Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis.
2016
Hemophagocytic lymphohistiocytosis(HLH) comprises an emerging spectrum of inherited and noninherited disorders of the immune system characterized by the excessive production of cytokines, including interferon-γ and interleukins 2, 6, and 10 (IL-2, IL-6, and IL-10). The
Janus kinases(JAKs) transduce signals initiated following engagement of specific receptors that bind a broad array of cytokines, including those overproduced in HLH. Based on the central role for cytokines in the pathogenesis of HLH, we sought to examine whether the inhibition of JAK function might lessen inflammation in murine models of the disease. Toward this end, we examined the effects of JAK inhibition using a model of primary (inherited) HLH in which
perforin-deficient ( Prf1 −∕− ) mice are infected with
lymphocytic choriomeningitisvirus (LCMV) and secondary (noninherited) HLH in which C57BL/6 mice receive repeated injections of CpG DNA. In both models, treatment with the JAK1/2 inhibitor
ruxolitinibsignificantly lessened the clinical and laboratory manifestations of HLH, including weight loss,
organomegaly, anemia, thrombocytopenia, hypercytokinemia, and tissue inflammation. Importantly,
ruxolitinibtreatment also significantly improved the survival of LCMV-infected Prf1 −∕− mice. Mechanistic studies revealed that in vivo exposure to
ruxolitinibinhibited signal transducer and activation of transcription 1–dependent gene expression, limited CD8 + T-cell expansion, and greatly reduced proinflammatory cytokine production, without effecting degranulation and cytotoxic function. Collectively, these findings highlight the JAKs as novel,
druggabletargets for mitigating the cytokine-driven hyperinflammation that occurs in HLH. These observations also support the incorporation of JAK inhibitors such as
ruxolitinibinto future clinical trials for patients with these life-threatening disorders.
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