Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal disorder characterized by the overactivation of T cells and macrophages that excessively produce proinflammatory cytokines, including interferon- (IFN-). Previously, we reported that the JAK inhibitor ruxolitinib dampens T-cell activation and lessens inflammation in a model of HLH in which perforin-deficient (Prf1–/–) mice are infected with lymphocytic choriomeningitis virus (LCMV). Ruxolitinib inhibits signaling downstream of IFN-, as well as several other JAK-dependent cytokines. As a consequence, it remained unclear whether ruxolitinib was exerting its beneficial effects in HLH by inhibiting IFN- signaling or by targeting signaling initiated by other proinflammatory cytokines. To address this question, we compared the effects of ruxolitinib with those obtained using an IFN-–neutralizing antibody (αIFN-) in 2 murine HLH models. In both models, ruxolitinib and αIFN- reduced inflammation-associated anemia, indicating that ruxolitinib operates in an IFN-–dependent manner to reverse this HLH manifestation. In contrast, the number and activation status of T cells and neutrophils, as well as their infiltration into tissues, were significantly reduced following treatment with ruxolitinib, but they remained unchanged or were increased following treatment with αIFN-. Notably, despite discontinuation of ruxolitinib, LCMV-infected Prf1–/– mice exhibited enhanced survival co...

Source: Blood - July 10, 2019 Category: Hematology Authors: Albeituni, S., Verbist, K. C., Tedrick, P. E., Tillman, H., Picarsic, J., Bassett, R., Nichols, K. E. Tags: Immunobiology and Immunotherapy Source Type: research