Aims: IFNγ mediates disease in the murine model of primary HLH. Similar to HLH, patients with MAS/sHLH often present with a cytokine storm, overwhelming inflammation and multiorgan dysfunction. Thus, to assess the potential implication of IFNγ in MAS, two variants of the murine MAS model were used.  Administration of an anti-mouse IFNγ monoclonal antibody (MAb) in both models allowed us to determine the level and pivotal role of this proinflammatory cytokine.

Methods: C57BL/6 mice received repeated injections on days 0, 2, 4, 7 & 9 of the TLR9 agonist, CpG oligodeoxynucleotides (CpG ODN). To mimic a more severe, fulminant disease, along with CpG ODN, the anti-IL-10 Receptor mAb, 1B1.3A, was coadministered at 200µg/mouse on days 0, 2, 4 & 6. To assess the significance of IFNγ on disease, the mAb, XMG1.2, was injected 100 mg/kg) on days 1, 3 & 6. Levels of total IFNγ werequantified by a fit-for-purpose ELISA.

Results: In these models, IFNγ neutralization lead to disease amelioration with parameters such as weight loss, splenomegaly, white blood cell counts, hyperferritinemia, hypercytokinemia and anemia successfully addressed. Post XMG1.2 administration, accumulation of immune-complexed IFNγ reached a steady state level of 250 ng/ml in both models. IFNγ-induced inflammatory genes, found to be upregulated locally in the spleen and liver, were normalized by IFNγ-blockade.

Conclusion: Neutralization of IFNγ improves clinical and laboratory features in even the more severe, fulminant model of MAS. These data suggest that IFNγ, present as one of the cytokines in MAS, is central to disease and therefore provides a rationale for the neutralization of IFNγ as a potential targeted therapeutic approach in patients with severe form of MAS.