Combined IFN-γ and JAK inhibition to treat hemophagocytic lymphohistiocytosis in mice

Familial hemophagocytic lymphohistiocytosis is a life-threatening hyperinflammatory disease caused by genetic defects in the granule-mediated cytotoxic pathway. Success of hematopoietic cell transplantation, the only cure, is correlated with the extent of disease control before transplantation. Unfortunately, disease refractoriness and toxicities to standard chemotherapy-based regimens are fatal in a fraction of patients. Novel targeted immunotherapies, such as IFN-γ blocking antibodies or ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, are promising but only partially effective at controlling disease.We asked whether combinations of cytokine-targeted therapies, using antibodies or JAK inhibitor, work synergistically to counteract HLH.Genetically predisposed mice were infected and treated with distinct combinations of immunotherapies. Disease outcome was monitored and compared to monotherapies.We showed that inhibiting IL-6 or IL-18 signaling in combination with IFN-γ blockade or ruxolitinib did not increase disease control compared to anti-IFN-γ antibodies or ruxolitinib monotherapies. In contrast, clinically relevant doses of ruxolitinib combined with low doses of anti-IFN-γ blocking antibodies corrected cytopenias, prevented overt neutrophilia, limited cytokinemia, and resolved HLH immunopathology and symptomatology.Our findings demonstrate that IFN-γ blockade and ruxolitinib act synergistically to suppress HLH progression. This supports the use of combined cytokine-targeted therapies as a bridge to hematopoietic cell transplantation in severe familial hemophagocytic lymphohistiocytosis.