Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis

Abstract

Key Points Ruxolitinib treatment lessens immunopathology and prolongs survival in murine models of hemophagocytic lymphohistiocytosis. In vivo exposure to ruxolitinib limits CD8+ T-cell expansion and proinflammatory cytokine production.

Ruxolitinib for treatment of refractory hemophagocytic lymphohistiocytosis

“…4 These cytokines bind to JAK receptors, leading to activation of the STAT family of transcription factors and regulation of downstream target genes.…”

“…6,7,[15][16][17][18][19][20][21][22] In murine models, ruxolitinib has been shown to both prevent and treat HLH by decreasing cytokine production and inflammation via inhibition of STAT1 signaling. 4,5 There is an active trial using ruxolitinib in adults with secondary HLH, but there have been no reports of pediatric patients who have received ruxolitinib for the treatment of HLH.…”

“…When administered empirically to perforin-deficient mice, ruxolitinib inhibits interferon g (IFN-g), interleukin-6 (IL-6), and IL-12 production and prevents clinical symptoms of HLH from developing. 4 Similarly, when ruxolitinib is administered after HLH symptom onset, cytokine production and tissue damage are decreased, leading to improved survival in mice. 5 The dramatic effect of ruxolitinib in murine models has led to interest in its use clinically for refractory HLH.…”

Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency

“…16,25 JAK1/2 inhibitors might provide an additional benefit if administered prior to the infusion of gene-corrected HSCs (a definitive curative approach for HLH disease).…”

Gene-corrected human Munc13-4–deficient CD8+ T cells can efficiently restrict EBV-driven lymphoproliferation in immunodeficient mice

“…Novel antiinflammatory modalities for IFNg blockade (such as the JAK1/2 inhibitor ruxolitinib) can reduce inflammation and correct certain manifestations of FHL (such as blood cytopenia) in murine models of FHL. 17,18 Ruxolitinib has already demonstrated clinical efficacy in other inflammatory conditions 19,20 ; if approved in HLH patients, this compound could be used as an anti-inflammatory agent for reducing immune system imbalance prior to T-cell immunotherapy. …”