Xenotransplantation: Current Status in Preclinical Research

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.