Modelling acute antibody-mediated rejection of human kidney transplants using ex-vivo warm machine perfusion.
Modelling acute antibody-mediated rejection of human kidney transplants using ex-vivo warm machine perfusion.
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DOI：
10.1016/j.ebiom.2022.104365
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发表时间：
2022-12
期刊：
影响因子：
11.1
通讯作者：
Mamode, Nizam
中科院分区：
文献类型：
--
作者：
Chandak, Pankaj;Phillips, Benedict L.;Bennett, Danothy;Uwechue, Raphael;Kessaris, Nicos;Shaw, Olivia;Maggs, Tim;Woodford, Luke;Veniard, David;Perera, Ranmith;Parmar, Kiran;Hunt, Beverley J.;Callaghan, Chris;Dorling, Anthony;Mamode, Nizam
关键词：
移植排斥反应是移植物丢失和发病的主要原因。目前，没有抗体介导的排斥反应（AMR）的人类模型存在，限制了机制研究和器官特异性靶向治疗。在这里，使用12个人肾和离体常温机器灌注，我们证明了AMR的表型后，添加抗体对人类HLA I类或血型抗原（A，B），从而模拟临床AMR，可以遵循HLA不相容（HLAi）或血型不相容（ABOi）移植。用红细胞和新鲜冷冻血浆（FFP）灌注具有广泛人口统计学和冷缺血时间（11-54 h）的废弃人肾，作为补体/凝血因子的来源。对于HLAi模型，将600 μg的W 6/32抗1类HLA抗体添加到回路中（时间“0”）。对于ABOi模型，添加相关血型抗体的高滴度FFP。测定肾血流指数（RBFi，mL/min/100 g）、C3 desArg、凝血酶原片段1 + 2和组织学。我们的终点包括血液动力学变化、血栓形成和活检证实的补体沉积。与没有抗供体抗体灌注的对照肾相比，两种模型在抗体灌注后均表现出血流动力学崩溃，仅HLAi模型显示肾小球C4d沉积。我们表明，一个临床相关的人类肾脏AMR模型是可行的，并预计这些模型，与完善，可以提供一个基础，以测试不同的策略，以防止AMR。Rosetrees and Stonygate Trust、英国皇家外科学院奖学金、NIHR生物医学研究中心/KCL早期职业资助、英国肾脏研究
Transplant rejection is a major cause of graft loss and morbidity. Currently, no human models of antibody-mediated rejection (AMR) exist, limiting mechanistic investigation and organ-specific targeted therapy. Here, using 12 human kidneys and ex-vivo normothermic machine perfusion, we demonstrate phenotypes of AMR after addition of antibodies against either human HLA class I or blood group antigens (A, B), thus modelling clinical AMR that can follow HLA incompatible (HLAi) or blood group incompatible (ABOi) transplantation. Discarded human kidneys with wide ranging demographics and cold ischaemia times (11–54 h) were perfused with red blood cells and fresh frozen plasma (FFP) as a source of complement/coagulation factors. For the HLAi model, 600 μg of W6/32 anti-class 1 HLA antibody was added to the circuit (time '0'). For the ABOi model, high titre FFP of the relevant blood group antibody was added. Renal blood flow index (RBFi, mL/min/100 g), C3 desArg, prothrombin fragments 1 + 2 and histology were determined. Our endpoints included haemodynamic changes, thrombosis, and biopsy proven complement deposition. Compared to control kidneys perfused without anti-donor antibodies, both models demonstrated haemodynamic collapse after antibody perfusion with only the HLAi model showing glomerular C4d deposition. We show that a clinically relevant human kidney model of AMR is feasible, and anticipate that these models, with refinements, could provide a basis to test different strategies to prevent AMR. The Rosetrees and Stonygate Trust, The Royal College of Surgeons of England Fellowship Grant, NIHR Biomedical Research Centre/KCL Early Career Grant, Kidney Research U.K.
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DOI：
10.1111/ajt.13688
发表时间：
2016-06
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Burghuber CK;Kwun J;Page EJ;Manook M;Gibby AC;Leopardi FV;Song M;Farris AB 3rd;Hong JJ;Villinger F;Adams AB;Iwakoshi NN;Knechtle SJ
通讯作者：
Knechtle SJ
影响因子：
7.4
作者：
Hosgood SA;Barlow AD;Dormer J;Nicholson ML
通讯作者：
Nicholson ML
影响因子：
13.6
作者：
Chua, Jamie S.;Baelde, Hans J.;Cohen, Danielle
通讯作者：
Cohen, Danielle
影响因子：
13.6
作者：
Aubert, Olivier;Loupy, Alexandre;Halloran, Philip F.
通讯作者：
Halloran, Philip F.
循环死亡肾移植后捐赠中捐赠中的随机对照，开放标签试验的随机对照，开放标签试验。
影响因子：
2.9
作者：
Hosgood SA;Saeb-Parsy K;Wilson C;Callaghan C;Collett D;Nicholson ML
通讯作者：
Nicholson ML