Interleukin-21 Is Required for the Development of Type 1 Diabetes in NOD Mice

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Interleukin-21 Is Required for the Development of Type 1 Diabetes in NOD Mice

Show simple item record Van Belle, Tom Wurster, Andrea L. Suto, Akira von Herrath, Matthias Sutherland, Andrew P Michaud, Monia Zhang, Dorothy Grusby, Michael J. 2010-11-04T20:51:18Z 2009
dc.identifier.citation Sutherland, Andrew P.R., Tom Van Belle, Andrea L. Wurster, Akira Suto, Monia Michaud, Dorothy Zhang, Michael J. Grusby, and Matthias von Herrath. 2009. Interleukin-21 Is Required for the Development of Type 1 Diabetes in NOD Mice. Diabetes 58(5): 1144-1155. en_US
dc.identifier.issn 0012-1797 en_US
dc.description.abstract OBJECTIVE: Interleukin (IL)-21 is a type 1 cytokine that has been implicated in the pathogenesis of type 1 diabetes via the unique biology of the nonobese diabetic (NOD) mouse strain. The aim of this study was to investigate a causal role for IL-21 in type 1 diabetes. RESEARCH DESIGN AND METHODS: We generated IL-21R–deficient NOD mice and C57Bl/6 mice expressing IL-21 in pancreatic β-cells, allowing the determination of the role of insufficient and excessive IL-21 signaling in type 1 diabetes. RESULTS: Deficiency in IL-21R expression renders NOD mice resistant to insulitis, production of insulin autoantibodies, and onset of type 1 diabetes. The lymphoid compartment in IL-21R−/− NOD is normal and does not contain an increased regulatory T-cell fraction or diminished effector cytokine responses. However, we observed a clear defect in autoreactive effector T-cells in IL-21R−/− NOD by transfer experiments. Conversely, overexpression of IL-21 in pancreatic β-cells induced inflammatory cytokine and chemokines, including IL-17A, IL17F, IFN-γ, monocyte chemoattractant protein (MCP)-1, MCP-2, and interferon-inducible protein-10 in the pancreas. The ensuing leukocytic infiltration in the islets resulted in destruction of β-cells and spontaneous type 1 diabetes in the normally diabetes-resistant C57Bl/6 and NOD × C57Bl/6 backgrounds. CONCLUSIONS: This work provides demonstration of the essential prodiabetogenic activities of IL-21 on diverse genetic backgrounds (NOD and C57BL/6) and indicates that IL-21 blockade could be a promising strategy for interventions in human type 1 diabetes. en_US
dc.language.iso en_US en_US
dc.publisher American Diabetes Association en_US
dc.relation.isversionof doi:10.2337/db08-0882 en_US
dc.relation.hasversion en_US
dash.license LAA
dc.subject immunology and transplantation en_US
dc.title Interleukin-21 Is Required for the Development of Type 1 Diabetes in NOD Mice en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal Diabetes en_US Grusby, Michael J. 2010-11-04T20:51:18Z
dash.affiliation.other SPH^Immunology and Infectious Diseases Immunology en_US
dash.affiliation.other SPH^Dean's Office Administration en_US

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