Analysis of Pathogen Associated Molecular Pattern(PAMP) in the vascular endothelial cell during acute Kawasaki Disease

急性川崎病血管内皮细胞病原体相关分子模式（PAMP）分析

• 批准号: 20790721
• 负责人: HIRONO Keiichi
• 金额: $ 2.66万
• 依托单位: University of Toyama
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20790721/
• 关键词: 川崎病; 冠動脈病変(CAL); 免疫グロブリン大量療法(IVIG); Pathogen Associated Molecular Pattern(PAMP); インフリキシマブ; 血管炎; サイトカイン

Background: Kawasaki disease (KD) is the most common systemic vasculitis syndrome primarily affecting small and medium-sized arteries, particularly the coronary artery. Although treatment with high-dose intravenous immune globulin (IVIG) is now accepted as reducing the incidence of coronary artery lesions (CAL), approximately 15% of the patients do not respond to IVIG treatment. During acute phase of KD, serum levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-α are elevated. Infliximab is a chimeric murin/human IgG1 monoclonal antibody that binds specifically to human TNF-α-1, and which is administered intravenously, is effective in a broad spectrum of immunologic disorders in which inflammation is mediated by TNF-α. Recent studies reported that patients with KD who did not to IVIG, methylprednisolone pulse therapy (IVMP), and were successfully treated with infliximab.Objective: The aim of our study was to evaluate the efficacy of infliximab for the treatment of p … More atients with refractory Kawasaki disease (KD) and investigate the dynamic changes of cytokines during infliximab treatment.Methods: We have performed a study of cytokine and pro-inflammatory molecule levels in 43 KD patients including 18 responders to IVIG, 14 non-responders, and 11 patients treated with infliximab. We determined serum levels of soluble TNF receptor I(sTNFR I) and IL-6, as well as VEGF, damage associated molecular pattern(DAMP) molecules; myeloid-related protein(MRP)8/MRP14 and S100A12 sequentially.Results: In 8 patients fever subsided immediately upon infliximab treatment. Four patients, who started infliximab after 12 days of illness, developed coronary artery lesions. Each of the cytokines was elevated before infliximab treatment in all patients. Although serum levels of pro-inflammatory cytokines decreased dramatically after infliximab treatment, DAMP molecules and VEGF and markers of local tissue damage were not suppressed. In contrast, in IVIG responders all cytokines decreased markedly after IVIG treatment.Conclusions: We show that infliximab is one of the adoptive therapies in refractory KD patients. Different behaviors of pro-inflammatory cytokines and DAMP molecules and VEGF after infliximab treatment suggest that infliximab is effective for suppression of cytokine-mediated inflammation, but could not completely block local vasculitis. Less

背景资料：川崎（KD）是最常见的系统性血管炎综合征，主要累及中小动脉，尤其是冠状动脉。尽管现在接受大剂量静脉注射免疫球蛋白（IVIG）治疗可降低冠状动脉病变（CAL）的发生率，但约15%的患者对IVIG治疗无反应。在KD急性期，促炎细胞因子如肿瘤坏死因子（TNF）-α的血清水平升高。英夫利西单抗是一种嵌合鼠/人IgG 1单克隆抗体，可特异性结合人TNF-α-1，经静脉给药，可有效治疗TNF-α介导炎症的广谱免疫性疾病。最近的研究报道，未接受IVIG、甲基强的松龙冲击治疗（IVMP）的KD患者，经英夫利昔单抗治疗后，疗效显著。目的：评价英夫利昔单抗治疗KD的疗效。 ...更多信息 方法：对43例难治性川崎病（KD）患者（其中IVIG有效18例，无效14例，英夫利昔单抗治疗11例）进行细胞因子和促炎分子水平的动态观察。结果：8例患者经英夫利西单抗治疗后，发热立即消退，其中8例患者经治疗后发热症状消失，其余患者经治疗后发热症状消失。4名患者在患病12天后开始英夫利西单抗治疗，发生冠状动脉病变。在所有患者中，每种细胞因子在英夫利西单抗治疗前均升高。虽然血清促炎细胞因子水平显着下降后，英夫利西单抗治疗，DAMP分子和VEGF和局部组织损伤的标志物没有受到抑制。与此相反，在IVIG应答者中，所有细胞因子在IVIG treatment.Conclusions后显著降低：我们表明英夫利西单抗是难治性KD患者的过继疗法之一。英夫利西单抗治疗后促炎细胞因子和DAMP分子以及VEGF的不同行为表明英夫利西单抗可有效抑制马尿苷介导的炎症，但不能完全阻断局部血管炎。少

项目成果

Cyclosporin improves coronary artery lesions and inflammation via down regulation of calcineurin-NFAT signaling in refractory Kawasaki disease

环孢素通过下调钙调神经磷酸酶-NFAT 信号传导改善难治性川崎病的冠状动脉损伤和炎症

• 发表时间: 2010
• 作者: 廣野恵一;他
• 通讯作者: 他

The efficacy of infliximab treatment and dynamic changes of inflammatory cytokines in patients with refractory Kawasaki disease.

英夫利昔单抗治疗难治性川崎病患者的疗效及炎性细胞因子的动态变化

• 发表时间: 2009
• 期刊: Peditaric Res 65
• 作者: Hirono K;Saito K;Ichida F;Saji T;et. al.
• 通讯作者: et. al.

Parvoviral Genomes are not present in endothelial cells of Kawasaki disease patients who develop coronary artery lesions.

发生冠状动脉病变的川崎病患者的内皮细胞中不存在细小病毒基因组。

• 发表时间: 2009
• 期刊: Pediatr Infect Dis J 28
• 作者: Neil E.B.;Hirono K.;et al.
• 通讯作者: et al.

シクロスポリンAを投与した難治性川崎病3症例におけるサイトカインの検討

环孢素A治疗难治性川崎病三例细胞因子检测

• 发表时间: 2009
• 作者: 斎藤和由;廣野恵一;伊吹圭二郎;小澤綾佳;渡辺一洋;上勢敬一郎;市田蕗子;宮脇利男
• 通讯作者: 宮脇利男

Reverse Kinetics of Circulating Soluble Receptor for Advanced Glycation End Products (sRAGE) and its Ligand S100A12 in Acute Kawasaki Disease.

急性川崎病中晚期糖基化终产物循环可溶性受体 (sRAGE) 及其配体 S100A12 的反向动力学。

• 发表时间: 2008
• 作者: Keiichi Hirono;Helmut Wittkowski;Thomas Vogl;Keijirou Ibuki;Kazuyoshi Saito;Keiichiro Uese;Fukiko Ichida;Toshio Miyawaki
• 通讯作者: Toshio Miyawaki