Título:
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Nonviral-Mediated Hepatic Expression of IGF-I Increases Treg Levels and Suppresses Autoimmune Diabetes in Mice
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Autor/a:
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Anguela, Xavier M.; Tafuro, Sabrina; Roca, Carles; Callejas, David; Agudo, Judith; Obach, Mercè; Ribera Sánchez, Albert; Ruzo, Albert; Mann, Christopher J.; Casellas, Alba; Bosch i Tubert, Fàtima
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Abstract:
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Altres ajuts: This work was supported by grants from Ministerio de Ciencia e Innovación (SAF2005-01262 and SAF2008-00962) and from the European Community (FP6 CLINIGENE, LSHB-CT-2006-018933). X.M.A., J.A., and A.R. were recipients of a predoctoral fellowship from Ministerio de Educación, Cultura y Deporte, and D.C. received a predoctoral fellowship from Instituto de Salud Carlos III, Spain. C.J.M. |
Abstract:
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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. |
Derechos:
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open access
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https://creativecommons.org/licenses/by-nc-nd/4.0/ |
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Article |
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Uri:
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https://ddd.uab.cat/record/184853
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