Gene Transfer of Manganese Superoxide Dismutase Extends Islet Graft Function in a Mouse Model of Autoimmune Diabetes

  1. Suzanne Bertera1,
  2. Megan L. Crawford1,
  3. Angela M. Alexander1,
  4. Glenn D. Papworth2,
  5. Simon C. Watkins2,
  6. Paul D. Robbins3 and
  7. Massimo Trucco1
  1. 1Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Rangos Research Center, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
  2. 2Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania
  3. 3Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

    Abstract

    Islet transplantation is a promising cure for diabetes. However, inflammation, allorejection, and recurrent autoimmune damage all may contribute to early graft loss. Pancreatic islets express lower levels of antioxidant genes than most other tissues of the body, and β-cells in particular are sensitive to oxidative damage. Therefore, damage from oxidative stress may pose a major obstacle to islet replacement therapy in that both the islet isolation and transplantation processes generate oxygen radicals. To determine whether antioxidant gene overexpression in isolated pancreatic islets can prevent oxidative damage and prolong islet function after transplantation, we used the NOD mouse model to study oxidative stress encountered during both transplantation and autoimmune attack. We transferred an antioxidant gene, manganese superoxide dismutase (MnSOD), by adenoviral infection into isolated islets that were transplanted into streptozotocin-treated NODscid recipient mice. Functioning islet grafts were subsequently exposed to diabetogenic spleen cells and monitored until graft failure. The results show that islet grafts overexpressing MnSOD functioned ∼50% longer than control grafts. This significant prolongation of graft function suggests that the antioxidant activity of MnSOD is beneficial to transplanted islet survival and may be used in combination with other strategies aimed at islet graft protection.

    Footnotes

    • Address correspondence and reprint requests to Suzanne Bertera, PhD, Children’s Hospital of Pittsburgh, Rangos Research Center, 3460 Fifth Ave., Pittsburgh, PA 15213. E-mail: subst5{at}pitt.edu.

      Received for publication 15 February 2002 and accepted in revised form 29 October 2002.

      FACS, fluorescence-activated cell sorter; IFN-γ, γ-interferon; IL, interleukin; KRB, Krebs-Ringer’s Buffer; MnSOD, manganese superoxide dismutase; NO, nitric oxide; PI, propidium iodide; SNAP, S-nitroso-N-acetylpenicillamine; STZ, streptozotocin; TNF-α, tumor necrosis factor-α

    | Table of Contents