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Diabetes 53:2588-2595, 2004
© 2004 by the American Diabetes Association, Inc.

Local Activation of Dendritic Cells Leads to Insulitis and Development of Insulin-Dependent Diabetes in Transgenic Mice Expressing CD154 on the Pancreatic ß-Cells

Claus Haase1, Kresten Skak1,2, Birgitte K. Michelsen1,3, and Helle Markholst1

1 Hagedorn Research Institute, Gentofte, Denmark
2 Pharmacology Research 4, Novo Nordisk, Måløv, Denmark
3 Early Projects, Novo Nordisk, Virum, Denmark

The initial events leading to activation of the immune system in type 1 diabetes are still largely unknown. In vivo, dendritic cells (DCs) are thought to be the only antigen-presenting cells (APCs) capable of activating naïve T-cells and are therefore important for the initiation of the autoimmune response. To test the effect of activating islet-associated APCs in situ, we generated transgenic mice expressing CD154 (CD40 ligand) under control of the rat insulin promoter (RIP). RIP-CD154 mice developed both insulitis and diabetes, although with different incidence in independent lines. We show that activated DCs could be detected both in the pancreas and in the draining pancreatic lymph nodes. Furthermore, diabetes development was dependent on the presence of T- and B-cells since recombination-activating gene (RAG)-deficient RIP-CD154 mice did not develop diabetes. Finally, we show that the activation of immune cells was confined to the pancreas because transplantation of nontransgenic islets to diabetic recipients restored normoglycemia. Together, these data suggest that expression of CD154 on the ß-cells can lead to activation of islet-associated APCs that will travel to the lymph nodes and activate the immune system, leading to insulitis and diabetes.

Address correspondence and reprint requests to Helle Markholst, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark. E-mail: hmar{at}hagedorn.dk


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2004 by the American Diabetes Association.