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C-reactive protein orchestrates acute allograft rejection in vascularized composite allotransplantation via selective activation of monocyte subsets

J. Kiefer, J. Zeller, L. Schneider, J. Thomé, JD. McFadyen, IA. Hoerbrand, F. Lang, E. Deiss, B. Bogner, AL. Schaefer, N. Chevalier, VK. Horner, S. Kreuzaler, U. Kneser, M. Kauke-Navarro, D. Braig, KJ. Woollard, B. Pomahac, K. Peter, SU. Eisenhardt

. 2024 ; (-) : . [pub] 20240709

Jazyk angličtina Země Egypt

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25000340

INTRODUCTION: Despite advancements in transplant immunology and vascularized composite allotransplantation (VCA), the longevity of allografts remains hindered by the challenge of allograft rejection. The acute-phase response, an immune-inflammatory reaction to ischemia/reperfusion that occurs directly after allogeneic transplantation, serves as a catalyst for graft rejection. This immune response is orchestrated by acute-phase reactants through intricate crosstalk with the mononuclear phagocyte system. OBJECTIVE: C-reactive protein (CRP), a well-known marker of inflammation, possesses pro-inflammatory properties and exacerbates ischemia/reperfusion injury. Thus, we investigated how CRP impacts acute allograft rejection. METHODS: Prompted by clinical observations in facial VCAs, we employed a complex hindlimb transplantation model in rats to investigate the direct impact of CRP on transplant rejection. RESULTS: Our findings demonstrate that CRP expedites allograft rejection and diminishes allograft survival by selectively activating non-classical monocytes. Therapeutic stabilization of CRP abrogates this activating effect on monocytes, thereby attenuating acute allograft rejection. Intravital imagining of graft-infiltrating, recipient-derived monocytes during the early phase of acute rejection corroborated their differential regulation by CRP and their pivotal role in driving the initial stages of graft rejection. CONCLUSION: The differential activation of recipient-derived monocytes by CRP exacerbates the innate immune response and accelerates clinical allograft rejection. Thus, therapeutic targeting of CRP represents a novel and promising strategy for preventing acute allograft rejection and potentially mitigating chronic allograft rejection.

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$a Kiefer, Jurij $u Department of Plastic and Hand Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
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$a INTRODUCTION: Despite advancements in transplant immunology and vascularized composite allotransplantation (VCA), the longevity of allografts remains hindered by the challenge of allograft rejection. The acute-phase response, an immune-inflammatory reaction to ischemia/reperfusion that occurs directly after allogeneic transplantation, serves as a catalyst for graft rejection. This immune response is orchestrated by acute-phase reactants through intricate crosstalk with the mononuclear phagocyte system. OBJECTIVE: C-reactive protein (CRP), a well-known marker of inflammation, possesses pro-inflammatory properties and exacerbates ischemia/reperfusion injury. Thus, we investigated how CRP impacts acute allograft rejection. METHODS: Prompted by clinical observations in facial VCAs, we employed a complex hindlimb transplantation model in rats to investigate the direct impact of CRP on transplant rejection. RESULTS: Our findings demonstrate that CRP expedites allograft rejection and diminishes allograft survival by selectively activating non-classical monocytes. Therapeutic stabilization of CRP abrogates this activating effect on monocytes, thereby attenuating acute allograft rejection. Intravital imagining of graft-infiltrating, recipient-derived monocytes during the early phase of acute rejection corroborated their differential regulation by CRP and their pivotal role in driving the initial stages of graft rejection. CONCLUSION: The differential activation of recipient-derived monocytes by CRP exacerbates the innate immune response and accelerates clinical allograft rejection. Thus, therapeutic targeting of CRP represents a novel and promising strategy for preventing acute allograft rejection and potentially mitigating chronic allograft rejection.
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$a Zeller, Johannes $u Department of Plastic and Hand Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany; Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
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$a Schneider, Laura $u Department of Plastic and Hand Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
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$a Thomé, Julia $u Department of Plastic and Hand Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
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$a McFadyen, James D $u Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
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$a Hoerbrand, Isabel A $u Department of Plastic and Hand Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
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$a Lang, Friederike $u Department of Plastic and Hand Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
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$a Deiss, Emil $u Department of Plastic and Hand Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
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$a Schaefer, Anna-Lena $u Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
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$a Woollard, Kevin J $u Centre for Inflammatory Disease, Imperial College London, London, UK
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$a Pomahač, Bohdan, $u Department of Surgery, Division of Plastic and Reconstructive Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, USA $d 1971- $7 xx0117402
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$a Eisenhardt, Steffen U $u Department of Plastic and Hand Surgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany. Electronic address: steffen.eisenhardt@uniklinik-freiburg.de
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