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Title: The potential for localised inhibition of complement and coagulation cascades in high risk renal transplantation
Author: Karegli, Julieta
ISNI:       0000 0004 5368 4653
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2015
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Transplantation is the preferred treatment for patients with end-stage kidney disease. However, antibodies against blood group and histocompatibility antigens on transplanted organs pose a high risk of accelerated humoral rejection. Allograft transplantation into sensitised recipients initiates complement activation and early thrombotic processes. The aim of the research described here was to determine whether cell protective therapy targeting the complement and coagulation cascades is effective at preventing graft rejection in highly sensitised renal allograft recipients. In this thesis, using novel membrane targeting (cytotopic) technology, a therapeutic complement regulator Mirococept (APT070) and coagulation inhibitors (PTL006, Thrombalexin/PTL004) were delivered to the endothelial surface within organs. In these studies, a rat model of hyperimmune rejection of renal allografts from fully MHC disparate donors and recipients was established. In vivo studies revealed the potential of the therapeutic reagents by assessment of graft survival, renal function and pathology. Mirococept only provided modest protection of the endothelium and in renal function, without any prolongation of survival compared to recipients of control-treated grafts. In contrast, treatment of kidneys with either anticoagulant agent (PTL006 or Thrombalexin/PTL004) alone resulted in significant prolongation of graft survival correlating with delayed loss of renal function compared to controls. To explore whether these findings were suitable for translation to clinical application, the investigations were extended to include standard immunosuppressive agents. However, Cyclosporine A treatment was associated with toxic effects in the rats, whereas therapy including Rapamycin failed to prevent lymphocyte migration into the grafts. This study provides evidence that ex vivo graft perfusion of locally acting biological response modifiers can have therapeutic effects in the transplant setting. The approach targets donor organs rather than the recipient. Additional and effective inhibition of cellular immune responses may demonstrate the full potential of this approach to attain graft acceptance against the most severe of immune barriers. These findings make this study clinically relevant.
Supervisor: Smith, Richard ; Sacks, Steven Howard Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available