Ischaemia reperfusion injury in islet and pancreas transplantation
File(s)
Author(s)
Sandhu, Bynvant
Type
Thesis
Abstract
The global prevalence of diabetes continues to rise, leading to an obvious need for effective treatment strategies. Whole organ pancreas or isolated islet transplantation is currently offered to a small proportion of the diabetic population, based upon selective indications and fitness for the procedure. The use of both treatment modalities is in part limited due to the potential complications associated with transplantation and imperfect long-term outcomes. Ischaemia reperfusion injury affects both islet and pancreas transplantation and impacts upon the effectiveness and longevity of the graft. Activation of the coagulation cascade has been described as a common mediator of ischaemia reperfusion injury, in both islet and pancreas transplantation. Cytotopic anticoagulant peptides have been proposed as a treatment strategy in other solid organ transplants as an alternative to systemic anticoagulation. This approach offers a cell-binding therapy, reducing coagulation-associated injury whilst avoiding bleeding risks associated with systemic anticoagulation. The aims of my project were to examine the efficacy of cytotopic anticoagulation in the context of islet and pancreas transplantation and to design a model for examination of reperfusion injury in the human pancreas.
I have explored the expression of Tissue Factor in donor pancreas grafts and shown an upregulation of TF expression in isolated human islets exposed to hypoxic, ischaemic conditions. Using a specialised coagulation assay I have confirmed the efficacy of the cytotopic anticoagulant in reducing Tissue Factor initiated coagulation. I have shown an improvement in endothelial viability and function using cytotopic anticoagulation in in vitro models of ischaemia reperfusion.
My project also investigated the use of cytotopic anticoagulation in human islet reperfusion models. I demonstrated a reduction in the expression of Tissue Factor and activation of the coagulation cascade in islets treated with the cytotopic anticoagulation, I also explored the impact upon activation of associated mechanisms of injury in islet reperfusion.
Finally, I have successfully developed a new model of ex vivo organ reperfusion for the examination of ischaemia reperfusion injury in the pancreas and other organs in the future.
I have explored the expression of Tissue Factor in donor pancreas grafts and shown an upregulation of TF expression in isolated human islets exposed to hypoxic, ischaemic conditions. Using a specialised coagulation assay I have confirmed the efficacy of the cytotopic anticoagulant in reducing Tissue Factor initiated coagulation. I have shown an improvement in endothelial viability and function using cytotopic anticoagulation in in vitro models of ischaemia reperfusion.
My project also investigated the use of cytotopic anticoagulation in human islet reperfusion models. I demonstrated a reduction in the expression of Tissue Factor and activation of the coagulation cascade in islets treated with the cytotopic anticoagulation, I also explored the impact upon activation of associated mechanisms of injury in islet reperfusion.
Finally, I have successfully developed a new model of ex vivo organ reperfusion for the examination of ischaemia reperfusion injury in the pancreas and other organs in the future.
Version
Open Access
Date Issued
2018-07
Date Awarded
2020-02
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Papalois, Vassilios
Pusey, Charles Dickson
Sponsor
Royal College of Surgeons of England
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)