Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Microbiology and Animal Resources Program, University of Alabama at Birmingham, Birmingham, AL, USA.
Xenotransplantation. 2020 Sep;27(5):e12596. doi: 10.1111/xen.12596. Epub 2020 Jun 25.
Genetically engineered pigs are now available for xenotransplantation in which all three known carbohydrate xenoantigens, against which humans have natural antibodies, have been deleted (triple-knockout [TKO] pigs). Furthermore, multiple human transgenes have been expressed in the TKO pigs, all of which are aimed at protecting the cells from the human immune response. Many human sera demonstrate no or minimal antibody binding to, and little or no cytotoxicity of, cells from these pigs, and this is associated with a relatively low T-cell proliferative response. Unfortunately, baboons and other Old World NHPs have antibodies against TKO pig cells, apparently directed to a fourth xenoantigen that appears to be exposed after TKO. In our experience, most, if not all, humans do not have natural antibodies against this fourth xenoantigen. This discrepancy between NHPs and humans is providing a hurdle to successful translation of pig organ transplantation into the clinic, and making it difficult to provide pre-clinical data that support initiation of a clinical trial. The potential methods by which this obstacle might be overcome are discussed. We conclude that, whatever currently available genetically engineered pig is selected for the final pre-clinical studies, this may not be the optimal pig for clinical trials.
基因工程猪现在可用于异种移植，其中已删除所有三种已知的碳水化合物异种抗原（三敲除 [TKO] 猪），针对这些抗原，人类具有天然抗体。此外，TKO 猪中还表达了多种人类转基因，所有这些都旨在保护细胞免受人体免疫反应的侵害。许多人类血清对来自这些猪的细胞表现出无或最小的抗体结合和很少或没有细胞毒性，并且与相对较低的 T 细胞增殖反应相关。不幸的是，狒狒和其他旧世界非人类灵长类动物具有针对 TKO 猪细胞的抗体，显然针对 TKO 后出现的第四种异种抗原。根据我们的经验，大多数（如果不是全部）人类没有针对这种第四种异种抗原的天然抗体。这种非人类灵长类动物和人类之间的差异为将猪器官移植成功转化为临床应用带来了障碍，并且难以提供支持临床试验启动的临床前数据。讨论了克服这一障碍的潜在方法。我们得出的结论是，无论选择哪种目前可用的基因工程猪进行最终的临床前研究，这都可能不是临床试验的最佳猪。
