Optimising islet transplantation : experimental and clinical observations
Clinical islet transplantation is an accepted treatment for the severe secondary complications of type 1 diabetes but is limited by the number of donors needed to achieve insulin independence. The requirement for multiple donors is probably due to the loss of up to 60% of islet mass after transplantation from hypoxia, caused by a lack of functional vasculature. Revascularisation of the transplanted islet does occur but takes up to 14 days. The aim of this project was to investigate the revascularisation process and devise a method of manipulating islets in order to improve islet engraftment. The scientific research was supplemented by the establishment of clinical transplantation. A sygeneic intraportal model of islet transplantation was used to explore the revascularisation of islets and develop a novel dual endothelial/insulin staining technique. The experiments show clear observation of revascularisation with quantifiable changes in vascular density and islet composition. Interestingly, the vascular density of transplanted islets was greater than native islets. Pre treatment of isolated islets with was desferrioxamine explored as a method for up regulating angiogenic growth factors. This method produced a sustained increase in VEGF expression that did not adversely affect islet viability or secretory function but did not improve clinical outcome post transplant. Three diabetic patients were transplanted with human islets and the outcome, clinical course and issues related to organ donation and processing are and also discussed. Islet revascularisation is quantifiable and can be explored to examine the effect of manipulating engraftment. Iron depletion offers a simple method for manipulating islets prior to transplantation but further work is necessary to establish if there is any improvement in islet engraftment with this technique. Clinical islet transplantation programmes within the UK are achievable but further progress, collaboration and funding are required to establish islet transplantation as a routine treatment.