Gene transfer of manganese superoxide dismutase extends islet graft function in a mouse model of autoimmune diabetes.
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 beta-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 approximately 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.
Bertera
Suzanne
S
Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pennsylvania, USA. subst5@pitt.edu
Crawford
Megan L
ML
Alexander
Angela M
AM
Papworth
Glenn D
GD
Watkins
Simon C
SC
Robbins
Paul D
PD
Trucco
Massimo
M
D000256:Adenoviridae; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000601:surgery*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000601:surgery*; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006085:Graft Survival / Q000502:physiology*; D006801:Humans; D016381:Islets of Langerhans Transplantation / Q000473:pathology / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D018384:Oxidative Stress; D013370:Subrenal Capsule Assay; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D013482:Superoxide Dismutase