鲁索利替尼
IRF7
医学
癌症研究
淋巴细胞性脉络膜脑膜炎
Janus激酶1
生物
CD8型
免疫学
贾纳斯激酶
骨髓纤维化
细胞因子
骨髓
先天免疫系统
免疫系统
作者
Camille Keenan,Sabrin Albeituni,Ninad Oak,Alexa Stroh,Heather Sheppard,Yingzhe Wang,Burgess B. Freeman,Silvia Alemán-Arteaga,Lauren K. Meyer,Rodney Woods,Katherine Verbist,Yinmei Zhou,Cheng Cheng,Kim E. Nichols
出处
期刊:Blood
[American Society of Hematology]
日期:2024-03-06
标识
DOI:10.1182/blood.2023021046
摘要
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 pre-clinical 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, the JAK2 inhibitor fedratinib and the JAK1/2 inhibitor ruxolitinib. All three drugs were well-tolerated and at the doses tested, they suppressed interferon-gamma (IFNg)-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, where 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, while 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 pro-inflammatory 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.
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