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Islet Cell Transplantation

Type I diabetes is a chronic, life-long autoimmune disease affecting over 140 000 Australians, where the insulin-producing islets of Langerhans in the pancreas are destroyed. The incidence of this disease is increasing and, even with daily insulin therapy, diabetic patients are at greater risk of serious complications including heart attack, stroke, ocular damage and kidney disease.

Our area of research focuses on the isolation and transplantation of healthy pancreatic islets as an innovative treatment and potential cure for Type I diabetes. As part of the Australian Islet Transplantation Consortium, the laboratory prepares and performs assays on purified islets that are ultimately transplanted into patients. To date, the Consortium has transplanted 15 patients across Australia. Factors limiting the success of islet transplantation include suboptimal engraftment, immune reaction and rapid cell death post transplant. Our laboratory is interested in identifying and combating the causes of islet cell death. We are also interested in basic islet biology, and how function can be protected/quickly restored following transplantation.

Isolation and transplantation of human islets to treat T1D is a major focus of research. As a member of the Australian Islet Consortium the laboratory regularly receives human islet preparations and performs QC assays to measure islet purity, function, viability and sterility prior to transplantation into T1D recipients. In South Australia we have performed 9 infusions into 4 recipients and currently 2 recipients no longer require exogenous insulin to control their diabetes and the remaining 2 no longer suffer the life threatening and debilitating hypoglycaemia unawareness they experienced prior to transplantation.

There are many factors that limit the long term success of islet transplantation including poor islet engraftment, apoptosis following transplant, immune reactions and hypoxia experienced during islet isolation and post-transplant prior to revascularisation.

Current Research

Gene therapy to prevent apoptosis in transplanted pancreatic islets

Apoptosis is the major cause of islet cell death post-transplantation. Anti-apoptotic factors, such as insulin-like growth factor II (IGF-II), have the potential to protect transplanted islets. This project involves transferring DNA encoding protective genes, such as IGF-II, to islet cells using an adeno-associated virus gene therapy vector. Function and viability of transduced islets will be evaluated using techniques such as ELISA, cytokine challenge and flow cytometry. Transduced islets will be assayed for in vivo function in a diabetic NOD-SCID model.

Role of zinc transporters in pancreatic islets:

Another limitation of islet transplantation is the damage that occurs during isolation due to mechanical and enzymatic stress. This leads to apoptosis and an insufficient number of cells to meet metabolic needs post-transplantation. Zinc plays a vital role in DNA replication, enzyme activity and cellular protection against apoptosis and oxidative stress. Zinc is very high in pancreatic beta cells (the cells that secrete insulin) and is important in synthesis, storage and release of insulin. We have shown that levels of zinc transporter molecules on the surface of islet beta cells vary greatly among diabetic and non-diabetic patients. Our aim is to measure the RNA and protein levels of various zinc transporters in isolated and cultured islets and correlate this with protection of insulin production. The importance of zinc transporters in vivo will be assessed using a diabetic mice model.

Endothelial progenitor cells to promote the success of pancreatic islet transplantation in the rat

The islets of the pancreas are one of the most heavily vascularised tissues in the body, requiring 10% of the pancreatic blood flow despite only making up 1% of the pancreatic mass. As such, islets become rapidly hypoxic (inadequate oxygen supply) following isolation. Endothelial progenitor cells (EPC) are multipotent cells that act as a circulating ‘repair kit’ for vasculature, assisting with the repair of endothelium and the growth of new vessels in hypoxic or damaged tissue. EPC may improve the revascularization and engraftment of isolated islets following transplantation. The aim of this project is to characterize EPC by flow cytometry using antibodies against cell surface markers (including VEGF receptor 2, CXCR4, CD146, VCAM-1, monocyte markers (CD14) and stem cell markers (CD133, CD34)) and a 3D tube-forming assay in Matrigel. The cells will be evaluated for their potential to improve revascularisation when cotransplanted with pancreatic islets in a rodent model of diabetes.