修回日期: 2008-12-14
接受日期: 2008-12-22
在线出版日期: 2009-01-18
肝脏移植是治疗终末期肝病的唯一有效手段, 肝移植后的排斥反应是移植器官失功能的主要因素之一, Kupffer细胞在肝移植中的免疫作用往往被忽视. 很多研究发现Kupffer细胞通过直接抗原提呈作用激活T细胞增殖, 加重移植排斥反应, 同时又通过FasL诱导T细胞凋亡, 诱导移植耐受. 本文就Kupffer细胞在肝移植中的免疫作用作一综述.
引文著录: 黄汉飞, 曾仲. Kupffer细胞在肝移植中的免疫作用. 世界华人消化杂志 2009; 17(2): 164-168
Revised: December 14, 2008
Accepted: December 22, 2008
Published online: January 18, 2009
Orthotopic liver transplantation (OLT) is an effective treatment for the end-stage liver diseases. Rejection reaction of graft remains a major cause of post-transplantation liver dysfunction and even failure. Immunologic role of Kupffer cells in liver transplantation is frequently ignored. Many investigations demonstrated that Kupffer cells activate T cells through direct antigen presentation, and aggravate transplantation rejection reaction. At the same time, Kupffer cells may induce apoptosis of T cells by FasL and evoke transplantation tolerance. This review discusses the immunologic role of Kupffer cells in liver transplantation.
- Citation: Huang HF, Zeng Z. Immunologic role of Kupffer cells in liver transplantation. Shijie Huaren Xiaohua Zazhi 2009; 17(2): 164-168
- URL: https://www.wjgnet.com/1009-3079/full/v17/i2/164.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v17.i2.164
Kupffer细胞是位于肝血窦内的巨噬细胞, 寄居于肝血窦内皮细胞之间或之上, 是体内固定型巨噬细胞中最大的群体, 约占肝细胞总数的10%-15%、全身巨噬细胞总数的80%左右. Kupffer细胞是肝脏清除肠道来源的内毒素、细菌、病毒等有害物质的第一道防线, 且同时具有胞饮、胞吞, 释放生物活性物质和免疫调节三大功能. 有研究表明, Kupffer细胞为长寿定居巨噬细胞, 大鼠肝Kupffer细胞的寿命为数周到14 mo, 而肝移植患者来源于供者的Kupffer细胞可以持续一年之久[1], 来源于供者的或受者的Kupffer细胞在肝脏移植中发挥着重要的免疫功能.
Kupffer细胞的前体细胞最初来源于胚胎卵黄囊, 分化成初级巨噬细胞和胚胎巨噬细胞, 随着胎儿心血管系统的发育, 这些细胞通过脐静脉和卵黄静脉到达胎肝, 进一步在GM-CSF和(或)M-CSF的作用下发育成熟. 出生后, 由骨髓分化出单核细胞释放入外周血, 并迁移到肝脏进一步发育为Kupffer细胞, 维持细胞数量的稳定. 将供者的组织或器官移植给受者后, 移植物和受者机体间相互作用, 受者免疫系统可识别移植物抗原, 移植物中免疫细胞也可识别受者组织抗原并产生免疫应答, 此为移植排斥反应. 排斥反应目前仍是影响移植器官成活的最大障碍, Kupffer细胞在肝移植急性排斥反应中发挥着重要的作用.
急性排斥反应是T细胞介导对供者抗原的炎性应答, T细胞的激活需要T细胞上的TCR与抗原提呈细胞(APC)上MHC复合物的识别以及共刺激信号相互识别的双信号. Kupffer细胞上表达有MHCⅡ类抗原, 在肝移植急性排斥反应中有很重要的抗原提呈和产生细胞因子作用. 通过供体抗原提呈细胞的抗原提呈被称作"直接抗原提呈", 会加重移植排斥反应[2], 降低移植物的免疫原性可以延长移植物在受体内的成活时间, 移植物的免疫原性来源于专业APC(DC, Kupffer细胞等)的抗原提呈作用. 有实验研究发现, 将清除供者Kupffer细胞的供肝移植给受者, 并清除受者迁移到供肝内的巨噬细胞, 能明显的延长移植物成活时间[3-4], 这表明供者Kupffer细胞与受者巨噬细胞在肝移植急性排斥中发挥着重要作用.
