Fathi Farshid, Suek Nathan, Vermette Benjamin, Breen Kevin, Saad Yasmeen S, Bay Constanza, Parks Christopher A, Stern Jeffrey, Khalil Karen, Kim Jacqueline, Jaffe Ian S, Aljabban Imad, Novikova Ekaterina, Severa Elizabeth, Herati Ramin Sedaghat, Burdorf Lars, Griesemer Adam D, Montgomery Robert A, Sykes Megan
Department of Medicine, Columbia Center for Translational Immunology, Columbia University Medical Center, Columbia University; New York, NY, USA.
Department of Surgery, Transplant Institute, New York University Langone Health; New York, NY, USA.
Res Sq. 2025 Apr 22:rs.3.rs-6474835. doi: 10.21203/rs.3.rs-6474835/v1.
Xenotransplantation of pig organs is a promising solution to the organ shortage; however, rejection remains a major obstacle. Pig-to-human decedent transplantation provides an opportunity to study immune barriers to xenotransplantation experimentally. We tracked donor-reactive T cell dynamics in a 61-day pig-to-human decedent thymokidney xenotransplant. Xenogeneic donor-reactive T cell clones (XDRTCCs) identified using high-throughput sequencing expanded markedly in peripheral blood in association with apparent antibody-mediated rejection (AMR). Single-cell RNA and TCR sequencing of leukocytes from the xenograft showed XDRTCC infiltration and effector transcript expression during AMR. Additionally, γδ and NK cells with cytotoxic effector phenotypes were prominent in the rejecting xenograft. These data suggest that improved suppression of innate immunity and T cell responses might enhance the success of xenotransplantation.
猪器官的异种移植是解决器官短缺问题的一个有前景的方案；然而，排斥反应仍然是一个主要障碍。猪到人类死者的移植为通过实验研究异种移植的免疫屏障提供了一个机会。我们在一项为期61天的猪到人类死者胸腺肾脏异种移植中追踪了供体反应性T细胞的动态变化。使用高通量测序鉴定出的异种供体反应性T细胞克隆（XDRTCCs）在外周血中显著扩增，同时伴有明显的抗体介导的排斥反应（AMR）。对异种移植物中白细胞进行的单细胞RNA和TCR测序显示，在AMR期间有XDRTCC浸润和效应转录本表达。此外，具有细胞毒性效应表型的γδ和NK细胞在发生排斥的异种移植物中很突出。这些数据表明，改善对先天免疫和T细胞反应的抑制可能会提高异种移植的成功率。
