Treatment with anti-interferon-γ monoclonal antibodies modifies experimental autoimmune encephalomyelitis in interferon-γ 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: C57B1/6x129Sv, 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 C57B1/6x129Sv IFN-gamma R-/- mice. Moreover, after anti-IFN-/- mAb treatment, oxidative stress levels, metallothionein I and H antioxidant protein expression, and apoptotic neuronal 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. (C) 2001 Elsevier Science.