Joly Josée-Anne, Vallée Alexis, Bourdin Benoîte, Bourbonnais Sara, Patey Natalie, Gaboury Louis, Théorêt Yves, Decaluwe Hélène
Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital Research Center, Université de Montréal, Montréal, Québec, Canada.
Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital Research Center, Université de Montréal, Montréal, Québec, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, Québec, Canada.
J Allergy Clin Immunol. 2023 Jan;151(1):247-259.e7. doi: 10.1016/j.jaci.2022.07.026. Epub 2022 Aug 13.
Familial hemophagocytic lymphohistiocytosis is a life-threatening hyperinflammatory disease caused by genetic defects in the granule-mediated cytotoxic pathway. Success of hematopoietic cell transplantation, the only cure, is correlated with the extent of disease control before transplantation. Unfortunately, disease refractoriness and toxicities to standard chemotherapy-based regimens are fatal in a fraction of patients. Novel targeted immunotherapies, such as IFN-γ blocking antibodies or ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, are promising but only partially effective at controlling disease.
We asked whether combinations of cytokine-targeted therapies, using antibodies or JAK inhibitor, work synergistically to counteract HLH.
Genetically predisposed mice were infected and treated with distinct combinations of immunotherapies. Disease outcome was monitored and compared to monotherapies.
We showed that inhibiting IL-6 or IL-18 signaling in combination with IFN-γ blockade or ruxolitinib did not increase disease control compared to anti-IFN-γ antibodies or ruxolitinib monotherapies. In contrast, clinically relevant doses of ruxolitinib combined with low doses of anti-IFN-γ blocking antibodies corrected cytopenias, prevented overt neutrophilia, limited cytokinemia, and resolved HLH immunopathology and symptomatology.
Our findings demonstrate that IFN-γ blockade and ruxolitinib act synergistically to suppress HLH progression. This supports the use of combined cytokine-targeted therapies as a bridge to hematopoietic cell transplantation in severe familial hemophagocytic lymphohistiocytosis.
家族性噬血细胞性淋巴组织细胞增生症是一种由颗粒介导的细胞毒性途径中的基因缺陷引起的危及生命的高炎症性疾病。造血细胞移植是唯一的治愈方法，其成功与移植前疾病控制的程度相关。不幸的是，疾病难治性以及对基于标准化疗方案的毒性在一部分患者中是致命的。新型靶向免疫疗法，如干扰素-γ阻断抗体或鲁索替尼（一种Janus激酶（JAK）1/2抑制剂），虽有前景但在控制疾病方面仅部分有效。
我们探究使用抗体或JAK抑制剂的细胞因子靶向疗法联合应用是否能协同对抗噬血细胞性淋巴组织细胞增生症（HLH）。
对具有遗传易感性的小鼠进行感染，并使用不同的免疫疗法组合进行治疗。监测疾病转归并与单一疗法进行比较。
我们发现，与抗干扰素-γ抗体或鲁索替尼单一疗法相比，抑制白细胞介素-6或白细胞介素-18信号传导联合干扰素-γ阻断或鲁索替尼并不能增强疾病控制效果。相反，临床相关剂量的鲁索替尼与低剂量抗干扰素-γ阻断抗体联合使用可纠正血细胞减少，预防明显的中性粒细胞增多，限制细胞因子血症，并消除HLH免疫病理学和症状。
我们的研究结果表明，干扰素-γ阻断和鲁索替尼具有协同作用以抑制HLH进展。这支持在严重家族性噬血细胞性淋巴组织细胞增生症中使用联合细胞因子靶向疗法作为造血细胞移植的桥梁。
