Nonviral-mediated hepatic expression of IGF-I increases treg levels and suppresses autoimmune diabetes in mice

Xavier M. Anguela, Sabrina Tafuro, Carles Roca, David Callejas, Judith Agudo, Mercè Obach, Albert Ribera, Albert Ruzo, Christopher J. Mann, Alba Casellas, Fatima Bosch

Research output: Contribution to journalArticleResearchpeer-review

23 Citations (Scopus)


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. © 2013 by the American Diabetes Association.
Original languageEnglish
Pages (from-to)551-560
Issue number2
Publication statusPublished - 1 Feb 2013


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