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- Title
Interleukin-21 Is Required for the Development of Type 1 Diabetes in NOD Mice.
- Authors
Sutherland, Andrew P. R.; Van Belle, Tom; Wurster, Andrea L.; Suto, Akira; Michaud, Monia; Zhang, Dorothy; Grusby, Michael J.; von Herrath, Matthias
- 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 C57B1/6 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 C57B1/6 and NOD x C57B1/6 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. Diabetes 58:1144-1155, 2009
- Subjects
INTERLEUKINS; DIABETES; LABORATORY mice; CYTOKINES; PANCREATIC beta cells
- Publication
Diabetes, 2009, Vol 58, Issue 5, p1144
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db08-0882