Adeno-associated virus-mediated IL-10 gene therapy inhibits diabetes recurrence in syngeneic islet cell transplantation of NOD mice

Y. Clare Zhang, Antonello Pileggi, Anupam Agarwal, R. Damaris Molano, Matthew Powers, Todd Brusko, Clive Wasserfall, Kevin Goudy, Elsie Zahr, Raffaella Poggioli, Marda Scott-Jorgensen, Martha Campbell-Thompson, James M. Crawford, Harry Nick, Terence Flotte, Tamir M. Ellis, Camillo Ricordi, Luca Inverardi, Mark A. Atkinson

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)708-716
Number of pages9
JournalDiabetes
Volume52
Issue number3
DOIs
StatePublished - Mar 1 2003

Keywords

  • 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

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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