LONG-TERM REVERSAL OF DIABETES BY THE INJECTION OF IMMUNOPROTECTED ISLETS

The intraperitoneal injection of insulin-producing islets immunoprotec ted by an alginate-poly(amino acid) membrane is a potential method of reversing diabetes without the need for lifelong immunosuppression. Pr evious attempts to demonstrate this technology in large animals have f ailed, preventing application in humans. We have determined that key f actors responsible for these past failures include cytokine (interleuk ins 1 and 6 and tumor necrosis factor) stimulation by mannuronic acid monomers from alginate capsules with weak mechanical integrity, which results in fibroblast proliferation. With this insight, we formulated mechanically stable microcapsules by using alginate high in guluronic acid content and report prolonged reversal of diabetes in the spontane ous diabetic dog model by the intraperitoneal injection of encapsulate d canine islet allografts. Euglycemia, independent of any exogenous in sulin requirement, was noted for up to 172 days. Graft survival, evide nced by positive C-peptide release, was noted for as long as 726 days in a recipient receiving a single injection of immunoprotected islets. Histological evidence of viable islets retrieved from the peritoneal cavity 6 months posttransplant confirmed the biocompatibility and immu noprotective nature of this capsule formulation. The finding that intr aperitoneal injection of alginate-immunoprotected islets, a minimally invasive surgical procedure, is effective in prolonged (>1 year) maint enance of glycemic control, without the need for lifelong immunosuppre ssion, may have significant implications for the future therapy of typ e I diabetes in humans.