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Cells Protects against Fas Ligand-Induced Apoptosis and Reduces Spontaneous Diabetes in Nonobese Diabetic Mice1
* Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia; St. Vincent’s Institute of Medical Research, Fitzroy, Australia; and Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Australia
In type 1 diabetes, many effector mechanisms damage the 
cell, a key one being perforin/granzyme B production by CD8+ T cells. The death receptor pathway has also been implicated in cell death, and we have therefore generated NOD mice that express a dominant-negative form of the Fas-associated death domain protein (FADD) adaptor to block death receptor signaling in cells. Islets developed normally in these animals, indicating that FADD is not necessary for cell development as it is for vasculogenesis. cells from the transgenic mice were resistant to killing via the Fas pathway in vitro. In vivo, a reduced incidence of diabetes was found in mice with higher levels of dominant-negative FADD expression. This molecule also blocked signals from the IL-1R in culture, protecting isolated islets from the toxic effects of cytokines and also marginally reducing the levels of Fas up-regulation. These data support a role for death receptors in cell destruction in NOD mice, but blocking the perforin/granzyme pathway would also be necessary for dominant-negative FADD to have a beneficial clinical effect.
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