Edward Y. Skolnik小组取得一项新突破。他们提出了猪到人肾脏异种移植的多组学分析。相关论文于2025年11月13日发表在《自然》杂志上。

为了了解猪对人肾脏异种移植的免疫反应，该团队对一名脑死亡的人类（已故）受体进行了为期61天的移植手术，对异种移植物和宿主血液进行了大规模的多组学分析。血浆母细胞、自然杀伤细胞（NK）和树突状细胞在术后第10天至第28天之间增加，与IgG/IgA b细胞克隆型的扩增以及随后在术后第33天活检证实的抗体介导的排斥反应（AbMR）一致。人类T细胞频率从POD21开始增加，并在POD33-49之间达到峰值，这与T细胞受体多样化、限制性TRBV2/J1克隆型扩增以及AbMR和细胞介导的POD49联合排斥的组织学证据相一致。在POD33，移植物中最丰富的人类免疫群体是CXCL9+巨噬细胞，与IFN-γ驱动的炎症和I型免疫反应一致。此外，课题组研究人员还发现了活化的猪巨噬细胞与浸润的人类免疫细胞之间相互作用的证据。异种移植组织在POD21-POD33处表现出促纤维化的小管和间质损伤，由S100A65、SPP16（骨桥蛋白）和COLEC117标记。蛋白质组学分析显示人和猪的补体激活，在补体抑制的AbMR治疗后，人的成分减少。总的来说，这些数据描述了人对猪肾免疫反应的分子协调，揭示了改善异种移植物存活的潜在免疫调节靶点。

据介绍，器官短缺仍然是移植的主要挑战，基因编辑猪器官提供了一个有希望的解决方案。尽管进行了基因编辑，异种移植后的免疫反应仍可能导致移植失败。

附：英文原文

Title: Multi-omics analysis of a pig-to-human decedent kidney xenotransplant

Author: Schmauch, Eloi, Piening, Brian D., Dowdell, Alexa K., Mohebnasab, Maedeh, Williams, Simon H., Stukalov, Alexey, Robinson, Fred L., Bombardi, Robin, Jaffe, Ian, Khalil, Karen, Kim, Jacqueline, Aljabban, Imad, Eitan, Tal, OBrien, Darragh P., Rophina, Mercy, Wang, Chan, Bartlett, Alexandra Q., Zanoni, Francesca, Albay, Jon, Andrijevic, David, Maden, Berk, Mauduit, Vincent, Vikman, Susanna, Argibay, Diana, Zayas, Zasha, Wu, Leah, Moi, Kiana, Lau, Billy, Zhang, Weimin, Gragert, Loren, Weldon, Elaina, Gao, Hui, Hamilton, Lauren, Kagermazova, Larisa, Camellato, Brendan R., Gandla, Divya, Bhatt, Riyana, Gao, Sarah, Al-Ali, Rudaynah A., Habara, Alawi H., Chang, Andrew, Ferdosi, Shadi, Chen, Han M., Motter, Jennifer D., Chacon, Fiorella A., Thomas, Scott C., Saxena, Deepak, Fairchild, Robert L., Loupy, Alexandre, Heguy, Adriana, Crawford, Ali, Batzoglou, Serafim, Snyder, Michael P., Siddiqui, Asim, Holmes, Michael V., Chong, Anita S., Kaikkonen, Minna U., Linna-Kuosmanen, Suvi, Ayares, David, Lorber, Marc, Nellore, Anoma, Skolnik, Edward Y.

Issue&Volume: 2025-11-13

Abstract: Organ shortage remains a major challenge in transplantation, and gene-edited pig organs offer a promising solution1–3. Despite gene-editing, the immune reactions following xenotransplantation can still cause transplant failure4. To understand the immunological response of a pig-to-human kidney xenotransplantation, we conducted large-scale multi-omics profiling of the xenograft and the host’s blood over a 61-day procedure in a brain-dead human (decedent) recipient. Blood plasmablasts, natural killer (NK) cells, and dendritic cells increased between postoperative day (POD)10 and 28, concordant with expansion of IgG/IgA B-cell clonotypes, and subsequent biopsy-confirmed antibody-mediated rejection (AbMR) at POD33. Human T-cell frequencies increased from POD21 and peaked between POD33-49 in the blood and xenograft, coinciding with T-cell receptor diversification, expansion of a restricted TRBV2/J1 clonotype and histological evidence of a combined AbMR and cell-mediated rejection at POD49. At POD33, the most abundant human immune population in the graft was CXCL9+ macrophages, aligning with IFN-γ-driven inflammation and a Type I immune response. In addition, we see evidence of interactions between activated pig-resident macrophages and infiltrating human immune cells. Xenograft tissue showed pro-fibrotic tubular and interstitial injury, marked by S100A65, SPP16 (Osteopontin), and COLEC117, at POD21–POD33. Proteomics profiling revealed human and pig complement activation, with decreased human component after AbMR therapy with complement inhibition. Collectively, these data delineate the molecular orchestration of human immune responses to a porcine kidney, revealing potential immunomodulatory targets for improving xenograft survival.

DOI: 10.1038/s41586-025-09846-7

Source: https://www.nature.com/articles/s41586-025-09846-7