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

被引：85

作者：

Prencipe, Giusi ^{[1
]}

Caiello, Ivan ^{[1
]}

Pascarella, Antonia ^{[1
]}

Grom, Alexei A. ^{[2
]}

Bracaglia, Claudia ^{[1
]}

Chatel, Laurence ^{[3
]}

Ferlin, Walter G. ^{[3
]}

Marasco, Emiliano ^{[1
]}

Strippoli, Raffaele ^{[4
]}

de Min, Cristina ^{[3
]}

De Benedetti, Fabrizio ^{[1
]}

机构：

[1] IRCCS, Bambino Gesu Childrens Hosp, Div Rheumatol, Rome, Italy

[2] Cincinnati Childrens Hosp Med Ctr, Div Rheumatol, ML 4010, Cincinnati, OH 45229 USA

[3] NovImmune SA, Geneva, Switzerland

[4] Sapienza Univ Rome, Dept Cellular Biotechnol & Haematol, Rome, Italy

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2018年 / 141卷 / 04期

基金：

美国国家卫生研究院;

关键词：

Macrophage activation syndrome; hemophagocytic lymphohistiocytosis; IFN-gamma; JUVENILE IDIOPATHIC ARTHRITIS; CYTOKINE-DIRECTED THERAPIES; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; INTERFERON-GAMMA; MICE; RECEPTOR; INTERLEUKIN-6; PATHOGENESIS; EXPRESSION; GENE;

D O I：

10.1016/j.jaci.2017.07.021

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

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-gamma and the therapeutic efficacy of IFN-gamma 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-gamma and IFN-gamma-inducible chemokines were evaluated by using real-time PCR in the liver and spleen and by means of ELISA in plasma. IFN-gamma neutralization was achieved by using the anti-IFN-gamma antibody XMG1.2 in vivo. Results: Mice with MAS showed a significant upregulation of the IFN-gamma pathway, as demonstrated by increased mRNA levels of Ifng and higher levels of phospho-signal transducer and activator of transcription 1 in the liver and spleen and increased expression of the IFN-gamma-inducible chemokines Cxcl9 and Cxcl10 in the liver and spleen, as well as in plasma. A marked increase in Il12a and Il12b expression 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-gamma 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-gamma 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-gamma in the setting of MAS.

引用

页码：1439 / 1449

页数：11

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