Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.
NHC Key Laboratory of Human Disease Comparative Medicine, The Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Front Immunol. 2020 Jan 23;10:3060. doi: 10.3389/fimmu.2019.03060. eCollection 2019.
The increasing life expectancy of humans has led to a growing numbers of patients with chronic diseases and end-stage organ failure. Transplantation is an effective approach for the treatment of end-stage organ failure; however, the imbalance between organ supply and the demand for human organs is a bottleneck for clinical transplantation. Therefore, xenotransplantation might be a promising alternative approach to bridge the gap between the supply and demand of organs, tissues, and cells; however, immunological barriers are limiting factors in clinical xenotransplantation. Thanks to advances in gene-editing tools and immunosuppressive therapy as well as the prolonged xenograft survival time in pig-to-non-human primate models, clinical xenotransplantation has become more viable. In this review, we focus on the evolution and current status of xenotransplantation research, including our current understanding of the immunological mechanisms involved in xenograft rejection, genetically modified pigs used for xenotransplantation, and progress that has been made in developing pig-to-pig-to-non-human primate models. Three main types of rejection can occur after xenotransplantation, which we discuss in detail: (1) hyperacute xenograft rejection, (2) acute humoral xenograft rejection, and (3) acute cellular rejection. Furthermore, in studies on immunological rejection, genetically modified pigs have been generated to bridge cross-species molecular incompatibilities; in the last decade, most advances made in the field of xenotransplantation have resulted from the production of genetically engineered pigs; accordingly, we summarize the genetically modified pigs that are currently available for xenotransplantation. Next, we summarize the longest survival time of solid organs in preclinical models in recent years, including heart, liver, kidney, and lung xenotransplantation. Overall, we conclude that recent achievements and the accumulation of experience in xenotransplantation mean that the first-in-human clinical trial could be possible in the near future. Furthermore, we hope that xenotransplantation and various approaches will be able to collectively solve the problem of human organ shortage.
人类预期寿命的延长导致患有慢性疾病和终末期器官衰竭的患者人数不断增加。移植是治疗终末期器官衰竭的有效方法；然而，器官供应与人类器官需求之间的不平衡是临床移植的一个瓶颈。因此，异种移植可能是一种有前途的替代方法，可以弥合器官、组织和细胞供应与需求之间的差距；然而，免疫屏障是临床异种移植的限制因素。由于基因编辑工具和免疫抑制疗法的进步以及猪到非人类灵长类动物模型中异种移植物存活时间的延长，临床异种移植变得更加可行。在这篇综述中，我们重点介绍了异种移植研究的演变和现状，包括我们目前对异种移植物排斥中涉及的免疫机制的理解、用于异种移植的基因修饰猪，以及在开发猪到猪到非人类灵长类动物模型方面取得的进展。异种移植后可能会发生三种主要类型的排斥反应，我们将详细讨论：（1）超急性异种移植物排斥反应，（2）急性体液性异种移植物排斥反应，（3）急性细胞性排斥反应。此外，在免疫排斥研究中，已经产生了基因修饰猪来桥接跨物种分子不相容性；在过去十年中，异种移植领域的大多数进展都源于基因工程猪的产生；因此，我们总结了目前可用于异种移植的基因修饰猪。接下来，我们总结了近年来临床前模型中固体器官最长的存活时间，包括心脏、肝脏、肾脏和肺异种移植。总的来说，我们得出结论，异种移植的最新成就和经验的积累意味着在不久的将来可能进行首例人体临床试验。此外，我们希望异种移植和各种方法能够共同解决人类器官短缺的问题。
