Treatment with anti-interferon-gamma monoclonal antibodies modifies experimental autoimmune encephalomyelitis in interferon-gamma receptor knockout mice.
The role of interferon-gamma (IFN-gamma) in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) is still controversial. We have studied the function of IFN-gamma and its receptor in the EAE model using two different IFN-gamma receptor knockout (IFN-gamma R(-/-)) mouse types: C57Bl/6x129Sv, with a disruption of the IFN-gamma receptor cytoplasmic domain, and 129Sv, homozygous for a disrupted IFN-gamma receptor gene. Mice were immunized with peptide 40-55 from rat myelin oligodendrocyte glycoprotein. A subgroup of mice was treated with anti-IFN-gamma monoclonal antibodies (mAb) on day 8 postimmunization. Clinical scoring and both histological and immunohistochemical studies were undertaken for all groups. We hereby show that treatment with anti-IFN-gamma mAb worsened the disease course of 129Sv wild-type mice. However, it decreased the mean daily score in IFN-gamma R(-/-) 129Sv and the incidence of the disease down to 50% in C57Bl/6x129Sv IFN-gamma R(-/-) mice. Moreover, after anti-IFN-gamma mAb treatment, oxidative stress levels, metallothionein I and II antioxidant protein expression, and apoptoticneuronal death were increased in wild-type mice while decreased in IFN-gamma R(-/-) mice. These results suggest a putative alternative mechanism of action of this cytokine that works independent of its receptor.
Espejo
C
C
Unitat de Neuroimmunologia Clínica, Hospital Vall d'Hebron, Barcelona, 08035, Spain.
Penkowa
M
M
Sáez-Torres
I
I
Xaus
J
J
Celada
A
A
Montalban
X
X
Martínez-Cáceres
E M
EM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000936:Antigen-Antibody Complex / Q000494:pharmacology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000503:physiopathology*; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007371:Interferon-gamma / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D051381:Rats; D017471:Receptors, Interferon / Q000172:deficiency* / Q000235:genetics; D000096743:Interferon gamma Receptor
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D000949:Histocompatibility Antigens Class II; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor