Pig-to-human kidney xenotransplants using genetically modified minipigs

作者：Yi Wang, Yi Wang, Gang Chen, Dengke Pan, Hui Guo, Hongtao Jiang, Jianli Wang, Hao Feng, Songzhe He, Jiaxiang Du, Man Zhang, Li Tao, Yong Wang, Yong Wang, Hang Yu, Huiling Gan, Quan Wen, Zhian Song, Desheng Li, Yifan Yu, Huanliang Wang, Bing Li, Yong You, Shen Zhou, Mingfa Wang, Lili Liu, Liang Xu, Meng Yang, H. Pei, Kang Zhang, Zhonghua K Chen · 发表于：Cell Reports Medicine · 年份：2024 · DOI：10.1016/j.xcrm.2024.101744 · 被引用次数：57 · 研究领域：Xenotransplantation and immune response、Pluripotent Stem Cells Research、Animal Genetics and Reproduction

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. • 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 s...