title: Nonviral-mediated hepatic expression of IGF-I increases Treg levels and suppresses autoimmune diabetes in mice.
abstract: In type 1 diabetes, loss of tolerance to β-cell antigens results in T-cell-dependent autoimmune destruction of β cells. The abrogation of autoreactive T-cell responses is a prerequisite to achieve long-lasting correction of the disease. The liver has unique immunomodulatory properties and hepatic gene transfer results in tolerance induction and suppression of autoimmune diseases, in part by regulatory T-cell (Treg) activation. Hence, the liver could be manipulated to treat or prevent diabetes onset through expression of key genes. IGF-I may be an immunomodulatory candidate because it prevents autoimmune diabetes when expressed in β cells or subcutaneously injected. Here, we demonstrate that transient, plasmid-derived IGF-I expression in mouse liver suppressed autoimmune diabetes progression. Suppression was associated with decreased islet inflammation and β-cell apoptosis, increased β-cell replication, and normalized β-cell mass. Permanent protection depended on exogenous IGF-I expression in liver nonparenchymal cells and was associated with increased percentage of intrapancreatic Tregs. Importantly, Treg depletion completely abolished IGF-I-mediated protection confirming the therapeutic potential of these cells in autoimmune diabetes. This study demonstrates that a nonviral gene therapy combining the immunological properties of the liver and IGF-I could be beneficial in the treatment of the disease.
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Xavier M
authors.initials: XM
authors.lastname: Anguela
authors.forename: Sabrina
authors.initials: S
authors.lastname: Tafuro
authors.forename: Carles
authors.initials: C
authors.lastname: Roca
authors.forename: David
authors.initials: D
authors.lastname: Callejas
authors.forename: Judith
authors.initials: J
authors.lastname: Agudo
authors.forename: Mercè
authors.initials: M
authors.lastname: Obach
authors.forename: Albert
authors.initials: A
authors.lastname: Ribera
authors.forename: Albert
authors.initials: A
authors.lastname: Ruzo
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Mann
authors.forename: Alba
authors.initials: A
authors.lastname: Casellas
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D015316:Genetic Therapy; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010195:Pancreatitis / Q000235:genetics / Q000276:immunology; D010957:Plasmids / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D007334:Insulin-Like Growth Factor I