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

Background: 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-y blocking antibodies or ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, are promising but only partially effective at controlling disease.Objective: We asked whether combinations of cytokine-targeted therapies, using antibodies or JAK inhibitor, work synergistically to counteract HLH.Methods: Genetically predisposed mice were infected and treated with distinct combinations of immunotherapies.Disease outcome was monitored and compared to monotherapies. Results: We showed that inhibiting IL-6 or IL-18 signaling in combination with IFN-y blockade or ruxolitinib did not increase disease control compared to anti-IFN-y antibodies or ruxolitinib monotherapies. In contrast, clinically relevant doses of ruxolitinib combined with low doses of anti-IFN-y blocking antibodies corrected cytopenias, prevented overt neutrophilia, limited cytokinemia, and resolved HLH immunopathology and symptomatology.Conclusions: Our findings demonstrate that IFN-y 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. (J Allergy Clin Immunol 2023;151:247-59.)