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

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Title: Interleukin-21 Is Required for the Development of Type 1 Diabetes in NOD Mice
Author: Van Belle, Tom; Wurster, Andrea L.; Suto, Akira; von Herrath, Matthias; Sutherland, Andrew P; Michaud, Monia; Zhang, Dorothy; Grusby, Michael J.

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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.
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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.
Published Version: doi:10.2337/db08-0882
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671036/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:4522609
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