1. Differential effects of itacitinib, fedratinib, and ruxolitinib in mouse models of hemophagocytic lymphohistiocytosis.
- Author
-
Keenan C, Albeituni S, Oak N, Stroh A, Tillman HS, Wang Y, Freeman BB 3rd, Alemán-Arteaga S, Meyer LK, Woods R, Verbist KC, Zhou Y, Cheng C, and Nichols KE
- Subjects
- Animals, Mice, Janus Kinase 1 antagonists & inhibitors, Janus Kinase 1 metabolism, Janus Kinase 1 genetics, Pyrroles pharmacology, Pyrroles therapeutic use, Janus Kinase 2 antagonists & inhibitors, Janus Kinase 2 genetics, Janus Kinase 2 metabolism, Mice, Inbred C57BL, Sulfonamides pharmacology, Sulfonamides therapeutic use, STAT1 Transcription Factor metabolism, STAT1 Transcription Factor genetics, Janus Kinase Inhibitors pharmacology, Janus Kinase Inhibitors therapeutic use, Piperidines pharmacology, Humans, Benzenesulfonamides, Bridged-Ring Compounds, Pyrrolidines, Nitriles, Pyrimidines pharmacology, Lymphohistiocytosis, Hemophagocytic drug therapy, Lymphohistiocytosis, Hemophagocytic chemically induced, Lymphohistiocytosis, Hemophagocytic pathology, Pyrazoles pharmacology, Pyrazoles therapeutic use, Disease Models, Animal
- Abstract
Abstract: Hemophagocytic lymphohistiocytosis (HLH) comprises a severe hyperinflammatory phenotype driven by the overproduction of cytokines, many of which signal via the JAK/STAT pathway. Indeed, the JAK1/2 inhibitor ruxolitinib has demonstrated efficacy in preclinical studies and early-phase clinical trials in HLH. Nevertheless, concerns remain for ruxolitinib-induced cytopenias, which are postulated to result from the blockade of JAK2-dependent hematopoietic growth factors. To explore the therapeutic effects of selective JAK inhibition in mouse models of HLH, we carried out studies incorporating the JAK1 inhibitor itacitinib, JAK2 inhibitor fedratinib, and JAK1/2 inhibitor ruxolitinib. All 3 drugs were well-tolerated and at the doses tested, they suppressed interferon-gamma (IFN-γ)-induced STAT1 phosphorylation in vitro and in vivo. Itacitinib, but not fedratinib, significantly improved survival and clinical scores in CpG-induced secondary HLH. Conversely, in primary HLH, in which perforin-deficient (Prf1-/-) mice are infected with lymphocytic choriomeningitis virus (LCMV), itacitinib, and fedratinib performed suboptimally. Ruxolitinib demonstrated excellent clinical efficacy in both HLH models. RNA-sequencing of splenocytes from LCMV-infected Prf1-/- mice revealed that itacitinib targeted inflammatory and metabolic pathway genes in CD8 T cells, whereas fedratinib targeted genes regulating cell proliferation and metabolism. In monocytes, neither drug conferred major transcriptional impacts. Consistent with its superior clinical effects, ruxolitinib exerted the greatest transcriptional changes in CD8 T cells and monocytes, targeting more genes across several biologic pathways, most notably JAK-dependent proinflammatory signaling. We conclude that JAK1 inhibition is sufficient to curtail CpG-induced disease, but combined inhibition of JAK1 and JAK2 is needed to best control LCMV-induced immunopathology., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Published
- 2024
- Full Text
- View/download PDF