Regulated cell death and DAMPs as biomarkers and therapeutic targets in normothermic perfusion of transplant organs. Part 2: implementation strategies
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-me...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Transplantation |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/frtra.2025.1575703/full |
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| author | Walter G. Land Walter G. Land Walter G. Land Andreas Linkermann Andreas Linkermann Andreas Linkermann |
| author_facet | Walter G. Land Walter G. Land Walter G. Land Andreas Linkermann Andreas Linkermann Andreas Linkermann |
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| description | 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. |
| format | Article |
| id | doaj-art-7fe0f6af4b9d4c06a91c79751909effa |
| institution | OA Journals |
| issn | 2813-2440 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Transplantation |
| spelling | doaj-art-7fe0f6af4b9d4c06a91c79751909effa2025-08-20T02:18:27ZengFrontiers Media S.A.Frontiers in Transplantation2813-24402025-04-01410.3389/frtra.2025.15757031575703Regulated cell death and DAMPs as biomarkers and therapeutic targets in normothermic perfusion of transplant organs. Part 2: implementation strategiesWalter G. Land0Walter G. Land1Walter G. Land2Andreas Linkermann3Andreas Linkermann4Andreas Linkermann5German Academy for Transplantation Medicine, Munich, GermanyLaboratoire 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, FranceDepartment of Integrated Medical Sciences, Medical Science Faculty, State University of Rio De Janeiro, Cabo Frio, BrazilDepartment of Medicine V, University Medical Centre Mannheim, University of Heidelberg, Mannheim, GermanyDivision of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, GermanyDivision of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United StatesThis 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.https://www.frontiersin.org/articles/10.3389/frtra.2025.1575703/fullDAMP-induced alloimmunityallotoleranceDCDDBDdonor and recipient dendritic cellsallorecognition |
| spellingShingle | Walter G. Land Walter G. Land Walter G. Land Andreas Linkermann Andreas Linkermann Andreas Linkermann Regulated cell death and DAMPs as biomarkers and therapeutic targets in normothermic perfusion of transplant organs. Part 2: implementation strategies Frontiers in Transplantation DAMP-induced alloimmunity allotolerance DCD DBD donor and recipient dendritic cells allorecognition |
| title | Regulated cell death and DAMPs as biomarkers and therapeutic targets in normothermic perfusion of transplant organs. Part 2: implementation strategies |
| title_full | Regulated cell death and DAMPs as biomarkers and therapeutic targets in normothermic perfusion of transplant organs. Part 2: implementation strategies |
| title_fullStr | Regulated cell death and DAMPs as biomarkers and therapeutic targets in normothermic perfusion of transplant organs. Part 2: implementation strategies |
| title_full_unstemmed | Regulated cell death and DAMPs as biomarkers and therapeutic targets in normothermic perfusion of transplant organs. Part 2: implementation strategies |
| title_short | Regulated cell death and DAMPs as biomarkers and therapeutic targets in normothermic perfusion of transplant organs. Part 2: implementation strategies |
| title_sort | regulated cell death and damps as biomarkers and therapeutic targets in normothermic perfusion of transplant organs part 2 implementation strategies |
| topic | DAMP-induced alloimmunity allotolerance DCD DBD donor and recipient dendritic cells allorecognition |
| url | https://www.frontiersin.org/articles/10.3389/frtra.2025.1575703/full |
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