The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo
The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo
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DOI：
10.1182/blood-2013-03-484642
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发表时间：
2013-08-15
期刊：
影响因子：
20.3
通讯作者：
Brossart, Peter
中科院分区：
文献类型：
--
作者：
Heine, Annkristin;Held, Stefanie Andrea Erika;Brossart, Peter
Janus激酶（JAK）抑制剂ruxolitinib通过与其抗克隆活性不同的机制降低骨髓纤维化（MF）患者的全身症状和脾脏大小。在这里，我们研究了ruxolitinib是否影响树突状细胞（DC）生物学。当在整个分化期加入化合物时，单核细胞衍生的DC的体外发育几乎完全被阻断。此外，当在最终脂多糖诱导的成熟步骤中单独应用时，鲁索利替尼减少了DC活化，如通过减少的白细胞介素-12产生和减弱的活化标志物表达所证明的。Ruxolitinib还损害体外和体内DC迁移。暴露于鲁索利替尼的DC的功能障碍通过其同种异体和抗原特异性T细胞应答的诱导受损而进一步强调。与溶剂处理的对照组相比，用卵清蛋白（OVA）/CpG免疫的Ruxolitinib处理的小鼠诱导的OVA特异性CD 8（+）T细胞的体内活化和增殖显著降低。最后，使用腺病毒感染模型，我们发现暴露于ruxolitinib的小鼠表现出延迟的腺病毒清除。我们的结果表明，鲁索替尼显著影响DC分化和功能，导致T细胞活化受损。DC功能障碍可能导致ruxolitinib治疗患者的感染率增加。然而，我们的研究结果也可以解释JAK抑制剂目前用于治疗MF和自身免疫性疾病的突出抗炎和免疫调节活性。
The Janus kinase (JAK)-inhibitor ruxolitinib decreases constitutional symptoms and spleen size of myelofibrosis (MF) patients by mechanisms distinct from its anticlonal activity. Here we investigated whether ruxolitinib affects dendritic cell (DC) biology. The in vitro development of monocyte-derived DCs was almost completely blocked when the compound was added throughout the differentiation period. Furthermore, when applied solely during the final lipopolysaccharide-induced maturation step, ruxolitinib reduced DC activation as demonstrated by decreased interleukin-12 production and attenuated expression of activation markers. Ruxolitinib also impaired both in vitro and in vivo DC migration. Dysfunction of ruxolitinib-exposed DCs was further underlined by their impaired induction of allogeneic and antigen-specific T-cell responses. Ruxolitinib-treated mice immunized with ovalbumin (OVA)/CpG induced markedly reduced in vivo activation and proliferation of OVA-specific CD8(+) T cells compared with vehicle-treated controls. Finally, using an adenoviral infection model, we show that ruxolitinib-exposed mice exhibit delayed adenoviral clearance. Our results demonstrate that ruxolitinib significantly affects DC differentiation and function leading to impaired T-cell activation. DC dysfunction may result in increased infection rates in ruxolitinib-treated patients. However, our findings may also explain the outstanding anti-inflammatory and immunomodulating activity of JAK inhibitors currently used in the treatment of MF and autoimmune diseases.