Challenges in pig-to-human kidney xenotransplantation
Authors: Liming Cheng, Kai Liu
Journal: The Lancet (2024)

Pig-to-human kidney xenotransplantation is our interest, and we read about it endlessly. We read Alexandre Loupy and colleagues' multimodal, in-depth phenotypic analysis of early immune responses in two porcine kidney xenotransplantations to human patients,1Loupy A Goutaudier V Giarraputo A et al.Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study.Lancet. 2023; 402: 1158-1169Summary Full Text Full Text PDF PubMed Google Scholar and this pioneering research has important implications for future xenotransplantation. However, we want to present modern immunology research insights to enlighten authors and readers. To reduce antibody-mediated rejection by naturally formed xenoantibodies, Loupy and colleagues genetically modified pig donors with a knockout of the alpha-1, 3-galactosyltransferase gene. However, genetic modification might not eliminate immunological incompatibility; N-glycolylneuraminic acid, alpha-1,2-galactose, and beta-1, 4-N-acetylglucosamine are other pig-specific antigens that humans might produce antibodies against.2Cooper DKC Ekser B Tector AJ A brief history of clinical xenotransplantation.Int J Surg. 2015; 23: 205-210Crossref PubMed Scopus (0) Google Scholar Thus, future research should use more powerful gene-editing approaches to reduce or eliminate these immunogenic antigens.3Wu G Pfeiffer S Lu SQ et al.Generation of pig-to-mouse heart xenografts using donors with six genetic modifications.Xenotransplantation. 2020; 27e12560Google Scholar Loupy and colleagues used the standard immunosuppressive regimen to induce and maintain human-to-human kidney allotransplantation.1Loupy A Goutaudier V Giarraputo A et al.Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study.Lancet. 2023; 402: 1158-1169Summary Full Text Full Text PDF PubMed Google Scholar This regimen might not work for pig-to-human kidney xenotransplantation—xenotransplants could need stronger or more specific immunosuppressants to prevent and resolve acute and chronic rejection,4Iwase H Ekser B Satyananda V et al.Pig-to-baboon heterotopic heart transplantation—exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens.Xenotransplantation. 2015; 22: 211-220Crossref PubMed Google Scholar but this treatment approach might increase risk of infection and cancer.5Mohiuddin MM Singh AK Corcoran PC et al.Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft.Nat Commun. 2016; 711138Crossref PubMed Scopus (339) Google Scholar The more rational and safer immunosuppressive methods, such as targeted drugs, tolerance induction, and cellular therapies, should be investigated before the use of specific immunosuppressants. Before participation in clinical trials, the immune status and function of patients receiving xenotransplant must be better characterised and measured. No standard method exists to test and compare immune systems across populations and individuals. Miscommunication can impair our understanding of the immune system's complexity and variety. The immune system and its interactions with microbiota and other factors should be studied using more sophisticated approaches and measurements. We declare no competing interests. Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping studyDespite favourable short-term outcomes and absence of hyperacute injuries, our findings suggest that antibody-mediated rejection in pig-to-human kidney xenografts might be occurring. Our results suggest specific therapeutic targets towards the humoral arm of rejection to improve xenotransplantation results. Full-Text PDF Challenges in pig-to-human kidney xenotransplantation – Authors' replyThe Correspondence from Liming Cheng and Kai Liu on our Article1 contains several comments that deserve further discussion. The decision to use thymokidneys from pigs with only the alpha-1, 3-galactosyltransferase antigen knocked out (Gal-KO) was made for several reasons.2 First, this herd is being successfully bred, making it easy to rapidly produce Gal-KO pigs at the large scale that is needed if xenotransplantation is to effectively address the shortage of organs for human transplantation. To consistently breed pigs with a substantial number of genetic edits is currently challenging. Full-Text PDF