes hepatoma cell proliferation, migration, and invasion via SPP1/PI3K/AKT signaling pathway[J]. Mol Carcinog, 2024, 63(7): 1275-1287. DOI: 10.1002/mc.23723.
[59]	Peng Y, Ye Y, Jia J, et al. Galectin-1-induced tolerogenic dendritic cells combined with apoptotic lymphocytes prolong liver allograft survival[J]. Int Immunopharmacol, 2018, 65: 470-482. DOI: 10.1016/j.intimp.2018.10.019.
[60]	Morath C, Schaier M, Ibrahim E, et al. Induction of long-lasting regulatory B lymphocytes by modified immune cells in kidney transplant recipients[J]. J Am Soc Nephrol, 2023, 34(1): 160-174. DOI: 10.1681/asn.2022020210.
[61]	Higham EM, Wittrup KD, Chen J. Activation of tolerogenic dendritic cells in the tumor draining lymph nodes by CD8⁺ T cells engineered to express CD40 ligand[J]. J Immunol, 2010, 184(7): 3394-3400. DOI: 10.4049/jimmunol.0903111.
[62]	Li S, Toriumi H, Takahashi D, et al. Safe and efficient oral allergy immunotherapy using one-pot-prepared mannan-coated allergen nanoparticles[J]. Biomaterials, 2023, 303: 122381. DOI: 10.1016/j.biomaterials.2023.122381.
[63]	Li S, Murakami D, Nagatoishi S, et al. One-pot preparation of mannan-coated antigen nanoparticles using human serum albumin as a matrix for tolerance induction[J]. J Colloid Interface Sci, 2023, 649: 955-965. DOI: 10.1016/j.jcis.2023.06.170.

[1]	刘建勇, 江艺. 免疫检查点抑制剂新辅助治疗在肝细胞癌肝移植中的应用[J/OL]. 中华普通外科学文献(电子版), 2026, 20(02): 127-132.
[2]	艾孜曼提·艾山江, 阿力木·土拉宏, 郭强, 张瑞青, 阿卜杜海外尔·阿卜杜合力力, 吐尔干艾力·阿吉. 成人肝移植中大肝综合征的诊疗进展[J/OL]. 中华普通外科学文献(电子版), 2026, 20(02): 133-137.
[3]	中华医学会器官移植学分会. 肝癌肝移植术后防治复发转移中国专家共识(2025版)[J/OL]. 中华移植杂志(电子版), 2025, 19(06): 385-397.
[4]	中华医学会器官移植学分会肝移植学组, 中国医师协会器官移植医师分会. 中国肝移植大肝综合征临床诊治指南(2025版)[J/OL]. 中华移植杂志(电子版), 2025, 19(06): 375-384.
[5]	李玲, 徐艳, 潘丽, 周鑫, 钟自彪, 刘忠忠, 薛承彪, 潘华勤, 叶少军. 长周期双重血浆分子吸附系统联合血浆置换在二次肝移植桥接治疗中的应用二例[J/OL]. 中华移植杂志(电子版), 2025, 19(06): 454-456.
[6]	何才华, 代天星, 陈焕权, 杨健良, 黄启恒, 李凯, 袁峰, 朱灿华, 陈志涛, 汪国营. 肝移植术后以腹壁结核为首发表现的早发性结核病一例[J/OL]. 中华移植杂志(电子版), 2025, 19(06): 457-461.
[7]	江金财, 郝建宏, 叶于富. 肝移植治疗不可切除结直肠癌肝转移的研究进展[J/OL]. 中华移植杂志(电子版), 2025, 19(06): 470-474.
[8]	陆铭, 马洪敏, 王佳骏, 陈荣, 钱文霞, 高锋. 血清细胞因子谱预测肺癌免疫治疗反应性机器学习模型的研究[J/OL]. 中华肺部疾病杂志(电子版), 2026, 19(02): 289-296.
[9]	朱轩逸, 赵一腾, 刘连新, 朱泽斌, 张树庚. 腹腔镜肝移植混合手术的关键技术应用现状与进展[J/OL]. 中华腔镜外科杂志(电子版), 2026, 19(01): 56-59.
[10]	曾桂能, 杨鹏辉, 刘荣. 表达IL-21的重组溶瘤流感病毒在胰腺癌中的抗肿瘤及免疫激活作用研究[J/OL]. 中华细胞与干细胞杂志(电子版), 2026, 16(03): 129-139.
[11]	杨健良, 张爱玲, 王晓明, 代天星, 袁峰, 朱灿华, 蓝岚, 杨汉宇, 汪国营. 早期拔除气管插管快通道麻醉在肝移植中应用[J/OL]. 中华肝脏外科手术学电子杂志, 2026, 15(03): 398-404.
[12]	麦吾兰江·麦麦提, 阿力娅·图拉丁, 吐尔洪江·吐逊. ABO血型不相容肝移植免疫抑制策略[J/OL]. 中华肝脏外科手术学电子杂志, 2026, 15(02): 152-159.
[13]	王小振, 陈灿辉, 唐善华, 代浩嘉, 丰扬舸, 王恺, 李清平, 李川江. 基于不同机器学习技术构建肝移植术后早期严重并发症预测模型和效能比较[J/OL]. 中华肝脏外科手术学电子杂志, 2026, 15(02): 197-204.
[14]	倪美铃, 周芳. 单细胞RNA测序技术在再生障碍性贫血中的应用研究进展[J/OL]. 中华临床医师杂志(电子版), 2025, 19(12): 945-950.
[15]	俞若婷, 高威, 刘宇浩, 刘琛. 肺挫伤病理生理机制及相关治疗研究[J/OL]. 中华临床医师杂志(电子版), 2025, 19(07): 536-543.

阅读次数

全文

摘要

选择文件类型/文献管理软件名称

选择包含的内容

Progress in application of tolerant dendritic cells in immune tolerance of liver transplantation

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

Progress in application of tolerant dendritic cells in immune tolerance of liver transplantation