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Thrombalexins: Cell-Localized Inhibition of Thrombin and its Effects in a Model of HighRisk Renal Transplantation

Karegli, J, Melchionna, T, Farrar, CA, Greenlaw, R, Smolarek, D, Horsfield, C, Charif, R, McVey, JH, Dorling, A, Sacks, SH and Smith, RAG (2017) Thrombalexins: Cell-Localized Inhibition of Thrombin and its Effects in a Model of HighRisk Renal Transplantation American Journal of Transplantation.

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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.

Item Type: Article
Subjects : Biosciences and Medicine
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
AuthorsEmailORCID
Karegli, JUNSPECIFIEDUNSPECIFIED
Melchionna, TUNSPECIFIEDUNSPECIFIED
Farrar, CAUNSPECIFIEDUNSPECIFIED
Greenlaw, RUNSPECIFIEDUNSPECIFIED
Smolarek, DUNSPECIFIEDUNSPECIFIED
Horsfield, CUNSPECIFIEDUNSPECIFIED
Charif, RUNSPECIFIEDUNSPECIFIED
McVey, JHUNSPECIFIEDUNSPECIFIED
Dorling, AUNSPECIFIEDUNSPECIFIED
Sacks, SHUNSPECIFIEDUNSPECIFIED
Smith, RAGUNSPECIFIEDUNSPECIFIED
Date : 1 January 2017
Identification Number : 10.1111/ajt.13951
Copyright Disclaimer : This is the peer reviewed version of the following article: Karegli, J, Melchionna, T, Farrar, CA, Greenlaw, R, Smolarek, D, Horsfield, C, Charif, R, McVey, JH, Dorling, A, Sacks, SH and Smith, RAG (2017) Thrombalexins: Cell-Localized Inhibition of Thrombin and its Effects in a Model of HighRisk Renal Transplantation, American Journal of Transplantation, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/ajt.13951/full. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Uncontrolled Keywords : accelerated antibody-mediated rejection, coagulation, thrombin, complement, cytotopic, immunosuppression, kidney, membrane-targeting therapy, Thrombalexin, transplant rejection.
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 01 Jul 2016 08:22
Last Modified : 12 Aug 2016 10:04
URI: http://epubs.surrey.ac.uk/id/eprint/811084

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