A mimic of viral double-stranded RNA triggers fulminant type 1 diabetes-like syndrome in regulatory T cell-deficient autoimmune diabetic mouse |
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Authors: | Tada Ai Shimada Akira Yamada Taketo Oikawa Yoichi Yamada Yoshifumi Okubo Yoshiaki Irie Junichiro Bluestone Jeffrey A Itoh Hiroshi |
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Institution: | Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan. |
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Abstract: | Human fulminant type 1 diabetes (FT1D) is an extremely aggressive disease. The delay of proper diagnosis results in high mortality. However, the pathophysiology of this disease remains unclear. We took advantage of CD28-deficient NOD (CD28(-/-) NOD) mice, which have limited numbers of regulatory T cells and develop aggressive autoimmune diabetes, to create a FT1D model that mimicked the disease in humans. Young CD28(-/-) NOD mice were injected with polyinosinic-polycytidylic acid to activate innate immunity in an effort to induce diabetes onset. In this model, innate immune cell activation precedes the onset of diabetes similar to ~70% of FT1D patients. Eighty-three percent of CD28(-/-) NOD mice developed diabetes within 1-6 d after injection of polyinosinic-polycytidylic acid. Moreover, T cells infiltrated the pancreatic exocrine tissue and destroyed α cells, an observation characteristic of human FT1D. We conclude that an FT1D-like phenotype can be induced in the background of autoimmune diabetes by a mimic of viral dsRNA, and this model is useful for understanding human FT1D. |
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