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Diabetes. 2010 Jun;59(6):1461-8. doi: 10.2337/db09-1129. Epub 2010 Mar 18.

Prevention of diabetes by FTY720-mediated stabilization of peri-islet tertiary lymphoid organs.

Author information

1
Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

Abstract

OBJECTIVE:

The nonobese diabetic (NOD) mouse is a well-established mouse model of spontaneous type 1 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.

PMID:
20299465
PMCID:
PMC2874707
DOI:
10.2337/db09-1129
[Indexed for MEDLINE]
Free PMC Article

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