肝移植免疫排斥与耐受：从传统免疫抑制到间充质干细胞治疗

冯子凡; 樊永强; 张瑞

doi:10.12449/JCH260933

肝移植免疫排斥与耐受：从传统免疫抑制到间充质干细胞治疗

DOI: 10.12449/JCH260933

冯子凡¹,
樊永强²,
张瑞^2, , ,

1.
山西医科大学第一临床医学院，太原 030000
2.
山西医科大学第一医院肝胆外科与肝移植中心，太原 030000

基金项目:

山西省自然科学基金 (20210302123255)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：冯子凡负责设计论文框架，起草文稿；樊永强负责论文修改、绘制图表；张瑞负责归纳分析，课题设计，拟定写作思路，指导撰写论文并最后定稿。

详细信息

通信作者:
张瑞， zhr2992@outlook.com （ORCID： 0000-0002-1078-1467）

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出版历程
- 收稿日期: 2026-01-11
- 录用日期: 2026-05-07
- 出版日期: 2026-09-25

Immune rejection and tolerance in liver transplantation: From traditional immunosuppression to mesenchymal stem cell therapy

1.
The First Clinical Medical College of Shanxi Medical University，Taiyuan 030000，China
2.
Department of Hepatobiliary Surgery and Liver Transplantation Center，The First Hospital of Shanxi Medical University，Taiyuan 030000，China

Research funding:

Shanxi Provincial Natural Science Foundation (20210302123255)

More Information

Corresponding author: Zhang Rui， zhr2992@outlook.com （ORCID： 0000-0002-1078-1467）

摘要

摘要: 肝移植术后免疫排斥反应是影响移植物长期存活的关键制约因素。传统以钙调磷酸酶抑制剂为基石的免疫抑制方案虽有效但伴随长期副作用，促使诱导免疫耐受成为重要目标。本文系统综述了肝移植术后免疫排斥机制及现有药物的局限性，并重点探讨间充质干细胞（MSC）作为新型免疫耐受诱导策略的潜力。初步临床试验证实MSC输注安全性良好，并呈现免疫调节效应，但仍面临输注时机、细胞来源、剂量及与传统方案协同等多重挑战。未来需通过大规模临床试验进一步验证其长期疗效与安全性，MSC疗法有望为肝移植免疫管理提供具有前景的新方向。
- 肝移植 /
- 免疫抑制剂 /
- 免疫耐受 /
- 移植物排斥 /
- 间质干细胞移植
Abstract: Immune rejection following liver transplantation is a critical factor affecting long-term graft survival. While traditional immunosuppressive regimens based on calcineurin inhibitors are effective， they are often accompanied by long-term side effects， making the induction of immune tolerance an important goal. This article systematically reviews the mechanisms of immune rejection following liver transplantation and the limitations of current drugs， with a focus on the potential of mesenchymal stem cells （MSCs） as a novel strategy for inducing immune tolerance. Preliminary clinical trials have confirmed that MSC infusion has a favorable safety profile and shows an immunomodulatory effect； however， there are still multiple challenges regarding the timing of infusion， cell source， dosage， and synergy with conventional regimens. Large-scale clinical trials are needed in the future to further validate their long-term efficacy and safety， and MSC therapy is expected to become a new direction for immune management in liver transplantation.
- Liver Transplantation /
- Immunosuppressive Agents /
- Immune Tolerance /
- Graft Rejection /
- Mesenchymal Stem Cell Transplantation

HTML全文

注： TNF-α，肿瘤坏死因子α；IL，白细胞介素；TGF-β，转化生长因子β；Treg，调节性T细胞；NK细胞，自然杀伤细胞；IFN-γ，干扰素γ；APC，抗原呈递细胞；MHC，主要组织相容性复合物。

图 1 肝移植免疫排斥机制

Figure 1. Mechanisms of immune rejection in liver transplantation

下载: 全尺寸图片幻灯片

注： MSC，间充质干细胞；PGE₂，前列腺素E₂；HGF，肝细胞生长因子；TGF-β，转化生长因子β；Treg，调节性T细胞；VEGF，血管内皮生长因子；IFN-γ，干扰素γ；bFGF，碱性成纤维细胞生长因子；TIMP，金属蛋白酶组织抑制剂；BDNF，脑源性神经营养因子；NGF，神经生长因子；IGFBP-1，胰岛素样生长因子结合蛋白1；M-CSF，巨噬细胞集落刺激因子；FoxP3，叉头框蛋白P3；Th，辅助性T细胞；IL，白细胞介素；IgM/G/A，免疫球蛋白M/G/A；PI3K，磷脂酰肌醇3-激酶；Akt，蛋白激酶B；CXCL，CXC亚族趋化因子配体；CXCR，CXC亚族趋化因子受体；CTL，细胞毒性T淋巴细胞；CICN-3，氯离子通道蛋白3。

