title: Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis.
abstract: 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 choriomeningitis virus (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 ruxolitinib significantly lessened the clinical and laboratory manifestations of HLH, including weight loss, organomegaly, anemia, thrombocytopenia, hypercytokinemia, and tissue inflammation. Importantly, ruxolitinib treatment also significantly improved the survival of LCMV-infectedPrf1(-∕-)mice. Mechanistic studies revealed that in vivo exposure to ruxolitinib inhibited 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, druggable targets for mitigating the cytokine-driven hyperinflammation that occurs in HLH. These observations also support the incorporation of JAK inhibitors such as ruxolitinib into future clinical trials for patients with these life-threatening disorders.
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI;
authors.forename: Rupali
authors.initials: R
authors.lastname: Das
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Peng
authors.initials: P
authors.lastname: Guan
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Leslee
authors.initials: L
authors.lastname: Sprague
authors.affiliation: Department of Oncology and.
authors.forename: Katherine
authors.initials: K
authors.lastname: Verbist
authors.affiliation: Department of Oncology and.
authors.forename: Paige
authors.initials: P
authors.lastname: Tedrick
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Qi Angel
authors.initials: QA
authors.lastname: An
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Microbiology, Institute for Immunology, University of Pennsylvania, Philadelphia, PA;
authors.forename: Makoto
authors.initials: M
authors.lastname: Kurachi
authors.affiliation: Department of Oncology, Memorial Sloan Kettering Cancer Center, New York, NY; and.
authors.forename: Ross
authors.initials: R
authors.lastname: Levine
authors.affiliation: Department of Microbiology, Institute for Immunology, University of Pennsylvania, Philadelphia, PA;
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.affiliation: Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Canna
authors.affiliation: Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Behrens
authors.affiliation: Department of Oncology and.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Nichols
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018899:CpG Islands; D004195:Disease Models, Animal; D007249:Inflammation / Q000517:prevention & control*; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009570:Nitriles; D054353:Perforin / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines; D014709:Vero Cells
chemical_list: D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C510467:perforin 1, mouse; D054353:Perforin; C540383:ruxolitinib; D053612:Janus Kinases
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