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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02972-1

摘要内容如下：

在先前的一项研究中，将10个基因编辑的猪的异种心脏移植物移植到两个人类死者体内，没有显示出急性发作的细胞或抗体介导的排斥反应的证据。在这里，为了更好地了解异种移植后的详细分子景观，我们对每6小时从移植死者获得的血液样本进行了整体和单细胞转录组学、脂质组学、蛋白质组学和代谢组学，以及组织学和转录组学组织图谱。我们在死者1（男性）的外周血单个核细胞和异种移植组织中观察到大量的早期免疫应答，与下游T细胞和自然杀伤细胞活性相关。纵向分析表明存在缺血再灌注损伤，并因T细胞免疫抑制不足而加剧，这与先前在猪到非人灵长类动物研究中发现的围术期异种心脏移植功能障碍一致。此外，在移植后42小时，细胞代谢和肝脏损伤途径发生了实质性的改变，这与器官范围内的严重生理功能障碍有关。相比之下，与死者1相比，死者2（女性）的RNA、蛋白质、脂质和代谢谱的变化相对较小。总体而言，这些多组学分析描述了两名人类死者对心脏异种移植的不同反应，并揭示了异种移植后早期分子和免疫反应的新见解。这些发现可能有助于开发靶向治疗方法，以限制缺血再灌注损伤相关的表型并改善预后。

英文原文如下：

Abstracts

In a previous study, heart xenografts from 10-gene-edited pigs transplanted into two human decedents did not show evidence of acute-onset cellular- or antibody-mediated rejection. Here, to better understand the detailed molecular landscape following xenotransplantation, we carried out bulk and single-cell transcriptomics, lipidomics, proteomics and metabolomics on blood samples obtained from the transplanted decedents every 6 h, as well as histological and transcriptomic tissue profiling. We observed substantial early immune responses in peripheral blood mononuclear cells and xenograft tissue obtained from decedent 1 (male), associated with downstream T cell and natural killer cell activity. Longitudinal analyses indicated the presence of ischemia reperfusion injury, exacerbated by inadequate immunosuppression of T cells, consistent with previous findings of perioperative cardiac xenograft dysfunction in pig-to-nonhuman primate studies. Moreover, at 42 h after transplantation, substantial alterations in cellular metabolism and liver-damage pathways occurred, correlating with profound organ-wide physiological dysfunction. By contrast, relatively minor changes in RNA, protein, lipid and metabolism profiles were observed in decedent 2 (female) as compared to decedent 1. Overall, these multi-omics analyses delineate distinct responses to cardiac xenotransplantation in the two human decedents and reveal new insights into early molecular and immune responses after xenotransplantation. These findings may aid in the development of targeted therapeutic approaches to limit ischemia reperfusion injury-related phenotypes and improve outcomes.

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