Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
IL-18 Binding Protein (IL-18BP) Dramatically Improves Liver Histological Lesions in an Animal Model of Macrophage Activation Syndrome (MAS).
Chiossone3, Laura, Audonnet3, Sandra, Mazodier2, Karin, Dalod3, Marc, Farnarier1, Catherine, Novick5, Daniela, Dinarello4, Charles A.
Assiatnce Publique-Hôpitaux de Marseille, Marseille, France
Assistance Publique-Hôpitaux de Marseille, Marseille, France
CIML, Marseille, France
University of Colorado Health Science, Denver, CO
Weizmann Institute of Science, Rehovot, Israel
MAS is a severe complication of various infectious, inflammatory or neoplastic diseases. Severely impaired lymphocyte cytotoxicity and large excess of inflammatory cytokines, notably IFN-g, participate in its pathogenesis. In patients with MAS, concentrations of IL-18, a strong inducer of IFN-g, are largely increased, but not those of its natural inhibitor IL-18BP, favoring a severe IL-18/IL-18BP imbalance.
We asked whether IL-18BP may be an efficient treatment in an animal model of MAS consisting in perforin-KO mice infected with murine cytomegalovirus (MCMV), which has been previously reported to be IFN-g and TNF-a-dependent.
712 days after infection, 100% KO mice died whereas all wild type (WT) mice survived. Injection of 10 microgram/mice/day IL-18BP starting at day 0 or day 4 post-infection did not improve KO mice survival, nor did anti-TNF-a treatment.
Liver showed very severe histological lesions in MCVM-infected KO mice which was almost completely abrogated by IL-18 BP, in a comparable way to anti-TNF-a treatment. Combination of both did not further improve the lesions.
Serum cytokine concentrations at day 6 post-infection showed very high concentrations of IFN-g (38+/-5 vs 1+/-1 ng/ml in WT) and TNF-a (13.8 +/-2 vs 0.5 ng/ml in WT) in MCMV-infected KO mice, which were 50% reduced by IL-18BP treatment (20 +/-10 ng/ml for IFN-g and 7.5+/-2 ng/ml for TNF-a, respectively). Combination of IL-18BP and anti-TNF-a treatment 100% inhibited IFN-g levels.
In this model of MAS which has been shown to be entirely IFN-g and TNF-a-mediated, IL-18BP appears to be as efficient as anti-TNF-a treatment in preventing liver damage through inhibition of both IFN-g and TNF-a, confirming the role of IL-18 in the pathogenesis of this disease.
To cite this abstract, please use the following information:
Chiossone, Laura, Audonnet, Sandra, Mazodier, Karin, Dalod, Marc, Farnarier, Catherine, Novick, Daniela, et al; IL-18 Binding Protein (IL-18BP) Dramatically Improves Liver Histological Lesions in an Animal Model of Macrophage Activation Syndrome (MAS). [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1664