Thrombalexins: Cell-Localized Inhibition of Thrombin and Its Effects in a Model of High-Risk Renal Transplantation

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• 作者：J. Karegli ; T. Melchionna ; C. A. Farrar ; R. Greenlaw ; D. Smolarek ; C. Horsfield ; R. Charif ; J. H. McVey ; A. Dorling ; S. H. Sacks and R. A. G. Smith
• 刊名：American Journal of Transplantation
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：17
• 期：1
• 页码：272-280
• 全文大小：981K
• ISSN：1600-6143

文摘

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.