但在肝移植后肝脏活检标本的检测中发现, 供者来源的Kupffer细胞可以持续数月至一年以上, 肝窦状隙内受者的淋巴细胞凋亡明显增加, 而肾移植患者则没有此现象[5], 他们认为这可能是肝移植效果优于其他实体器官移植的原因之一. 有研究发现, 肝移植受者发生急性排斥反应后, Kupffer细胞的凋亡增加, 这种现象可能由NO诱导的[6]. NO是生物体内极为重要的自由基活性基团, 在细胞凋亡过程中发挥着多种功能, 由Kupffer细胞释放的NO诱导细胞凋亡, 在肝移植急性排斥的患者, 诱导型一氧化氮合酶(iNOS)的表达、亚硝酸盐以及有害的NO代谢产物均增加[7]. 从大鼠的肝移植急性排斥模型中发现Kupffer细胞的功能明显降低[8], 这种功能的降低可能是Kupffer细胞产生的NO诱导了自身凋亡.
另一方面, Kupffer细胞也会诱导T细胞凋亡. 在离体的Kupffer细胞与T细胞共同培养的混合淋巴细胞反应试验中可以观察到Kupffer细胞对T淋巴细胞增殖的抑制作用[9]. 肝移植后Kupffer细胞上FasL表达增加, 这与T细胞通过Fas-FasL途径凋亡有关, Fas-FasL间的相互作用及引起的细胞凋亡在同种移植排斥方面有重要的作用. Kupffer细胞是驻留于肝内的巨噬细胞, 并与受者T淋巴细胞作用使其激活、增殖及合成细胞因子. 然而, 在动物肝移植模型中发现激活的T细胞发生凋亡[10], 最近的研究也表明, Kupffer细胞有诱导激活的T细胞凋亡和调节T细胞分化的功能[11], 提出Fas-FasL凋亡途径在移植物排斥中发挥重要作用. 通过临床研究发现, APC上FasL的表达和FasL+Kupffer细胞吞噬凋亡T细胞是肝移植排斥反应的一项指标[12], T细胞凋亡和吞噬凋亡的T细胞可以作为评估排斥反应的严重程度和检测治疗效果, Kupffer细胞调节T细胞亚群的分化并参与肝移植后的免疫调节.
同种异体移植炎性因子(AIF-1)是由143个氨基酸组成的含有一个EF螺旋结构的钙结合蛋白, 分子质量为17 kDa, 他首先是从人活化巨噬细胞和发生慢性排斥反应的同种异体心脏移植物中克隆出来, 后来发现在人的肝脏、结肠、小肠和动脉粥样硬化斑块中都有AIF-1 mRNA的表达, 参与同种异体移植的排斥是其主要的生物学作用之一, 被认为是活化的巨噬细胞标志物. 在发生急性排斥反应的肝脏及外周血淋巴细胞AIF-1表达增加2倍[13], 并且发现在ED2阳性的Kupffer细胞上表达, 研究还发现Th1细胞分泌的IFN-g能上调Kupffer上AIF-1的表达. 越来越多的证据表明AIF-1的高表达水平反映了肝移植物的急慢性排斥反应, 外周血淋巴细胞的AIF-1可能会作为监测肝移植受体治疗的一项指标[14], AIF-1的转录和表达水平可能会成为急慢性器官移植排斥的临床标志之一[15].
慢性排斥反应也是导致肝移植失败的重要原因之一, 临床特征表现为持续的胆红素增高而对免疫抑制剂治疗无反应, 组织学以移植物内大中型血管闭塞性病变为特征. 尽管他的病理生理机制仍未完全阐明, 但目前认为以免疫介导的移植物损伤为主, 闭塞性血管病变的移植肝发生增厚的血管内膜损伤来源于受者循环中泡沫状巨噬细胞和间充质细胞[16], 损伤为不可逆性, 目前尚无有效的治疗方法.
