title: Adeno-associated virus-mediated IL-10 gene therapy inhibits diabetes recurrence in syngeneic islet cell transplantation of NOD mice.
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 x 10(9) 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 10(8) 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.
authors.affiliation: Department of Pathology, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610-0275, USA.
authors.forename: Y Clare
authors.initials: YC
authors.lastname: Zhang
authors.forename: Antonello
authors.initials: A
authors.lastname: Pileggi
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.forename: R Damaris
authors.initials: RD
authors.lastname: Molano
authors.forename: Matthew
authors.initials: M
authors.lastname: Powers
authors.forename: Todd
authors.initials: T
authors.lastname: Brusko
authors.forename: Clive
authors.initials: C
authors.lastname: Wasserfall
authors.forename: Kevin
authors.initials: K
authors.lastname: Goudy
authors.forename: Elsie
authors.initials: E
authors.lastname: Zahr
authors.forename: Raffaella
authors.initials: R
authors.lastname: Poggioli
authors.forename: Marda
authors.initials: M
authors.lastname: Scott-Jorgensen
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.forename: James M
authors.initials: JM
authors.lastname: Crawford
authors.forename: Harry
authors.initials: H
authors.lastname: Nick
authors.forename: Terence
authors.initials: T
authors.lastname: Flotte
authors.forename: Tamir M
authors.initials: TM
authors.lastname: Ellis
authors.forename: Camillo
authors.initials: C
authors.lastname: Ricordi
authors.forename: Luca
authors.initials: L
authors.lastname: Inverardi
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
mesh_terms: D000818:Animals; D015551:Autoimmunity; D000229:Dependovirus / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy*; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006085:Graft Survival; D049452:Green Fluorescent Proteins; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D051547:Heme Oxygenase-1; D007249:Inflammation / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics*; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D008164:Luminescent Proteins / Q000235:genetics; D008214:Lymphocytes / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D016688:Mice, Inbred NOD; D018482:Muscle, Skeletal / Q000378:metabolism; D055502:Secondary Prevention; D013482:Superoxide Dismutase / Q000096:biosynthesis
chemical_list: D008164:Luminescent Proteins; D008565:Membrane Proteins; D016753:Interleukin-10; D049452:Green Fluorescent Proteins; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D013482:Superoxide Dismutase