Karegli J, Melchionna T, Farrar C A, Greenlaw R, Smolarek D, Horsfield C, Charif R, McVey J H, Dorling A, Sacks S H, Smith R A G
MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
West London Renal and Transplantation Centre, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK.
Am J Transplant. 2017 Jan;17(1):272-280. doi: 10.1111/ajt.13951. Epub 2016 Aug 8.
Allograft transplantation into sensitized recipients with antidonor antibodies results in accelerated antibody-mediated rejection (AMR), complement activation, and graft thrombosis. We have developed a membrane-localizing technology of wide applicability that enables therapeutic agents, including anticoagulants, to bind to cell surfaces and protect the donor endothelium. We describe here how this technology has been applied to thrombin inhibitors to generate a novel class of drugs termed thrombalexins (TLNs). Using a rat model of hyperacute rejection, we investigated the potential of one such inhibitor (thrombalexin-1 [TLN-1]) to prevent acute antibody-mediated thrombosis in the donor organ. TLN-1 alone was able to reduce intragraft thrombosis and significantly delay rejection. The results confirm a pivotal role for thrombin in AMR in vivo. This approach targets donor organs rather than the recipient and is intended to be directly translatable to clinical use.
将同种异体移植物移植到带有抗供体抗体的致敏受体中会导致加速的抗体介导排斥反应（AMR）、补体激活和移植物血栓形成。我们开发了一种具有广泛适用性的膜定位技术，该技术能使包括抗凝剂在内的治疗剂与细胞表面结合，从而保护供体内皮。我们在此描述了该技术如何应用于凝血酶抑制剂，以生成一类新型药物，称为血栓抑制素（TLNs）。使用超急性排斥反应的大鼠模型，我们研究了一种此类抑制剂（血栓抑制素-1 [TLN-1]）预防供体器官急性抗体介导血栓形成的潜力。单独使用TLN-1能够减少移植物内血栓形成并显著延迟排斥反应。结果证实了凝血酶在体内AMR中的关键作用。这种方法针对的是供体器官而非受体，并且旨在直接转化为临床应用。