CD40L主要表达在激活的T细胞表面, 是CD40的配体, 然而在树突状细胞、巨噬细胞、B细胞和肝窦上皮细胞等细胞上也有表达. CD40/CD40L是移植免疫中重要的共刺激信号, 肝移植慢性排斥反应患者Kupffer细胞表面CD40L的表达明显增强[17-18], 在动物模型中, 抑制CD40/CD40L间的相互作用可以阻止慢性排斥反应的进展[19-20], 这说明移植肝的慢性排斥反应发病机理与CD40/CD40L间的相互作用有一定关系. CD40L具有促炎性和促纤维化作用[21], 导致移植物内炎性细胞的集聚和对移植物动脉血管内膜损伤, CD40/CD40L在移植慢性排斥反应中的表达可能与此有关, 但对于Kupffer细胞在慢性排斥反应中的作用仍有待进一步研究.
肝脏又称为免疫特惠器官, 肝移植后会引起针对供者抗原特异性耐受或易于诱导耐受, 而移植前给予供者抗原也可以诱导耐受产生, 但通过门静脉和外周静脉两种途径输注供者血淋巴细胞获得不同的效果[22]. 通过实验证明了Kupffer细胞参与免疫耐受的诱导[23], 抑制Kupffer细胞功能则会阻碍门静脉诱导耐受[24-26], 也有实验得出相反的结果, 提出激活的Kupffer细胞不利于门静脉耐受诱导, 激活的Kupffer细胞和NKT细胞都会加速移植物的排斥反应和细胞毒T细胞的作用[27]. 当非己淋巴细胞进入门静脉, 在肝内不可避免的与肝血窦内大量Kupffer细胞相遇, Kupffer细胞上表达有脂多糖(LPS)受体CD14和TLR4, 进入门静脉的外来抗原与CD14和TLR4结合并激活NF-κB, 引发炎症反应, 分泌促炎性细胞因子(IL-12, IL-18等), 进一步激活CD4+ T细胞和CD8+ T细胞[28-29]. 但Kupffer细胞在分泌促炎性因子的同时, 也合成抗炎性因子和免疫抑制细胞因子IL-10, 而IL-10又抑制IL-6和TNF-α的释放[30-31], 这与Kupffer细胞的抗炎性和免疫抑制作用相符.
肝移植急性排斥反应以T细胞的激活和局部组织外周淋巴细胞浸润为特征, 肝移植物内浸润的T淋巴细胞凋亡与耐受诱导密切相关. 肝移植后Kupffer细胞诱导T细胞凋亡是通过上调FasL的表达, 并且FasL的表达与NF-κB的激活、IL-4的产量呈正相关, 认为Kupffer细胞诱导移植肝免疫耐受通过NF-κB的激活促进FasL表达和抗炎性因子IL-4增加来发挥作用的[26]. Kupffer细胞的NF-κB激活后, 通过诱导细胞因子、免疫受体和细胞黏附分子的产生, 促进FasL转录并参与免疫调节[32-33], NF-κB的激活在肝移植后缺血再灌注损伤中也发挥着重要的作用, 给予GdCl3预处理可以减轻这种损伤[34-35], 但却降低了Kupffer细胞诱导耐受作用.
通过诱导T细胞凋亡维持耐受, Kupffer细胞上表达FasL和T细胞上表达Fas发挥着重要的作用. 有研究表明, 树突状细胞(DC)和APC经转染FasL能诱导抗原特异性免疫抑制和T细胞耐受[36-37], 长期接受的移植肝Kupffer细胞上FasL的表达比急性排斥的明显增高, 并且这些Kupffer细胞更能提高诱导激活的T细胞凋亡[38]. 肠道来源的内毒素、细菌刺激Kupffer使ROS产生增多, Kupffer细胞ROS的产生与FasL的表达有关, 用LPS处理的Kupffer细胞表达FasL上调并诱导Fas阳性靶细胞凋亡[39-40], 内源性ROS的产生是Kupffer细胞表达FasL的一个重要信号转导途径. 在Kupffer细胞与卵清蛋白(OVA)抗原共培养的实验中, 上调内源性的ROS产生、MHCⅡ类分子和共刺激分子表达增加, 通过Kupffer细胞的抗原提呈致OVA特异性CD4+ T细胞增殖, 抑制ROS产生则不具有此效应, 因此, 内源性ROS在Kupffer细胞抗原提呈过程中可能提供了必要的第二信号[41].
