Development of a Prevascularized "Deviceless" Subcutaneous Site for Islet Transplantation and Exploring Redox Modulation as a Means to Prolong Islet Graft Survival
Dr. James Shapiro
Today, islet transplantation is an accepted treatment modality for a sub-population of diabetic patients with life threatening and frequent blood sugar instability, whereby donor insulin producing islets are transplanted into the liver of the diabetic recipient. In 2000, the "Edmonton Protocol" became a milestone in patient care, by reporting sustained C-peptide production and high rates of insulin-independence after transplant in T1DM patients. However, two islet infusions into the liver were typically required for patients to become totally free of insulin injections. Long-term analysis of these initial results indicated that insulin-independence was not durable, as most patients returned to moderate amounts of insulin approximately five years post-transplant (despite the absences of recurrent and potentially deadly hypoglycemia events). A multitude of factors have been identified as causes for islet graft dysfunction. Efforts are now aimed to improve the quality of islets before transplant and their engrafting process, as well as more optimized immunosupppression to ultimately produce robust long-term function. In addition, alternative sites are being explored in effort to avoid the limitations and deleterious factors associated with the islets being bathed in blood within the liver. By harnessing the natural foreign body response, we aim to develop a "deviceless" transplant site that transforms the tissue under the skin into a densely vascularized transplant site, rich in an islet supporting vascular matrix leading to long-term islet graft function. This approach would provide natural collagen scaffold, allowing for the safe transplantation of insulin producing stem cells that could be removed should complications arise. In parallel, we hypothesize that reducing the oxidative stresses that occur during the islet isolation and transplantation processes, we will be able to make inroads in the patient care of type 1 diabetics. If successful, this work will potentially improve the safety and efficiency of clinical islet transplantation, provide a unique opportunity to develop minimal immunosuppressive approaches and importantly, will open up an accelerated avenue for future clinical evaluation of catalytic antioxidants to abrogate disease progression in early onset type 1 diabetics, with the potential of ameliorating and reversing the inflammatory mediate injury to the patients' own endogenous insulin producing beta cells.