Investigation of the regulation of the innate immune response by C-reactive protein in vascularized composite allotransplantation (VCA)

血管化复合同种异体移植（VCA）中 C 反应蛋白对先天免疫反应的调节研究

• 批准号: 450025008
• 负责人: Professor Dr. Steffen Ulrich Eisenhardt
• 金额: --
• 依托单位: Klinik für Plastische und Handchirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/450025008?language=en
• 关键词: Investigation; regulation; innate; immune; response

The field of reconstructive microsurgery has made significant progress by the introduction of vascularized composite tissue allotransplantation (VCA) the most common being hand and face transplantations, which are slowly gaining popularity in reconstructive surgery. However, the wide-spread clinical acceptance is limited by the side effects of long-term immuno-suppression and the risk of transplant vasculopathy leading to chronic transplant rejection. Therefore, in order to further develop this promising field of surgical reconstruction, we must target the clinical problems before expanding these still highly experimental reconstructive strategies. There is growing evidence that cells of the mononuclear phagocyte system (MPS) including monocytes and macrophages as part of the innate immune response, are critical in priming of the immune response in the initial inflammatory stage after transplantation characterized by ischemia/reperfusion injury (IRI) as well as in the long-term allograft survival. Chronic rejection is understood to be dependent on a chronic inflammatory process leading to transplant vasculopathy, in which graft-infiltrating macrophages play a significant role. Vasculopathy is characterized by intimal proliferation and progressive narrowing of the arterial lumen resulting in ischemic changes of the allograft, fibrosis, and dysfunction. Previously we have shown that the homopentameric acute phase reactant C-reactive protein (pCRP) is regulating the innate immune response via a conformational change towards pro-inflammatory pCRP* mediated by activated cell membranes on activated or necrotic cells. pCRP* is mediating a selective activation of the CD14dim/CD16+ monocyte subset that has been identified as a key cell of the MPS in acute allograft rejection. Therefore, we want to test the hypothesis, that conformationally altered CRP (pCRP*) is a key mediator of IRI leading to increased acute allograft rejection via activation of CD14dim/CD16+ monocytes. We will use an animal model of VCA investigate the role of CD14dim/CD16+ in acute allograft rejection. In this model we will track the fate of graft-infiltrating pCRP*-stimulated CD14dim/CD16+ monocytes over time in the allograft. We hypothesize that graft-infiltrating non-classical monocytes will turn into sessile pro-inflammatory primed macrophages that activate the adaptive immune response, fuel intimal proliferation and fibrosis ultimately leading to chronic allograft rejection. This pathway might be linking exacerbated acute postoperative inflammation with an increased rate of chronic transplant failure.

随着血管化复合组织异体移植（VCA）的引入，重建显微外科领域取得了重大进展，其中最常见的是手部和面部移植，这在重建外科中逐渐普及。然而，长期免疫抑制的副作用和移植血管病变导致慢性移植排斥的风险限制了广泛的临床接受。因此，为了进一步发展这一有前景的外科重建领域，我们必须针对临床问题，然后再扩展这些仍处于高度实验性的重建策略。越来越多的证据表明，单核吞噬细胞系统（MPS）的细胞，包括单核细胞和巨噬细胞，作为先天免疫反应的一部分，在移植后以缺血/再灌注损伤（IRI）为特征的初始炎症阶段的免疫反应的启动以及同种异体移植的长期存活中起着至关重要的作用。慢性排斥反应被认为依赖于导致移植血管病变的慢性炎症过程，其中移植物浸润性巨噬细胞起重要作用。血管病变的特征是内膜增生和动脉管腔进行性狭窄，导致同种异体移植物缺血改变、纤维化和功能障碍。先前我们已经证明，同戊二胺急性期反应物c -反应蛋白（pCRP）通过激活细胞膜介导的促炎性pCRP*构象变化调节先天免疫反应。pCRP*介导CD14dim/CD16+单核细胞亚群的选择性激活，该亚群已被确定为急性同种异体移植排斥反应中MPS的关键细胞。因此，我们想要验证这一假设，即构象改变的CRP （pCRP*）是IRI通过激活CD14dim/CD16+单核细胞导致急性同种异体移植排斥反应增加的关键介质。我们将使用VCA动物模型研究CD14dim/CD16+在急性同种异体移植排斥反应中的作用。在这个模型中，我们将追踪同种异体移植物中浸润的pCRP*刺激的CD14dim/CD16+单核细胞的命运。我们假设移植物浸润的非经典单核细胞将转变为可激活适应性免疫反应的无底促炎启动巨噬细胞，促进内膜增殖和纤维化，最终导致慢性同种异体移植物排斥反应。这一途径可能与急性术后炎症加剧与慢性移植失败率增加有关。