Platt J L
Duke University Medical Center, Durham, NC 27710.
Immunol Rev. 1994 Oct;141:127-49. doi: 10.1111/j.1600-065x.1994.tb00875.x.
There is increasing interest in the potential clinical application of xenotransplantation. This interest derives in part from the need to identify a more abundant source of organs for transplantation and in part from rapid progress in understanding the cellular and molecular events that contribute to xenograft rejection. Recent areas of progress include the characterization of xenoreactive antibodies which would initiate the rejection of porcine organs transplanted into primates. These antibodies consist predominantly of IgM and their binding is characterized by high avidity and surprising uniformity. Xenoreactive antibodies recognize porcine glycoproteins of the integrin family; the determinants residing on N-linked substitutions. The predominant substitution has a terminal alpha Gal residue. Antibody binding initiates activation of complement through the classical pathway triggering a number of effector mechanisms. These mechanisms may include loss of heparan sulfate from endothelial cells mediated by C5a and xenoreactive antibody; a change in endothelial cell shape mediated by C5b-7 or the membrane-attack complex; procoagulant changes mediated by the membrane-attack complex; and neutrophil adhesion mediated by iC3b. If hyperacute rejection is prevented by the depletion of xenoreactive antibody and/or the inhibition of complement, acute vascular rejection may be seen some days later. Acute vascular rejection is characterized by prominent evidence of thrombosis and neutrophil infiltration. The cause of acute vascular rejection is unknown, but may reflect profound alterations in the function of endothelial cells lining blood vessels in the graft. In some cases, when recipients of xenografts are modified by depletion of xenoreactive antibodies, acute vascular rejection does not occur; rather, a process called accommodation allows the xenograft to survive despite the return to the circulation of xenoreactive antibodies and complement. The mechanism for accommodation is not known. New therapeutic strategies including the development of specific immunoabsorbants, identification of preferred donor animals expressing low levels of antigen and the development of transgenic donor animals expressing human complement regulatory proteins are among the strategies which may bring xenotransplantation closer to the clinical arena.
人们对异种移植的潜在临床应用兴趣日益浓厚。这种兴趣部分源于需要找到更丰富的移植器官来源，部分源于在理解导致异种移植排斥的细胞和分子事件方面取得的快速进展。最近取得进展的领域包括对异种反应性抗体的特性描述，这些抗体会引发移植到灵长类动物体内的猪器官的排斥反应。这些抗体主要由IgM组成，其结合具有高亲和力和惊人的一致性。异种反应性抗体识别整合素家族的猪糖蛋白；决定簇位于N-连接取代基上。主要的取代基有一个末端α-半乳糖残基。抗体结合通过经典途径启动补体激活，触发多种效应机制。这些机制可能包括由C5a和异种反应性抗体介导的内皮细胞硫酸乙酰肝素的丧失；由C5b-7或膜攻击复合物介导的内皮细胞形状改变；由膜攻击复合物介导的促凝变化；以及由iC3b介导的中性粒细胞黏附。如果通过去除异种反应性抗体和/或抑制补体来预防超急性排斥反应，几天后可能会出现急性血管排斥反应。急性血管排斥反应的特征是有明显的血栓形成和中性粒细胞浸润证据。急性血管排斥反应的原因尚不清楚，但可能反映了移植物中血管内皮细胞功能的深刻改变。在某些情况下，当异种移植受体通过去除异种反应性抗体进行修饰时，急性血管排斥反应不会发生；相反，一个称为适应的过程使异种移植能够存活，尽管异种反应性抗体和补体又回到了循环中。适应的机制尚不清楚。新的治疗策略包括开发特异性免疫吸附剂、鉴定表达低水平抗原的优选供体动物以及开发表达人类补体调节蛋白的转基因供体动物等，这些策略可能会使异种移植更接近临床应用。
