In vivo blockade of the Fas-Fas ligand pathway inhibits cyclophosphamide-induced diabetes in NOD mice

Citation
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
Citations number
63
Categorie Soggetti
Immunology
Journal title
JOURNAL OF AUTOIMMUNITY
ISSN journal
08968411 → ACNP
Volume
16
Issue
4
Year of publication
2001
Pages
431 - 440
Database
ISI
SICI code
0896-8411(200106)16:4<431:IVBOTF>2.0.ZU;2-Y
Abstract
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.