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Diabetes 52:708-716, 2003
© 2003 by the American Diabetes Association, Inc.

Adeno-Associated Virus-Mediated IL-10 Gene Therapy Inhibits Diabetes Recurrence in Syngeneic Islet Cell Transplantation of NOD Mice

Y. Clare Zhang1, Antonello Pileggi2, Anupam Agarwal3, R. Damaris Molano2, Matthew Powers1, Todd Brusko1, Clive Wasserfall1, Kevin Goudy1, Elsie Zahr2, Raffaella Poggioli2, Marda Scott-Jorgensen1, Martha Campbell-Thompson1, James M. Crawford1, Harry Nick4, Terence Flotte5,6,7, Tamir M. Ellis1, Camillo Ricordi2, Luca Inverardi2, and Mark A. Atkinson1

1 Department of Pathology, University of Florida, Gainesville, Florida
2 Diabetes Research Institute, University of Miami, Miami, Florida
3 Department of Medicine, University of Florida, Gainesville, Florida
4 Department of Neuroscience, University of Florida, Gainesville, Florida
5 Genetics Institute, University of Florida, Gainesville, Florida
6 Powell Gene Therapy Center, University of Florida, Gainesville, Florida
7 Department of Pediatrics, University of Florida, Gainesville, Florida

Islet transplantation represents a potential cure for type 1 diabetes, yet persistent autoimmune and allogeneic immunities currently limit its clinical efficacy. For alleviating the autoimmune destruction of transplanted islets, newly diagnosed NOD mice were provided a single intramuscular injection of recombinant adeno-associated viral vector encoding murine IL-10 (rAAV-IL-10) 4 weeks before renal capsule delivery of 650 syngeneic islets. A dose-dependent protection of islet grafts was observed. Sixty percent (3 of 5) of NOD mice that received a transduction of a high-dose (4 x 109 infectious units) rAAV-IL-10 remained normoglycemic for at least 117 days, whereas diabetes recurred within 17 days in mice that received a low-dose rAAV-IL-10 (4 x 108 infectious units; 5 of 5) as well as in all of the control mice (5 of 5 untreated and 4 of 4 rAAV-green fluorescent protein-transduced). Serum IL-10 levels positively correlated with prolonged graft survival and were negatively associated with the intensity of autoimmunity. The mechanism of rAAV-IL-10 protection involved a reduction of lymphocytic infiltration as well as induction of antioxidant enzymes manganese superoxide dismutase and heme oxygenase 1 in islet grafts. These studies support the utility of immunoregulatory cytokine gene therapy delivered by rAAV for preventing autoimmune disease recurrence in transplant-based therapies for type 1 diabetes.


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