期刊
DIABETES
卷 59, 期 6, 页码 1461-1468出版社
AMER DIABETES ASSOC
DOI: 10.2337/db09-1129
关键词
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资金
- National Institutes of Health [R37 AI-46643, P30 DK-63720]
- Juvenile Diabetes Research Foundation
- National Institute of General Medical Sciences (NIGMS) [1 R25 GM56847]
OBJECTIVE-The nonobese diabetic (NOD) mouse is a well-established mouse model of spontaneous type I diabetes, which is characterized by an autoimmune destruction of the insulin-secreting pancreatic beta-cells. In this study, we address the role of tertiary lymphoid organs (TLOs) that form in the pancreas of NOD mice during disease progression. METHODS-We developed a model designed to lock lymphocytes in the pancreatic lymph node (PLN) and pancreas by the use of FTY720, which blocks the exit of lymphocytes from lymph nodes. A combination of flow cytometry, immunofluorescence, and analysis of clinical scores was used to study the effects of long-term FTY720 treatment on TLO development and development of diabetes. RESULTS-Continuous treatment of NOD mice with FTY720 prevented diabetes development even at a time of significant insulitis. Treatment withdrawal led to accelerated disease independent of the PLN. Interestingly, naive T-cells trafficked to and proliferated in the TLOs. In addition, morphological changes were observed that occurred during the development of the disease. Remarkably, although the infiltrates are not organized into T/B-cell compartments in 8-week-old mice, by 20 weeks of age, and in age-matched mice undergoing FTY720 treatment, the infiltrates showed a high degree of organization. However, in naturally and FTY720-induced diabetic mice, T/B-cell compartmentalization was lost. CONCLUSION-Our data show that TLOs are established during diabetes development and suggest that islet destruction is due to a loss of TLO integrity, which may be prevented by FTY720 treatment. Diabetes 59:1461-1468, 2010
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