IL-10是具有免疫抑制作用的重要抗炎性因子之一, Kupffer细胞激活后2 h即开始表达, 并且通过IL-10的释放影响肝窦其他细胞的功能, 在调节肝窦状隙局部免疫反应中发挥着重要作用. IL-10能下调MHCⅡ类分子和共刺激分子的表达, 并抑制T细胞的激活和增殖, 减少炎性因子的产生[42]. CD4+CD25+ T细胞是具有抑制免疫应答的一类调节细胞, 促进CD4+ Th细胞向调节T细胞转化, 体内IL-10和(或)TGF-β是反映调节T细胞活性的关键因子[43-44]. 在体内CD45RBlow或CD25+的CD4+ T细胞有利于移植耐受的维持, 通过间接的抗原识别、对同种抗原的应答需要IL-10的参与发挥功能[45]. 在自身免疫性心肌炎的大鼠实验中[46-47], 经IL-10修饰的骨髓来源未成熟树突状细胞(iDC)诱导抗原特异性免疫耐受, 这可能与IL-10诱导Th2细胞偏离、共刺激分子的下调和NF-κB途径的抑制有关. 研究还发现, Kupffer细胞释放的IL-10通过自分泌(或旁分泌)途径减少促炎性因子的释放[48], 调节IL-6和TNF-α的产生.
肝脏是人体最重要、最复杂的脏器之一, 是唯一接受双重血液供应的器官, 具有独特的生理和免疫功能. 但同时肝脏的发病率也很高, 严重的会导致肝功能衰竭, 肝移植是其唯一有效的治疗措施, Kupffer细胞在肝移植手术过程中及术后的恢复均发挥着重要的作用. Kupffer细胞对移植肝的作用机制还没有完全弄清楚, 在移植肝免疫调节中具有独特的功能, 一方面承担着直接抗原提呈的作用, 加重移植排斥反应, 另一方面又诱导特异性T细胞凋亡诱导移植耐受. Kupffer细胞作为肝血窦内重要的一员, 维持肝窦状隙微环境的稳定, 对移植肝起到多重效应, 如何让Kupffer细胞的多效性达成统一将有待进一步研究.
肝脏移植是治疗终末期肝病的唯一有效手段, 移植后的排斥反应和诱导免疫耐受是现代医学的两大难题, Kupffer细胞在肝移植后排斥反应和诱导免疫耐受过程中发挥着重要的作用, 调节两者的内在平衡关系, 成为肝移植后移植免疫领域中新的研究方向.
刘占举, 教授, 郑州大学第二附属医院消化内科
器官移植术后诱导移植免疫耐受是当前研究的热点和难点, 越来越多的研究报道Kupffer细胞有利于诱导肝移植免疫耐受, 但其作用机制复杂, 尚需进一步探索研究.
Miyagawa-Hayashino et al通过临床研究发现, APC上FasL的表达和FasL+ Kupffer细胞吞噬凋亡T细胞是肝移植排斥反应的一项指标, 可以作为评估排斥反应的严重程度和检测治疗效果.
本文从一个全新的角度剖析了Kupffer细胞在肝移植后的排斥反应和诱导免疫耐受中的作用, 总结了有关该领域的最新研究成果, 有助于读者了解该领域的研究动态与进展, 为进一步研究探索指明方向.
本文简要地阐述了肝脏移植过程中的Kupffer's cells的免疫病理作用, 对研究肝移植免疫排斥和耐受有一定的指导意义.
编辑:李军亮 电编:吴鹏朕
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