Localised inhibition of coagulation limits acute complement mediated damage in high risk renal transplantation

TY - JOUR

T1 - Localised inhibition of coagulation limits acute complement mediated damage in high risk renal transplantation

AU - Karegli, Julieta

AU - Farrar, Conrad

AU - Melchionna, Teresa

AU - Horsfield, Catherine

AU - Dorling, Anthony

AU - Smith, Richard

AU - Sacks, Steven

PY - 2012/11

Y1 - 2012/11

N2 - Pre-existing antibodies against histocompatibility antigens on transplanted organs pose a high risk of accelerated humoral rejection. We have used membrane targeting technology to deliver therapeutic complement (Mirococept) and coagulation inhibitors (Thrombalexin/PTL004) to endothelium within organs. Thrombalexin alone significantly prolonged survival of the treated kidney. To explore whether our findings are suitable for clinical application, we extended them to include standard immunosuppression. We have developed a model of hyperimmune rejection using renal allografts from fully MHC disparate rats. Prior to transplantation, Lewis recipients were presensitised by sequential grafting of three DA donor tail skin segments. Investigative agents were administered before Tx by ex vivo perfusion of the donor kidney. Treatment of the graft recipient with Cyclosporine A commenced 2 days prior to Tx, alternatively Rapamycin administration was given on the day of the Tx. Both treatments were continued daily. Thrombalexin alone (n = 6) resulted in prolongation of graft survival to a mean survival time of 5 days post Tx (p < 0.01). C5b-9 deposition within 24–48 h post Tx in surviving animals was reduced, suggesting that inhibition of thrombin influenced the degree of complement activation. Cyclosporine A treatment did not result in significant prolongation of graft survival (n = 8, p = 0.4298) due to toxicity. However, therapy including Rapamycin (n = 6) was not toxic and prolonged survival significantly compared to untreated (p < 0.01) controls.

AB - Pre-existing antibodies against histocompatibility antigens on transplanted organs pose a high risk of accelerated humoral rejection. We have used membrane targeting technology to deliver therapeutic complement (Mirococept) and coagulation inhibitors (Thrombalexin/PTL004) to endothelium within organs. Thrombalexin alone significantly prolonged survival of the treated kidney. To explore whether our findings are suitable for clinical application, we extended them to include standard immunosuppression. We have developed a model of hyperimmune rejection using renal allografts from fully MHC disparate rats. Prior to transplantation, Lewis recipients were presensitised by sequential grafting of three DA donor tail skin segments. Investigative agents were administered before Tx by ex vivo perfusion of the donor kidney. Treatment of the graft recipient with Cyclosporine A commenced 2 days prior to Tx, alternatively Rapamycin administration was given on the day of the Tx. Both treatments were continued daily. Thrombalexin alone (n = 6) resulted in prolongation of graft survival to a mean survival time of 5 days post Tx (p < 0.01). C5b-9 deposition within 24–48 h post Tx in surviving animals was reduced, suggesting that inhibition of thrombin influenced the degree of complement activation. Cyclosporine A treatment did not result in significant prolongation of graft survival (n = 8, p = 0.4298) due to toxicity. However, therapy including Rapamycin (n = 6) was not toxic and prolonged survival significantly compared to untreated (p < 0.01) controls.

U2 - 10.1016/j.imbio.2012.08.155

DO - 10.1016/j.imbio.2012.08.155

M3 - Meeting abstract

SN - 0171-2985

VL - 217

SP - 1183

EP - 1183

JO - Immunobiology

JF - Immunobiology

IS - 11

ER -