IL-1 Inhibition May Have an Important Role in Treating Refractory Kawasaki Disease.
IL-1 Inhibition May Have an Important Role in Treating Refractory Kawasaki Disease.
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DOI：
10.3389/fphar.2017.00163
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发表时间：
2017
影响因子：
5.6
通讯作者：
Koné-Paut I
中科院分区：
文献类型：
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作者：
Dusser P;Koné-Paut I
川崎（Kawasaki disease，KD）是一种急性炎症性血管炎，好发于5岁以下儿童，是先天性心脏病的主要病因。单次输注2 g/kg静脉注射免疫球蛋白沿着阿司匹林可将冠状动脉瘤的发生率从25%降至5%。然而，10-20%的患者对标准治疗没有反应，心脏并发症和死亡的风险增加。因此，迫切需要开发更有效的KD治疗方法。KD和全身性幼年特发性关节炎之间的表型和免疫学相似性导致KD可以被认为是一种自身炎症性疾病的假设。关于KD发病机制的新见解已经从遗传和转录组学数据的组合中融合，揭示了白细胞介素-1（IL-1）信号传导在血管炎发病机制中的关键作用。一旦激活，IL-1α和IL-1β触发局部促炎环境，诱导血管舒张并将单核细胞和中性粒细胞吸引到导致组织损伤和应激的部位。在KD的干酪乳杆菌细胞壁提取物小鼠模型中，IL-1α和IL-1β均显示出诱导心肌炎和动脉瘤形成; IL-1阻断治疗（如阿那白滞素）均成功改善了这两种情况。高危三磷酸肌醇3-激酶C基因型患者治疗失败与最高的基础和刺激细胞内钙水平、IL-1β和IL-18的细胞产生增加以及两种细胞因子的循环水平升高相关。目前在西欧和美国正在进行三项招募KD患者的IL-1阻断剂临床试验，它们可能会改变KD的结局。
Kawasaki disease (KD) is an acute inflammatory vasculitis occurring in young children before 5 years and representing at this age, the main cause of acquired heart disease. A single infusion of 2 g/kg of intravenous immunoglobulins along with aspirin has reduced the frequency of coronary artery aneurysms from 25 to 5%. However, 10–20% of patients do not respond to standard treatment and have an increased risk of cardiac complications and death. The development of more potent therapeutic approaches of KD is an urgent need. Phenotypical and immunological similarities between KD and systemic juvenile idiopathic arthritis led to the hypothesis that KD could be considered as an autoinflammatory disease. New insights regarding KD’s pathogenesis have merged from the combination of genetic and transcriptomic data revealing the key role of interleukin-1 (IL-1) signaling in the pathogenesis of the vasculitis. Once activated, IL-1α and IL-1β trigger a local proinflammatory environment-inducing vasodilatation and attracting monocytes and neutrophils to sites causing tissue damage and stress. Both IL-1α and IL-1β have been shown to induce myocarditis and aneurysm formation in Lactobacillus casei cell-wall extract mouse model of KD; both being successfully improved with IL-1 blockade treatment such as anakinra. Treatment failure in patients with the high-risk inositol-triphosphate 3-kinase C genotype was associated with highest basal and stimulated intracellular calcium levels, increased cellular production of IL-1β, and IL-18, and higher circulating levels of both cytokines. Three clinical trials of IL-1 blockade enrolling KD patients are currently being conducted in Western Europe and in USA, they could change KD outcome.