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

Jurij Kiefer, Johannes Zeller, Laura Schneider, Julia Thomé, James D McFadyen, Isabel A Hoerbrand, Friederike Lang, Emil Deiss, Balázs Bogner, Anna-Lena Schaefer, Nina Chevalier, Verena K Horner, Sheena Kreuzaler, Ulrich Kneser, Martin Kauke-Navarro, David Braig, Kevin J Woollard, Bohdan Pomahac, Karlheinz Peter, Steffen U Eisenhardt
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Abstract

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.

C 反应蛋白通过亚群选择性单核细胞活化协调血管化复合异体移植中的急性异体移植排斥反应。
导言:尽管最近在血管化复合异体移植(VCA)(如面部移植)方面取得了重大进展,但短期和长期的异体移植存活率仍受到异体移植排斥反应的严重限制。同种异体移植后直接出现的急性期反应是对缺血/再灌注的免疫炎症反应,是移植物排斥反应的早期诱因。急性期反应物通过与单核吞噬细胞系统串联来介导这种免疫反应:C反应蛋白(CRP)是一种众所周知的炎症标志物,具有促炎特性,会加重缺血/再灌注损伤。因此,我们研究了 CRP 如何影响急性异体移植排斥反应:方法:基于对面部 VCA 的临床观察,我们在大鼠身上应用了一种复杂的后肢移植模型来研究 CRP 是否会直接影响移植排斥反应。我们进一步分析了急性排斥反应早期受体源性单核细胞的亚群特异性浸润和组织分布,并使用眼内成像技术评估了 CRP 对它们的不同调节作用:结果:我们证明了CRP通过选择性激活非典型单核细胞加速了异体移植排斥反应并降低了异体移植存活率。治疗性稳定 CRP 可减弱这种对单核细胞的激活作用,从而减轻急性异体移植排斥反应。在急性排斥反应的早期阶段,对移植物浸润的受体源性单核细胞进行的显微成像证实了CRP对它们的不同调节作用,以及它们在推动移植物排斥反应早期阶段的关键作用:CRP对受体源性单核细胞的差异化激活会加重先天性免疫反应并加速临床移植物排斥反应。
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