Transgenic expression of dominant-negative Fas-associated death domain protein in beta cells protects against Fas ligand-induced apoptosis and reduces spontaneous diabetes in nonobese diabetic mice.
In type 1 diabetes, many effector mechanisms damage the beta cell, a key one being perforin/granzyme B production by CD8(+) T cells. The death receptor pathway has also been implicated in beta 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 beta cells. Islets developed normally in these animals, indicating that FADD is not necessary for beta cell development as it is for vasculogenesis. beta 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 beta 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.
Allison
Janette
J
Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia. janettea@unimelb.edu.au
Thomas
Helen E
HE
Catterall
Tara
T
Kay
Thomas W H
TW
Strasser
Andreas
A
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D005260:Female; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; C505533:FADD protein, human; C505661:FASLG protein, human; C505534:Fadd protein, mouse; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; C505658:Fasl protein, mouse; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D007371:Interferon-gamma