- Dr Charmaine Simeonovic, Principal Investigator
- Prof. Christopher Parish, Co-Investigator
- Dr Craig Freeman, Collaborator
- Ms Sarah Popp, Research Assistant
- Mrs Debra Brown, Technician
- The Australian National University, Canberra, Australia
- Immune Destruction and Protection of Pancreatic Islet Transplants
Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing β cells of pancreatic islets are destroyed. The imperfect control of hyperglycemia by exogenous insulin therapy inevitably leads to microvascular disease, e.g. kidney disease. The clinical transplantation of pancreatic islets potentially offers an improved treatment for T1D because insulin can be delivered physiologically, as required. Clinical islet transplantation has progressed considerably in recent years with implementation of the Edmonton protocol for preventing immune destruction of the transplants. Despite this progress, the heavy use of immunosuppressive drugs has severely limited its application to only adult patients whose diabetes has been difficult to control. In the long term, however, islet function is eventually lost and insulin therapy is again required. This graft failure is due to toxicity of the immunosuppressive drugs used to prevent immunological rejection of the transplant and recurrence of autoimmune disease. It is therefore essential that better anti-graft rejection/destruction strategies are developed to eliminate the need for toxic drugs and thus preserve the health status of the patients and the integrity of the transplant.
Our study will ascertain whether (i) the enzyme heparanase contributes to the rejection and/ or autoimmune destruction of islet transplants by arming activated leukocytes with a degradative mechanism for facilitating their invasion into transplanted islets and whether (ii) inhibition of heparanase with PI-88 can protect islet grafts from these destructive immunological processes. PI-88 has now entered Phase III clinical trials as an anti-cancer drug; it is safe for patients, well-tolerated and has minimal side-effects. Our objectives are therefore to identify a non-toxic therapy (PI-88) for protecting islet transplants from rejection and/or autoimmune damage. Ultimately our goal is to optimize islet transplantation as a safe treatment for T1D in patients of all ages and to re-establish a normal lifestyle in those transplant recipients.