图 2 MSC的免疫调节与组织修复功能

Figure 2. Immunomodulatory and tissue repair functions of MSC

下载: 全尺寸图片幻灯片

表 1 肝移植常用免疫抑制剂对比

Table 1. Comparison of commonly used immunosuppressants in liver transplantation

免疫抑制方案	药物	作用机制	不良事件	临床应用
CNI	CsA	通过结合细胞内亲环素抑制T细胞活化及钙调磷酸酶活性，阻碍活化T细胞核因子去磷酸化及IL-2转录，从而抑制排斥反应	肾毒性、神经毒性、震颤、代谢紊乱、牙龈过度生长、多毛症	第一代CNI，已被TAC取代
CNI	TAC	通过结合FKBP12抑制钙调神经磷酸酶	肾毒性、神经毒性、代谢紊乱（糖尿病、血脂异常）、心血管并发症（高血压、心律失常）、罕见病毒感染等	免疫抑制的基石，药效是CsA 的100倍，单药TAC是稳定受者长期维持治疗的首选
mTOR抑制剂	SRL、	PI3K/Akt/mTOR通路调控细胞生长、代谢、自噬及血管生成，在HCC中，mTOR通路常被异常激活，与肿瘤进展、复发和预后不良相关。 mTOR抑制剂通过与FKBP12结合，抑制 mTOR丝氨酸苏氨酸激酶活性，从而减少蛋白质合成和细胞增殖	口腔炎、皮疹、感染、肺毒性、代谢并发症、贫血、血小板减少	协同CNI以减轻其暴露，优化受者肾功能，避免或减少其他不良事件发生，并潜在降低HCV与HCC复发以及肝移植术后新发恶性肿瘤风险
mTOR抑制剂	EVR		口腔炎、皮疹、感染、肺毒性、代谢并发症、贫血、血小板减少
抗增殖剂	MPA	可逆性地抑制次黄嘌呤单核苷酸脱氢酶，该酶是鸟嘌呤核苷酸经典合成途径中的限速酶。T细胞和B细胞高度依赖此途径增殖，且无法通过补救途径合成，故MPA能相对选择性地抑制淋巴细胞增殖；此外，MPA被证明可以增加T细胞，尤其是活化T细胞的凋亡	胃肠道紊乱（腹泻和结肠炎）、贫血、白细胞或血小板减少、感染、新发恶性肿瘤等	通常使用12个月后停用，以减少长期副作用（如胃肠道反应、骨髓抑制）
皮质类固醇	GC	抑制树突状细胞上调共刺激分子（CD40、 CD80、CD83、CD86）及MHC-Ⅱ类分子，从而削弱其启动T细胞的能力；诱导单核细胞向抗炎表型转化（IL-10↑、IL-1β及IL-12↓）；抑制中性粒细胞的NADPH氧化酶、诱导型一氧化氮合酶和环氧合酶-2活性，削弱其趋化、吞噬及细胞因子分泌功能；通过长期低浓度GC 减少穿孔素和颗粒酶B的组蛋白启动子乙酰化（如H3K9Ac、H3K27Ac、H4K8Ac）降低NK 细胞活性；通过减少IL-1、IL-2及IL-3等细胞因子的产生，抑制T细胞活化	库欣样症状、精神症状、骨质疏松症、糖尿病、心血管疾病、肥胖等	CNI、GC与MMF的三联药物方案是最常见的诱导方案（肝移植术后30 d内为诱导期）；合并自身免疫性肝病或曾患TCMR需长期低剂量GC 维持治疗
注：CsA，环孢素；TAC，他克莫司；SRL，西罗莫司；EVR，依维莫司；MPA，麦考酚酸；GC，糖皮质激素；mTOR，哺乳动物雷帕霉素靶蛋白；CNI，钙调磷酸酶抑制剂；HCC，肝细胞癌；HCV，丙型肝炎病毒；IL，白细胞介素；TCMR，T细胞介导排斥反应；NK细胞，自然杀伤细胞；PI3K，磷脂酰肌醇3-激酶；Akt，蛋白激酶B；NADPH，还原型烟酰胺腺嘌呤二核苷酸磷酸；MMF，麦考酚酯；MHC，主要组织相容性复合物。

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