Zhu Peng, Bailey Stefanie R, Lei Biao, Paulos Chrystal M, Atkinson Carl, Tomlinson Stephen
1 Department of Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China. 2 Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC. 3 Department of Surgery, Division of Transplantation, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, Charleston, SC. 4 South Carolina Investigators in Transplantation (SCIT), Medical University of South Carolina, Charleston, SC. 5 Ralph H. Johnson Veteran Affairs Medical Center, Charleston, SC.
Transplantation. 2017 Apr;101(4):e75-e85. doi: 10.1097/TP.0000000000001625.
Recipients of vascularized composite allografts require aggressive and lifelong immunosuppression, and because the surgery is usually performed in nonlife-threatening situations, the development of strategies to minimize immunosuppression is especially pertinent for this procedure. We investigated how complement affects acute graft injury, alloimmunity, and immunosuppressive therapy.
Vascularized composite allografts were transplanted from Balb/C to C57BL/6 mice that were complement deficient (C3 or double C3a Receptor (R)/C5aR), or treated with a targeted complement inhibitor (CR2-Crry). Allografts were analyzed for acute inflammation and injury, subacute T cell response, and survival in the absence and presence of cyclosporine A (CsA) therapy.
Allografts in C3-deficient or CR2-Crry-treated recipients were protected from skin and muscle ischemia-reperfusion injury (IRI). C3aR/C5aR-deficient recipients were more modestly protected. IgM and C3d colocalized within allografts from wild type and C3aR/C5aR-deficient recipients indicating IgM-mediated complement activation, and C3d deposition was almost absent in allografts from C3-deficient and CR2-Crry-treated recipients. Inflammatory cell infiltration and P-selectin expression was also significantly reduced in C3-deficient and CR2-Crry-treated recipients. Acute treatment with CR2-Crry or with 3 mg/kg per day CsA modestly, but significantly increased median allograft survival from 5.8 to 7.4 and 7.2 days, respectively. However, combined acute CR2-Crry treatment and CsA therapy increased mean graft survival to 17.2 days. Protection was associated with significantly reduced T cell infiltration of allografts and Tc1 cells in recipient spleens.
Complement-mediated IRI augments graft allogenicity, and appropriate complement inhibition ameliorates IRI, decreases alloimmune priming and allows more immune-sparing CsA dosing.
血管化复合组织异体移植受者需要积极且终身的免疫抑制，并且由于该手术通常在非危及生命的情况下进行，因此制定尽量减少免疫抑制的策略对于此手术尤为重要。我们研究了补体如何影响急性移植物损伤、同种免疫和免疫抑制治疗。
将血管化复合组织异体移植从Balb/C小鼠移植到补体缺陷（C3或双C3a受体（R）/C5aR）的C57BL/6小鼠，或用靶向补体抑制剂（CR2-Crry）治疗。在有和没有环孢素A（CsA）治疗的情况下，分析异体移植的急性炎症和损伤、亚急性T细胞反应及存活情况。
C3缺陷或CR2-Crry治疗的受者的异体移植免受皮肤和肌肉缺血再灌注损伤（IRI）。C3aR/C5aR缺陷的受者受到的保护作用较弱。IgM和C3d在野生型和C3aR/C5aR缺陷受者的异体移植中共定位，表明IgM介导的补体激活，而在C3缺陷和CR2-Crry治疗受者的异体移植中几乎不存在C3d沉积。C3缺陷和CR2-Crry治疗的受者的炎症细胞浸润和P-选择素表达也显著降低。用CR2-Crry或每天3mg/kg CsA进行急性治疗适度但显著地将异体移植的中位存活时间分别从5.8天增加到7.4天和7.2天。然而，联合急性CR2-Crry治疗和CsA治疗可将平均移植物存活时间增加到17.2天。保护作用与异体移植中T细胞浸润和受者脾脏中Tc1细胞显著减少有关。
补体介导的IRI增强移植物同种异体性，适当的补体抑制可改善IRI，减少同种免疫启动，并允许更节省免疫抑制剂的CsA给药剂量。
