title: Thrombalexins: Cell-Localized Inhibition of Thrombin and Its Effects in a Model of High-Risk Renal Transplantation.
abstract: 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.
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Karegli
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: T
authors.initials: T
authors.lastname: Melchionna
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: C A
authors.initials: CA
authors.lastname: Farrar
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Greenlaw
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Smolarek
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Horsfield
authors.affiliation: West London Renal and Transplantation Centre, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Charif
authors.affiliation: School of Bioscience & Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
authors.forename: J H
authors.initials: JH
authors.lastname: McVey
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Dorling
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: S H
authors.initials: SH
authors.lastname: Sacks
authors.affiliation: MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
authors.forename: R A G
authors.initials: RA
authors.lastname: Smith
mesh_terms: D000818:Animals; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D006085:Graft Survival; D007676:Kidney Failure, Chronic / Q000601:surgery*; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D011379:Prognosis; D051381:Rats; D011917:Rats, Inbred Lew; D012307:Risk Factors; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*
chemical_list: D010455:Peptides; C000619912:thrombalexin; D013917:Thrombin
keywords: animal models; basic (laboratory) research/science; kidney transplantation/nephrology; thrombosis and thromboembolism; translational research/science