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- Title
Nonviral-Mediated Hepatic Expression of IGF-I Increases Treg Levels and Suppresses Autoimmune Diabetes in Mice.
- Authors
Anguela, Xavier M.; Tafuro, Sabrina; Roca, Carles; Callejas, David; Agudo, Judith; Obach, Mercè; Ribera, Albert; Ruzo, Albert; Mann, Christopher J.; Casellas, Alba; Bosch, Fatima
- 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 non-viral gene therapy combining the immunological properties of the liver and IGF-I could be beneficial in the treatment of the disease.
- Subjects
TREATMENT of diabetes; GENE therapy; GENETIC transformation; T cells; APOPTOSIS; CELL death
- Publication
Diabetes, 2013, Vol 62, Issue 2, p551
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db11-1776