Adeno-associated virus-mediated IL-10 gene therapy inhibits diabetes recurrence in syngeneic islet cell transplantation of NOD mice.
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.
Zhang
Y Clare
YC
Department of Pathology, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610-0275, USA.
Pileggi
Antonello
A
Agarwal
Anupam
A
Molano
R Damaris
RD
Powers
Matthew
M
Brusko
Todd
T
Wasserfall
Clive
C
Goudy
Kevin
K
Zahr
Elsie
E
Poggioli
Raffaella
R
Scott-Jorgensen
Marda
M
Campbell-Thompson
Martha
M
Crawford
James M
JM
Nick
Harry
H
Flotte
Terence
T
Ellis
Tamir M
TM
Ricordi
Camillo
C
Inverardi
Luca
L
Atkinson
Mark A
MA
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
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