Thrombalexins: Cell-localized inhibition of thrombin and its effects in a model of high-risk renal transplantation

J Karegli; T Melchionna; C A Farrar; R Greenlaw; D Smolarek; C Horsfield; R Charif; J H McVey; A Dorling; S H Sacks; R A G Smith

doi:10.1111/ajt.13951

Thrombalexins: Cell-localized inhibition of thrombin and its effects in a model of high-risk renal transplantation

J Karegli, T Melchionna, C A Farrar, R Greenlaw, D Smolarek, C Horsfield, R Charif, J H McVey, A Dorling, S H Sacks, R A G Smith

King's College London

Research output: Other contribution

11 Citations (Scopus)

Abstract

Allograft transplantation into sensitised recipients with anti-donor 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 (TLN). Using a rat model of hyperacute rejection we have investigated the potential of one such inhibitor (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. This article is protected by copyright. All rights reserved.

Original language	English
Type	Brief Communication
DOIs	https://doi.org/10.1111/ajt.13951
Publication status	Published - 1 Jan 2017

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abstract = "Allograft transplantation into sensitised recipients with anti-donor 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 (TLN). Using a rat model of hyperacute rejection we have investigated the potential of one such inhibitor (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. This article is protected by copyright. All rights reserved.",

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AU - Karegli, J

AU - Melchionna, T

AU - Farrar, C A

AU - Greenlaw, R

AU - Smolarek, D

AU - Horsfield, C

AU - Charif, R

AU - McVey, J H

AU - Dorling, A

AU - Sacks, S H

AU - Smith, R A G

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N2 - Allograft transplantation into sensitised recipients with anti-donor 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 (TLN). Using a rat model of hyperacute rejection we have investigated the potential of one such inhibitor (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. This article is protected by copyright. All rights reserved.

AB - Allograft transplantation into sensitised recipients with anti-donor 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 (TLN). Using a rat model of hyperacute rejection we have investigated the potential of one such inhibitor (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. This article is protected by copyright. All rights reserved.

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Thrombalexins: Cell-localized inhibition of thrombin and its effects in a model of high-risk renal transplantation

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