Fas/Fas ligand interactions play an essential role in the initiation of murine autoimmune diabetes.
Apoptosis via Fas/Fas ligand (FasL) interactions has been proposed to be a major T-cell-mediated effector mechanism in autoimmune diabetes. To elucidate the role of Fas/FasL interactions in NOD diabetes, the effects of neutralizing anti-FasL antibody on autoimmune responses were evaluated. Islet-specific CD8(+) and CD4(+) T-cells expressed FasL upon activation and mediated FasL-dependent cytotoxicity against Fas-expressing target cells in vitro, although their cytotoxicity against islet cells was not blocked by anti-FasL antibody. Moreover, administration of anti-FasL antibody failed to inhibit diabetes in vivo in the CD8(+) T-cell adoptive transfer model. On the other hand, blockade of Fas/FasL interactions significantly inhibited CD4(+) T-cell-dependent diabetes in adoptive transfer models. These results suggest a substantial contribution of Fas/FasL interactions to CD4(+), but not CD8(+), T-cell-mediated destruction of pancreatic beta-cells. When anti-FasL antibody was administered to NOD mice between 5 and 15 weeks of age, the onset of diabetes was slightly delayed but the incidence was not decreased. However, administration of anti-FasL antibody at 2-4 weeks of age completely prevented insulitis and diabetes. These results suggest that Fas/FasL interactions contribute to CD4(+) T-cell-mediated beta-cell destruction and play an essential role in the initiation of autoimmune NOD diabetes.
Nakayama
Maki
M
Department of Diabetes, Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe, Japan.
Nagata
Masao
M
Yasuda
Hisafumi
H
Arisawa
Kenji
K
Kotani
Reiko
R
Yamada
Katsumi
K
Chowdhury
Shahead Ali
SA
Chakrabarty
Sagarika
S
Jin
Zhen Zi
ZZ
Yagita
Hideo
H
Yokono
Koichi
K
Kasuga
Masato
M
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism*; D053222:Fas Ligand Protein; D005260:Female; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor