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Effective Destruction of Fas-deficient Insulin-producing ß Cells in Type 1 Diabetes

Irina Apostolou¹, Zhenyue Hao², Klaus Rajewsky³ and Harald von Boehmer¹

¹ Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02115
² Advanced Medical Discovery Institute, Toronto, Ontario M5G 2C1, Canada
³ Harvard Medical School, Center for Blood Research, Boston, MA 02115

Address correspondence to Harald von Boehmer, Harvard Medical School, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115, Phone: (617) 632-6882; Fax: (617) 632-6881; e-mail: Harald_von_Boehmer{at}dfci.harvard.edu

In type 1 diabetes, autoimmune T cells cause destruction of pancreatic ß cells by largely unknown mechanism. Previous analyses have shown that ß cell destruction is delayed but can occur in perforin-deficient nonobese diabetic (NOD) mice and that Fas-deficient NOD mice do not develop diabetes. However, because of possible pleiotropic functions of Fas, it was not clear whether the Fas receptor was an essential mediator of ß cell death in type 1 diabetes. To directly test this hypothesis, we have generated a ß cell–specific knockout of the Fas gene in a transgenic model of type 1 autoimmune diabetes in which CD4⁺ T cells with a transgenic TCR specific for influenza hemagglutinin (HA) are causing diabetes in mice that express HA under control of the rat insulin promoter. Here we show that the Fas-deficient mice develop autoimmune diabetes with slightly accelerated kinetics indicating that Fas-dependent apoptosis of ß cells is a dispensable mode of cell death in this disease.

Key Words: Fas receptor • diabetes • ß cell death • autoimmunity • conditional knockout

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