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 Flotte567,
- Tamir M. Ellis1,
- Camillo Ricordi2,
- Luca Inverardi2 and
- Mark A. Atkinson1
- 1Department of Pathology, University of Florida, Gainesville, Florida
- 2Diabetes Research Institute, University of Miami, Miami, Florida
- 3Department of Medicine, University of Florida, Gainesville, Florida
- 4Department of Neuroscience, University of Florida, Gainesville, Florida
- 5Genetics Institute, University of Florida, Gainesville, Florida
- 6Powell Gene Therapy Center, University of Florida, Gainesville, Florida
- 7Department of Pediatrics, University of Florida, Gainesville, Florida
Abstract
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 × 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 × 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.
Footnotes
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Address correspondence and reprint requests to Mark A. Atkinson, Department of Pathology, College of Medicine, University of Florida, ARB-R3-128, 1600 SW Archer Rd., Gainesville, FL 32610-0275. E-mail: atkinson{at}ufl.edu.
Received for publication 3 July 2002 and accepted in revised form 25 November 2002.
Y.C.Z. and A.P. contributed equally to this work.
GFP, green fluorescent protein; HO-1, heme oxygenase 1; IFN-γ, γ-interferon; IU, infectious units; LPS, lipopolysaccharide; rAAV, recombinant adeno-associated virus; SOD, superoxide dismutase.
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