J. Mahiou et al., In vivo blockade of the Fas-Fas ligand pathway inhibits cyclophosphamide-induced diabetes in NOD mice, J AUTOIMMUN, 16(4), 2001, pp. 431-440
There is compelling evidence to show that insulin dependent diabetes ensues
from selective apoptosis of pancreatic beta -cells mediated by autoreactiv
e T-lymphocytes. The respective implication in this phenomenon of the vario
us apoptotic pathways driven by Fas, perforin, or tumor necrosis factor is
still ill-defined. Here we took advantage of the cyclophosphamide-induced m
odel of accelerated diabetes in NOD mice to explore the physiopathological
role of the Fas-Fas Ligand pathway. A single injection of cyclophosphamide
(200 mg/kg) to 7-8 week-old prediabetic NOD mice triggered diabetes within
10-15 days in 85-100% of the animals. Cyclophosphamide also induced a signi
ficant decrease in spleen T cells, that was most evident by days 6-10 after
treatment, and selectively affected the CD3(+)CD62L(+) compartment that in
cludes immunoregulatory T cells. To block the in vivo Fas-Fas Ligand (Fas L
) interaction we administered a biologically active recombinant fusion prot
ein coupling mouse Fas to the Fc portion of human IgG1 (FAS-Fc). Mice treat
ed with FAS-Fc (10 doses iv of 15 mug) starting on the day of cyclophospham
ide injection up to day 22, were fully protected from disease. Unexpectedly
this protective effect was not due to blockade of Fas-FasL-mediated beta -
cell apoptosis but rather to the inhibition of the cyclophosphamide effect
on T cells. Indeed FAS-Fc treatment prevented the drug-induced T cell deple
tion in general and that of immunoregulatory T cells in particular. Additio
nally, FAS-Fc administration limited to the phase of beta -cell destruction
did not afford any protection. (C) 2001 Academic Press.