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Titolo:
In vivo blockade of the Fas-Fas ligand pathway inhibits cyclophosphamide-induced diabetes in NOD mice
Autore:
Mahiou, J; Walter, U; Lepault, F; Godeau, F; Bach, JF; Chatenoud, L;
Indirizzi:
Hop Necker Enfants Malad, INSERM, U25, F-75015 Paris, France Hop Necker Enfants Malad Paris France F-75015 U25, F-75015 Paris, France Hop Necker Enfants Malad, CNRS, URA 1461, F-75015 Paris, France Hop NeckerEnfants Malad Paris France F-75015 461, F-75015 Paris, France Inst Necker, INSERM, U373, F-75015 Paris, France Inst Necker Paris France F-75015 er, INSERM, U373, F-75015 Paris, France
Titolo Testata:
JOURNAL OF AUTOIMMUNITY
fascicolo: 4, volume: 16, anno: 2001,
pagine: 431 - 440
SICI:
0896-8411(200106)16:4<431:IVBOTF>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; APO-1/FAS RECEPTOR/LIGAND SYSTEM; DELAYED-TYPE HYPERSENSITIVITY; DRUG-INDUCED APOPTOSIS; ACTIVATED B-CELLS; CD4(+) T-CELLS; AUTOIMMUNE-DISEASE; DEFICIENT MICE; BETA-CELLS; MOUSE;
Keywords:
FAS/CD95; autoimmunity; tolerance; diabetes; apoptosis;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
63
Recensione:
Indirizzi per estratti:
Indirizzo: Chatenoud, L Hop Necker Enfants Malad, INSERM, U25, 161 Rue Sevres, F-75015 Paris, France Hop Necker Enfants Malad 161 Rue Sevres Paris France F-75015
Citazione:
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

Abstract

There is compelling evidence to show that insulin dependent diabetes ensues from selective apoptosis of pancreatic beta -cells mediated by autoreactive T-lymphocytes. The respective implication in this phenomenon of the various apoptotic pathways driven by Fas, perforin, or tumor necrosis factor isstill ill-defined. Here we took advantage of the cyclophosphamide-induced model of accelerated diabetes in NOD mice to explore the physiopathologicalrole of the Fas-Fas Ligand pathway. A single injection of cyclophosphamide(200 mg/kg) to 7-8 week-old prediabetic NOD mice triggered diabetes within10-15 days in 85-100% of the animals. Cyclophosphamide also induced a significant decrease in spleen T cells, that was most evident by days 6-10 after treatment, and selectively affected the CD3(+)CD62L(+) compartment that includes immunoregulatory T cells. To block the in vivo Fas-Fas Ligand (Fas L) interaction we administered a biologically active recombinant fusion protein coupling mouse Fas to the Fc portion of human IgG1 (FAS-Fc). Mice treated with FAS-Fc (10 doses iv of 15 mug) starting on the day of cyclophosphamide 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 effecton T cells. Indeed FAS-Fc treatment prevented the drug-induced T cell depletion in general and that of immunoregulatory T cells in particular. Additionally, FAS-Fc administration limited to the phase of beta -cell destruction did not afford any protection. (C) 2001 Academic Press.

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Documento generato il 14/07/20 alle ore 04:18:51