Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, United States.
Front Immunol. 2023 Apr 27;14:1137037. doi: 10.3389/fimmu.2023.1137037. eCollection 2023.
Primary hemophagocytic lymphohistiocytosis (pHLH) is an inherited inflammatory syndrome driven by the exuberant activation of interferon-gamma (IFNg)-producing CD8 T cells. Towards this end, ruxolitinib treatment or IFNg neutralization (aIFNg) lessens immunopathology in a model of pHLH in which perforin-deficient mice (-/-) are infected with Lymphocytic Choriomeningitis virus (LCMV). However, neither agent completely eradicates inflammation. Two studies combining ruxolitinib with aIFNg report conflicting results with one demonstrating improvement and the other worsening of disease manifestations. As these studies used differing doses of drugs and varying LCMV strains, it remained unclear whether combination therapy is safe and effective.
We previously showed that a ruxolitinib dose of 90 mg/kg lessens inflammation in -/- mice infected with LCMV-Armstrong. To determine whether this dose controls inflammation induced by a different LCMV strain, we administered ruxolitinib at 90mg/kg to -/- mice infected with LCMV-WE. To elucidate the impacts of single agent versus combination therapy, -/- animals were infected with LCMV, treated or not with ruxolitinib, aIFNg or both agents, and analyzed for disease features and the transcriptional impacts of therapy within purified CD8 T cells.
Ruxolitinib is well-tolerated and controls disease regardless of the viral strain used. aIFNg, administered alone or with ruxolitinib, is most effective at reversing anemia and reducing serum IFNg levels. In contrast, ruxolitinib appears better than aIFNg, and equally or more effective than combination therapy, at lessening immune cell expansion and cytokine production. Each treatment targets distinct gene expression pathways with aIFNg downregulating IFNg, IFNa, and IL-6-STAT3 pathways, and ruxolitinib downregulating IL-6-STAT3, glycolysis, and reactive oxygen species pathways. Unexpectedly, combination therapy is associated with upregulation of genes driving cell survival and proliferation.
Ruxolitinib is tolerated and curtails inflammation regardless of the inciting viral strain and whether it is given alone or in combination with aIFNg. When administered at the doses used in this study, the combination of ruxolitinb and aIFNg appears no better than treatment with either drug alone in lessening inflammation. Further studies are warranted to elucidate the optimal doses, schedules, and combinations of these agents for the treatment of patients with pHLH.
原发性噬血细胞性淋巴组织细胞增生症（pHLH）是一种由干扰素-γ（IFNg）产生的 CD8 T 细胞过度激活驱动的遗传性炎症综合征。为此，鲁索利替尼治疗或 IFNg 中和（aIFNg）可减轻穿孔素缺陷型（-/-）小鼠感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）的 pHLH 模型中的免疫病理学。然而，这两种药物都不能完全消除炎症。两项联合鲁索利替尼和 aIFNg 的研究报告的结果相互矛盾，一项研究显示疾病表现改善，另一项研究显示疾病表现恶化。由于这些研究使用了不同剂量的药物和不同的 LCMV 株，因此仍不清楚联合治疗是否安全有效。
我们之前表明，鲁索利替尼 90mg/kg 的剂量可减轻感染 LCMV-Armstrong 的-/-小鼠的炎症。为了确定该剂量是否可控制由不同 LCMV 株引起的炎症，我们用 90mg/kg 的鲁索利替尼处理感染 LCMV-WE 的-/-小鼠。为了阐明单药治疗与联合治疗的影响，-/-动物感染 LCMV，用或不用鲁索利替尼、aIFNg 或两种药物治疗，并分析疾病特征和治疗对纯化的 CD8 T 细胞的转录影响。
鲁索利替尼耐受性良好，无论使用哪种病毒株，都能控制疾病。单独使用或与鲁索利替尼联合使用的 aIFNg 最能逆转贫血和降低血清 IFNg 水平。相比之下，鲁索利替尼似乎优于 aIFNg，与联合治疗一样或更有效，可减轻免疫细胞扩增和细胞因子产生。每种治疗方法都针对不同的基因表达途径，aIFNg 下调 IFNg、IFNa 和 IL-6-STAT3 途径，鲁索利替尼下调 IL-6-STAT3、糖酵解和活性氧途径。出乎意料的是，联合治疗与驱动细胞存活和增殖的基因上调有关。
鲁索利替尼耐受性良好，可减轻炎症，无论引起炎症的病毒株如何，无论单独使用还是与 aIFNg 联合使用。在本研究中使用的剂量下，鲁索利替尼和 aIFNg 的联合使用在减轻炎症方面似乎并不优于单独使用任何一种药物。需要进一步的研究来阐明这些药物的最佳剂量、方案和联合用药治疗 pHLH 患者的方法。
