In vivo blockade of the Fas-Fas ligand pathway inhibits cyclophosphamide-induced diabetes in NOD mice.
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 is still ill- defined. Here we took advantage of the cyclophosphamide-induced model 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 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 microg) 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 effect on 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.
Mahiou
J
J
INSERM U 25, Hôpital Necker, 161 rue de Sèvres, Paris, 75015, France.
Walter
U
U
Lepault
F
F
Godeau
F
F
Bach
J F
JF
Chatenoud
L
L
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D003520:Cyclophosphamide / Q000009:adverse effects; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000276:immunology*; D053222:Fas Ligand Protein; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007515:Islets of Langerhans / Q000166:cytology / Q000276:immunology; D019041:L-Selectin / Q000276:immunology; D008212:Lymphocyte Depletion; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D019014:fas Receptor / Q000276:immunology*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D019014:fas Receptor; D019041:L-Selectin; D003520:Cyclophosphamide