Pig-to-human kidney xenotransplants using genetically modified minipigs

• Published in: Cell reports. Medicine 2024-10, Vol.5 (10), p.101744, Article 101744
• Main Authors: Wang, Yi, Chen, Gang, Pan, Dengke, Guo, Hui, Jiang, Hongtao, Wang, Jianli, Feng, Hao, He, Songzhe, Du, Jiaxiang, Zhang, Man, Li, Tao, Wang, Yong, Yu, Hang, Gan, Huiling, Wen, Quan, Song, Zhian, Li, Desheng, Yu, Yifan, Wang, Huanliang, Li, Bing, You, Yong, Zhou, Shen, Wang, Mingfa, Liu, Lili, Xu, Liang, Yang, Meng, Pei, Hua, Zhang, Kang, Chen, Zhonghua K.
• Format: Article
• Language: English
• Subjects: acute xenograft rejection; Animals; Animals, Genetically Modified; brain-dead human decedent; Galactosyltransferases - genetics; genetically engineered pig; Graft Rejection - genetics; Graft Rejection - immunology; Heterografts; Humans; Kidney - immunology; Kidney - pathology; kidney transplantation; Kidney Transplantation - methods; Killer Cells, Natural - immunology; PCMV/PRV; Swine; Swine, Miniature; Transplantation, Heterologous - methods; xenotransplantation
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101744

This study develops an observational model to assess kidney function recovery and xenogeneic immune responses in kidney xenotransplants, focusing on gene editing and immunosuppression. Two brain-dead patients undergo single kidney xenotransplantation, with kidneys donated by minipigs genetically modified to include triple-gene knockouts (GGTA1, β4GalNT2, CMAH) and human gene transfers (hCD55 or hCD55/hTBM). Renal xenograft functions are fully restored; however, immunosuppression without CD40-CD154 pathway blockade is ineffective in preventing acute rejection by day 12. This rejection manifests as both T cell-mediated rejection and antibody-mediated rejection (AMR), confirmed by natural killer (NK) cell and macrophage infiltration in sequential xenograft biopsies. Despite donor pigs being pathogen free before transplantation, xenografts and recipient organs test positive for porcine cytomegalovirus/porcine roseolovirus (PCMV/PRV) by the end of the observation period, indicating reactivation and contributing to significant immunopathological changes. This study underscores the critical need for extended clinical observation and comprehensive evaluation using deceased human models to advance xenograft success. [Display omitted] •Successfully completed two pig-to-human kidney transplants in brain-dead human recipients•Renal function restoration in kidney xenografts from genetically modified minipigs•Acute rejection occurred by day 12 without CD40-CD154 blockade•Reactivation of PCMV led to significant immunopathological changes in recipients Yi Wang et al. successfully performed two pig-to-human kidney xenotransplants using genetically modified minipigs, which led to restored renal functions. The study described immunological and pathological changes and the impact of porcine cytomegalovirus reactivation on graft survival, highlighting the potential of this model to advance xenotransplantation toward clinical applications.