Pig-to-human kidney xenotransplants using genetically modified minipigs.

IF 11.7 1区医学 Q1 CELL BIOLOGY Cell Reports Medicine Pub Date : 2024-10-15 Epub Date: 2024-09-23 DOI:10.1016/j.xcrm.2024.101744

Yi Wang, Gang Chen, Dengke Pan, Hui Guo, Hongtao Jiang, Jianli Wang, Hao Feng, Songzhe He, Jiaxiang Du, Man Zhang, Tao Li, 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, Hua Pei, Kang Zhang, Zhonghua K Chen

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Abstract

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.

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利用转基因小猪进行猪-人肾脏异种移植。

本研究建立了一个观察模型，以评估肾脏异种移植中肾功能的恢复和异种免疫反应，重点关注基因编辑和免疫抑制。两名脑死亡患者接受了单肾异种移植，肾脏由小猪捐献，小猪经过基因修饰，包括三基因敲除（GGTA1、β4GalNT2、CMAH）和人类基因转移（hCD55 或 hCD55/hTBM）。肾脏异种移植的功能已完全恢复；但是，到第 12 天时，不阻断 CD40-CD154 通路的免疫抑制无法有效防止急性排斥反应。这种排斥反应表现为 T 细胞介导的排斥反应和抗体介导的排斥反应（AMR），在连续的异种移植物活检中，自然杀伤（NK）细胞和巨噬细胞浸润证实了这一点。尽管供体猪在移植前没有病原体，但在观察期结束时，异种移植物和受体器官的猪巨细胞病毒/猪玫瑰豚病毒（PCMV/PRV）检测呈阳性，这表明猪巨细胞病毒/猪玫瑰豚病毒重新活化并导致了显著的免疫病理变化。这项研究强调了延长临床观察期和使用已故人类模型进行综合评估以促进异种移植成功的迫切需要。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.