美国纽约大学朗格尼移植研究所Megan Sykes研究小组报道了猪死肾异种移植的生理学和免疫学研究。相关论文于2025年11月13日发表在《自然》杂志上。

转基因猪肾脏异种移植为解决终末期肾脏疾病患者器官短缺问题提供了一种解决方案研究团队进行了为期61天的α-Gal敲除猪肾脏和胸腺自体移植物移植到肾切除的脑死亡人类中，主题是临床批准的免疫抑制，没有CD40阻断或额外的基因修饰。血流动力学和电解质稳定，透析独立。术后10天（POD）活检显示肾小球IgM和IgA沉积，早期补体成分激活，肾系膜溶解，肾功能稳定，无蛋白尿，这是同种异体移植中未见的表型。在POD 33中，血清肌酐的突然增加与抗体介导的排斥反应和供体特异性IgG的增加有关。血浆交换，C3/C3b抑制和兔抗胸腺细胞球蛋白（rATG），完全逆转异种移植排斥反应。先前存在的供体反应性T细胞克隆在移植后的循环中逐渐扩增，获得了效应转录谱，并在接受rATG治疗前的POD 33排斥异种移植物中被检测到。这项研究首次对猪-人异种肾脏移植进行了长期的生理、免疫学和感染性疾病监测，并表明，尽管存在显著的免疫抑制，但预先存在的异种反应性T细胞和针对未知表位的诱导抗体仍存在重大挑战。它还表明，最低限度的基因编辑猪肾可以支持人类长期维持生命的生理功能。

附：英文原文

Title: Physiology and immunology of pig-to-human decedent kidney xenotransplant

Author: Montgomery, Robert A., Stern, Jeffrey M., Fathi, Farshid, Suek, Nathan, Kim, Jacqueline I., Khalil, Karen, Vermette, Benjamin, Tatapudi, Vasishta S., Mattoo, Aprajita, Skolnik, Edward Y., Jaffe, Ian S., Aljabban, Imad, Eitan, Tal, Bisen, Shivani, Weldon, Elaina P., Goutaudier, Valentin, Morgand, Erwan, Mezine, Fariza, Giarraputo, Alessia, Boudhabhay, Idris, Bruneval, Patrick, Sannier, Aurelie, Breen, Kevin, Saad, Yasmeen S., Muntnich, Constanza Bay, Williams, Simon H., Zhang, Weimin, Kagermazova, Larisa, Schmauch, Eloi, Goparaju, Chandra, Dieter, Rebecca, Lawson, Nikki, Dandro, Amy, Fazio-Kroll, Ana Laura, Burdorf, Lars, Ayares, David, Lorber, Marc, Segev, Dorry, Ali, Nicole, Goldfarb, David S., Costa, Victoria, Hilbert, Timothy, Mehta, Sapna A., Herati, Ramin S., Pass, Harvey I., Wu, Ming, Boeke, Jef D., Keating, Brendan, Mangiola, Massimo, Sommer, Philip M., Loupy, Alexandre, Griesemer, Adam, Sykes, Megan

Issue&Volume: 2025-11-13

Abstract: Xenotransplantation of genetically-modified pig kidneys offers a solution to the scarcity of organs for end-stage renal disease patients.1 We performed a 61-day alpha-Gal knock-out pig kidney and thymic autograft transplant into a nephrectomized brain-dead human using clinically approved immunosuppression, without CD40 blockade or additional genetic modification. Hemodynamic and electrolyte stability and dialysis independence were achieved. Post-operative day (POD) 10 biopsies revealed glomerular IgM and IgA deposition, activation of early complement components and mesangiolysis with stable renal function without proteinuria, a phenotype not seen in allotransplantation. On POD 33, an abrupt increase in serum creatinine was associated with antibody-mediated rejection and increased donor-specific IgG. Plasma exchange, C3/C3b inhibition and rabbit anti-thymocyte globulin (rATG), completely reversed xenograft rejection. Pre-existing donor-reactive T cell clones expanded progressively in the circulation post-transplant, acquired an effector transcriptional profile and were detected in the POD 33 rejecting xenograft prior to rATG treatment. This study provides the first long-term physiologic, immunologic, and infectious disease monitoring of a pig-to-human kidney xenotransplant and indicates that pre-existing xenoreactive T cells and induced antibodies to unknown epitope(s) present a major challenge, despite significant immunosuppression. It also demonstrates that a minimally gene-edited pig kidney can support long-term life-sustaining physiologic functions in a human.

DOI: 10.1038/s41586-025-09847-6

Source: https://www.nature.com/articles/s41586-025-09847-6