Neutralization of IFN-γ reverts clinical and laboratory features in a mouse model of macrophage activation syndrome


    loading  Checking for direct PDF access through Ovid

Abstract

Background:The pathogenesis of macrophage activation syndrome (MAS) is not clearly understood: a large body of evidence supports the involvement of mechanisms similar to those implicated in the setting of primary hemophagocytic lymphohistiocytosis.Objective:We sought to investigate the pathogenic role of IFN-γ and the therapeutic efficacy of IFN-γ neutralization in an animal model of MAS.Methods:We used an MAS model established in mice transgenic for human IL-6 (IL-6TG mice) challenged with LPS (MAS mice). Levels of IFN-γ and IFN-γ–inducible chemokines were evaluated by using real-time PCR in the liver and spleen and by means of ELISA in plasma. IFN-γ neutralization was achieved by using the anti–IFN-γ antibody XMG1.2in vivo.Results:Mice with MAS showed a significant upregulation of the IFN-γ pathway, as demonstrated by increased mRNA levels ofIfngand higher levels of phospho–signal transducer and activator of transcription 1 in the liver and spleen and increased expression of the IFN-γ–inducible chemokinesCxcl9andCxcl10in the liver and spleen, as well as in plasma. A marked increase inIl12aandIl12bexpression was also found in livers and spleens of mice with MAS. In addition, mice with MAS had a significant increase in numbers of liver CD68+ macrophages. Mice with MAS treated with an anti–IFN-γ antibody showed a significant improvement in survival and body weight recovery associated with a significant amelioration of ferritin, fibrinogen, and alanine aminotransferase levels. In mice with MAS, treatment with the anti–IFN-γ antibody significantly decreased circulating levels of CXCL9, CXCL10, and downstream proinflammatory cytokines. The decrease in CXCL9 and CXCL10 levels paralleled the decrease in serum levels of proinflammatory cytokines and ferritin.Conclusion:These results provide evidence for a pathogenic role of IFN-γ in the setting of MAS.

    loading  Loading Related Articles