Double deficiency in IL-17 and IFN-γ signalling significantly suppresses the development of diabetes in the NOD mouse

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• 作者：G. Kuriya (1)
  T. Uchida (2)
  S. Akazawa (1)
  M. Kobayashi (1)
  K. Nakamura (1)
  T. Satoh (1)
  I. Horie (1)
  E. Kawasaki (3)
  H. Yamasaki (4)
  L. Yu (5)
  Y. Iwakura (6)
  H. Sasaki (2)
  Y. Nagayama (7)
  A. Kawakami (1)
  N. Abiru (1)
  
• 关键词：IFN ; γ ; IL ; 17 ; Lymphopenia ; NOD mice ; Th17 ; Type 1 diabetes
• 刊名：Diabetologia
• 出版年：2013
• 出版时间：August 2013
• 年：2013
• 卷：56
• 期：8
• 页码：1773-1780
• 全文大小：376KB
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• 作者单位：G. Kuriya (1)
  T. Uchida (2)
  S. Akazawa (1)
  M. Kobayashi (1)
  K. Nakamura (1)
  T. Satoh (1)
  I. Horie (1)
  E. Kawasaki (3)
  H. Yamasaki (4)
  L. Yu (5)
  Y. Iwakura (6)
  H. Sasaki (2)
  Y. Nagayama (7)
  A. Kawakami (1)
  N. Abiru (1)
  
  1. Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
  2. Department of Hospital Pharmacy, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
  3. Department of Metabolism/Diabetes and Clinical Nutrition, Nagasaki University Hospital, Nagasaki, Japan
  4. Center for Health and Community Medicine, Nagasaki University, Nagasaki, Japan
  5. Barbara Davis Center for Diabetes, UCHSC, Aurora, CO, USA
  6. Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
  7. Department of Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  

文摘

Aims/hypothesis T helper type (Th) 17 cells have been shown to play important roles in mouse models of several autoimmune diseases that have been classified as Th1 diseases. In the NOD mouse, the relevance of Th1 and Th17 is controversial, because single-cytokine-deficient NOD mice develop diabetes similarly to wild-type NOD mice. Methods We studied the impact of IL-17/IFN-γ receptor double deficiency in NOD mice on the development of insulitis/diabetes compared with IL-17 single-deficient mice and wild-type mice by monitoring diabetes-related phenotypes. The lymphocyte phenotypes were determined by flow cytometric analysis. Results IL-17 single-deficient NOD mice showed delayed onset of diabetes and reduced severity of insulitis, but the cumulative incidence of longstanding diabetes in the IL-17-deficient mice was similar to that in wild-type mice. The IL-17/IFN-γ receptor double-deficient NOD mice showed an apparent decline in longstanding diabetes onset, but not in insulitis compared with that in the IL-17 single-deficient mice. We also found that double-deficient NOD mice had a severe lymphopenic phenotype and preferential increase in regulatory T cells among CD4+ T cells compared with the IL-17 single-deficient mice and wild-type NOD mice. An adoptive transfer study with CD4+CD25?/sup> T cells from young non-diabetic IL-17 single-deficient NOD mice, but not those from older mice, showed significantly delayed disease onset in immune-deficient hosts compared with the corresponding wild-type mice. Conclusions/interpretation These results indicate that IL-17/Th17 participates in the development of insulitis and that both IL-17 and IFN-γ signalling may synergistically contribute to the development of diabetes in NOD mice.