Land Walter G, Linkermann Andreas
German Academy for Transplantation Medicine, Munich, Germany.
Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Institut Thématique Interdisciplinaire TRANSPLANTEX NG, Université de Strasbourg, Strasbourg, France.
Front Transplant. 2025 Apr 24;4:1575703. doi: 10.3389/frtra.2025.1575703. eCollection 2025.
This Part 2 of a bipartite review commences with the delineation of a conceptual model outlining the fundamental role of injury-induced regulated cell death (RCD) in the release of DAMPs that drive innate immune responses involved in early inflammation-related allograft dysfunction and alloimmune-mediated allograft rejection. In relation to this topic, the focus is on the divergent role of donor and recipient dendritic cells (DCs), which become immunogenic in the presence of DAMPs to regulate alloimmunity, but in the absence of DAMPs acquire tolerogenic properties to promote allotolerance. With respect to this scenario, proposals are then made for leveraging RCD and DAMPs as biomarkers during normothermic regional perfusion (NRP) and normothermic machine perfusion (NMP) of transplant organs from DCD donors, a strategy poised to significantly enhance current policies for assessing donor organ quality. The focus is then on the ambitious goal to target RCD and DAMPs therapeutically during NRP and NMP, aiming to profoundly suppress subsequently early allograft inflammation and alloimmunity in the recipient. This strategic approach seeks to prevent the activation of intragraft innate immune cells including DCs during donor organ reperfusion in the recipient, which is driven by ischemia/reperfusion injury-induced DAMPs. In this context, available inhibitors of various types of RCD, as well as scavengers and inhibitors of DAMPs are highlighted for their promising therapeutic potential in NRP and NMP settings, building on their proven efficacy in other experimental disease models. If successful, this kind of therapeutic intervention should also be considered for application to organs from DBD donors. Finally, drawing on current global insights into the critical role of RCD and DAMPs in driving innate inflammatory and (allo)immune responses, targeting their inhibition and/or prevention during normothermic perfusion of transplant organs from DCD donors - and potentially DBD donors - holds the transformative potential to not only alleviate transplant dysfunction and suppress allograft rejection but also foster allograft tolerance.
本二分综述的第2部分首先描绘了一个概念模型，概述了损伤诱导的调节性细胞死亡（RCD）在释放驱动先天性免疫反应的损伤相关分子模式（DAMPs）中的基本作用，这些反应参与早期炎症相关的同种异体移植功能障碍和同种免疫介导的同种异体移植排斥反应。关于这一主题，重点是供体和受体树突状细胞（DC）的不同作用，它们在存在DAMPs的情况下具有免疫原性以调节同种免疫，但在没有DAMPs的情况下获得耐受性特性以促进同种耐受。针对这种情况，随后提出了在脑死亡后捐赠者（DCD）供体的移植器官进行常温区域灌注（NRP）和常温机器灌注（NMP）期间，将RCD和DAMPs用作生物标志物的建议，这一策略有望显著加强当前评估供体器官质量的政策。然后重点是在NRP和NMP期间对RCD和DAMPs进行治疗性靶向的宏伟目标，旨在深刻抑制受体随后的早期同种异体移植炎症和同种免疫。这种战略方法旨在防止受体中供体器官再灌注期间包括DC在内的移植物内先天性免疫细胞的激活，这是由缺血/再灌注损伤诱导的DAMPs驱动的。在此背景下，强调了各种类型RCD的可用抑制剂以及DAMPs的清除剂和抑制剂在NRP和NMP环境中的潜在治疗潜力，这基于它们在其他实验性疾病模型中已证实的疗效。如果成功，这种治疗干预也应考虑应用于脑死亡捐赠者（DBD）供体的器官。最后，借鉴当前全球对RCD和DAMPs在驱动先天性炎症和（同种）免疫反应中的关键作用的见解，在DCD供体（可能还有DBD供体）的移植器官常温灌注期间靶向抑制和/或预防它们，不仅具有缓解移植功能障碍和抑制同种异体移植排斥反应的变革潜力，还具有促进同种异体移植耐受的潜力。
