Effects of IL-10-and FasL-overexpressing dendritic cells on liver transplantation tolerance in a heterotopic liver transplantation rat model
Effects of IL-10-and FasL-overexpressing dendritic cells on liver transplantation tolerance in a heterotopic liver transplantation rat model
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DOI：
10.1111/imcb.12252
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发表时间：
2019-09-01
影响因子：
4
通讯作者：
Huang, Aimin
中科院分区：
文献类型：
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作者：
Chen, Lihong;Zhang, Lina;Huang, Aimin
急性排斥反应是肝移植后供肝长期存活的主要决定因素。本研究旨在探讨IL-10-FasL过表达的未成熟树突状细胞(ImDC)对移植肝局部免疫抑制的治疗作用。用表达人IL-10和/或Fas配体(FasL)基因的慢病毒载体(S)转导供者来源的imDC，检测其表面分子的表达和诱导T细胞增殖的能力。将免疫树突状细胞(ImDC)注射于受体大鼠体内作为移植模型，观察移植后排斥反应分级[Banff排斥反应指数(RAI)]、肝功能[丙氨酸氨基转移酶(ALT)、天冬氨酸转氨酶(AST)和总胆红素(TBIL)]及移植后存活时间。联合转导IL-10和FasL的imDC与单独转导或未转导的imDC相比，CD80、CD86和主要组织相容性复合体II类(MHC II)的表达显著降低(P<；0.05)，而培养上清液中IL-10和FasL的水平升高(P<；0.05)。与单一转导或未转导imDC治疗的同种异体肝移植相比，联合转导的imDC输注可降低肝移植受者的RAI评分，降低血浆AST和TBIL，延长存活期。结果表明，输注IL-10-FasL/imDC可提高移植肝的免疫耐受性，延长移植肝存活时间。IL-10和FasL修饰的imDC的免疫调节活性可能是预防临床器官移植排斥反应的新途径。
Acute rejection is the major determinant for the long-term survival of donor liver after liver transplantation (LT). The aim of this study was to examine the therapeutic potential of interleukin (IL)-10-FasL-overexpressing immature dendritic cells (imDCs) to induce local immunosuppression in liver grafts. imDCs derived from donors were transduced by lentiviral vectors expressing human IL-10 and/or Fas ligand (FasL) gene(s), and the expression of surface molecules and the ability to induce T-cell proliferation were measured. imDCs were intraperitoneally injected into recipient rats as a model of LT to examine the rejection grade [Banff rejection activity index (RAI)], liver functions [Alanine aminotransferase, Aspartate aminotransferase (AST) and total bilirubin (TBIL)] and post-transplant survival. IL-10 and FasL co-transduction of imDCs induced a greater reduction in CD80, CD86 and major histocompatibility complex class II (MHC II) expression, as well as T-cell proliferation, but increased levels of IL-10 and FasL in culture supernatants compared with mono-transduced or untransduced imDCs (P < 0.05). The infusion of co-transduced imDCs in LT recipients reduced RAI scores, decreased plasma AST and TBIL, and prolonged survival compared with mono-transduced or untransduced imDC-treated liver allografts. These findings demonstrated that the transfusion of IL-10-FasL/imDCs enhanced immune tolerance and prolonged the survival of liver allografts after LT. The immunomodulatory activity of IL-10- and FasL-modified imDCs might be a new therapeutic approach to prevent organ rejection in clinical transplantation.