Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama.
Xenotransplantation. 2019 May;26(3):e12497. doi: 10.1111/xen.12497. Epub 2019 Feb 15.
Pig liver xenotransplantation appears to be more perplexing when compared to heart or kidney xenotransplantation, even though great progress has been achieved. The relevant molecular mechanisms involved in xenogeneic rejection, including coagulopathy, and particularly thrombocytopenia, are complex, and need to be systematically investigated. The deletion of expression of Gal antigens in the liver graft highlights the injurious impact of nonGal antigens, which continue to induce humoral rejection. Innate immunity, particularly mediated by macrophages and natural killer cells, interplays with inflammation and coagulation disorders. Kupffer cells and liver sinusoidal endothelial cells (LSECs) together mediate leukocyte, erythrocyte, and platelet sequestration and phagocytosis, which can be exacerbated by increased cytokine production, cell desialylation, and interspecies incompatibilities. The coagulation cascade is activated by release of tissue factor which can be dependent or independent of the xenoreactive immune response. Depletion of endothelial anticoagulants and anti-platelet capacity amplify coagulation activation, and interspecies incompatibilities of coagulation-regulatory proteins facilitate dysregulation. LSECs involved in platelet phagocytosis and transcytosis, coupled with hepatocyte-mediated degradation, are responsible for thrombocytopenia. Adaptive immunity could also be problematic in long-term liver graft survival. Currently, relevant evidence and study results of various genetic modifications to the pig donor need to be fully determined, with the aim of identifying the ideal transgene combination for pig liver xenotransplantation. We believe that clinical trials of pig liver xenotransplantation should initially be considered as a bridge to allotransplantation.
猪肝异种移植似乎比心脏或肾脏异种移植更为复杂，尽管已经取得了很大的进展。异种排斥反应涉及的相关分子机制包括凝血障碍，特别是血小板减少症，非常复杂，需要系统地研究。肝移植物中 Gal 抗原的缺失突出了非 Gal 抗原的损伤作用，这些抗原继续诱导体液排斥反应。固有免疫，特别是由巨噬细胞和自然杀伤细胞介导的免疫，与炎症和凝血障碍相互作用。Kupffer 细胞和肝窦内皮细胞（LSEC）共同介导白细胞、红细胞和血小板的捕获和吞噬作用，细胞去唾液酸化和种间不相容性可加剧这种作用。组织因子的释放激活了凝血级联反应，其可以依赖或不依赖于异种反应性免疫反应。内皮抗凝剂和抗血小板能力的耗竭放大了凝血激活作用，凝血调节蛋白的种间不相容性促进了失调。涉及血小板吞噬和转胞作用的 LSEC，加上肝细胞介导的降解，是导致血小板减少症的原因。适应性免疫在长期肝移植物存活中也可能是一个问题。目前，需要充分确定猪供体各种基因修饰的相关证据和研究结果，以确定猪肝异种移植的理想转基因组合。我们认为，猪肝异种移植的临床试验应首先被视为同种移植的桥梁。
