title: Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice.
abstract: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome, characterized by severe hyperinflammation and immunopathological manifestations in several tissues. These features result from organ infiltration by overactivated CD8 T-cells and macrophages, which produce high levels of pro-inflammatory cytokines, such as IFN-γ, TNF-α, IL-6, and IL-18. Recently, several Janus kinase 1/2 (JAK1/2) inhibitors, such as ruxolitinib, have been developed as immunosuppressive agents. They have proven beneficial effects in the treatment of myeloproliferative disorders and inflammatory conditions. To determine whether pharmacological inhibition of the JAK1/2 not only prevents the onset of HLH immunopathology but also is effective against existing HLH, cytotoxicity-impaired Prf1(-/-) and Rab27a(-/-) mice with full-blown HLH syndrome were treated with a clinically relevant dose of ruxolitinib. In vivo, ruxolitinib treatment suppressed signal transducer and activator of transcription 1 activation and led to recovery from HLH manifestations in both murine models. In the Prf1(-/-) mice, these beneficial effects were evidenced by a greater survival rate, and in both murine models, they were evidenced by the correction of blood cytopenia and a rapid decrease in serum IL-6 and TNF-α levels. During ruxolitinib treatment, liver tissue damage receded concomitantly with a decrease in the number of infiltrating inflammatory macrophages and an increase in the number of alternatively activated macrophages. In Rab27a(-/-) mice, central nervous system involvement was significantly reduced by ruxolitinib therapy. Our findings demonstrate that clinically relevant doses of the JAK1/2 inhibitor ruxolitinib suppresses the harmful consequences of macrophage overactivation characterizing HLH in 2 murine models. The results could be readily translated into the clinic for the treatment of primary, and perhaps even secondary, forms of HLH.
authors.affiliation: INSERM UMR1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France;
authors.forename: Sophia
authors.initials: S
authors.lastname: Maschalidi
authors.affiliation: INSERM UMR1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France;
authors.forename: Fernando E
authors.initials: FE
authors.lastname: Sepulveda
authors.affiliation: INSERM UMR1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France;
authors.forename: Alexandrine
authors.initials: A
authors.lastname: Garrigue
authors.affiliation: INSERM UMR1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France; Immunology and Pediatric Hematology Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Collège de France, Paris, France; and.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: INSERM UMR1163, Laboratory of Normal and Pathological Homeostasis of the Immune System, Paris, France; Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France; Centre d'Etudes des Déficits Immunitaires, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009570:Nitriles; D054353:Perforin / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins
chemical_list: D016207:Cytokines; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C510467:perforin 1, mouse; D000075745:rab27 GTP-Binding Proteins; D054353:Perforin; C540383:ruxolitinib; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins