Organ Transplant and Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Academy of an Transplant Science & Sichuan Provincial People's Hospital, Chengdu, China.
School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Xenotransplantation. 2019 Jan;26(1):e12492. doi: 10.1111/xen.12492.
Pig-to-human organ transplantation provides an alternative for critical shortage of human organs worldwide. Genetically modified pigs are promising donors for xenotransplantation as they show many anatomical and physiological similarities to humans. However, immunological rejection including hyperacute rejection (HAR), acute humoral xenograft rejection (AHXR), immune cell-mediated rejection, and other barriers associated with xenotransplantation must be overcome with various strategies for the genetic modification of pigs. In this review, we summarize the outcomes of genetically modified and cloned pigs achieved by Chinese scientists to resolve the above-mentioned problems in xenotransplantation. It is now possible to knockout several porcine genes associated with the expression of sugar residues, antigens for (naturally) existing antibodies in humans, including GGTA1, CMAH, and β4GalNT2, and thereby preventing the antigen-antibody response. Moreover, insertion of human complement- and coagulation-regulatory transgenes, such as CD46, CD55, CD59, and hTBM, can further overcome effects of the humoral immune response and coagulation dysfunction, while expression of regulatory factors of immune responses can inhibit the adaptive immune rejection. Furthermore, transgenic strategies have been developed by Chinese scientists to reduce the potential risk of infections by endogenous porcine retroviruses (PERVs). Breeding of multi-gene low-immunogenicity pigs in China is also presented in this review. Lastly, we will briefly mention the preclinical studies on pig-to-non-human primate xenotransplantation conducted in several centers in China.
猪到人体器官移植为全球范围内人体器官严重短缺提供了一种替代方案。基因修饰猪作为异种移植的潜在供体具有很大的优势，因为它们在解剖学和生理学上与人类有许多相似之处。然而，免疫排斥反应，包括超急性排斥反应（HAR）、急性体液性异种移植物排斥反应（AHXR）、免疫细胞介导的排斥反应以及异种移植相关的其他障碍，必须通过各种策略来克服，这些策略包括对猪进行基因修饰。在这篇综述中，我们总结了中国科学家在解决异种移植中上述问题方面所取得的基因修饰和克隆猪的成果。现在已经有可能敲除几个与糖残基表达相关的猪基因，以及人类（自然）存在的抗体的抗原，包括 GGTA1、CMAH 和 β4GalNT2，从而防止抗原-抗体反应。此外，插入人类补体和凝血调节转基因，如 CD46、CD55、CD59 和 hTBM，可进一步克服体液免疫反应和凝血功能障碍的影响，而免疫反应调节因子的表达可以抑制适应性免疫排斥。此外，中国科学家还开发了转基因策略来降低内源性猪逆转录病毒（PERVs）感染的潜在风险。本文还介绍了中国在培育多基因低免疫原性猪方面的进展。最后，我们将简要提及中国几个中心进行的猪到非人类灵长类动物异种移植的临床前研究。
