Establishment of the anti-IL-6 receptor therapy for refractory autoimmune diseases

难治性自身免疫性疾病抗IL-6受体疗法的建立

• 批准号: 17390290
• 负责人: NISHIMOTO Norihiro
• 金额: $ 9.92万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390290/
• 关键词: signal transduction; DNA microarray; immunology; drug efficacy; DNAマイクロアレイ; IL-6阻害治療; インターフェロンα; defellsin-α; インターフェロン; defensin-α

We have confirmed the efficacy of an anti-Interleukin-6 (IL-6) receptor antibody, tocilizumab, for rheumatoid arthritis (RA) and systemic-onset juvenile idiopathic arthritis (soJIA). IL-6 blockade increased serum androgen which has anti-inflammatory effect for RA. IL-6 blockade also retarded the progression of joint damage and the long-term efficacy was predicted by the decrease in the serum MMP-3, CRP and PIIANP in the first 3 months after the start of tocilizumab. In the patients with soJIA, an exhaustive DNA microarray analysis of mRNA expression revealed 24 molecules differentially expressed compared to healthy donors. Those included the molecules related to innate immunity, signal transduction and cell growth. Gene Ontology and Network, Pathway analysis also revealed the stimulation of IFN-γ, TNF cascades in both soJIA and polyarticular JIA. ATP synthesis related genes were down-regulated only in soJIA. These molecules might play a pathological role in soJIA. We are now studying a pathological role in relation to IL-6. In systemic lupus erythematosus (SLE), DNA microarray analysis identified 24 molecules which include 9 IFN-α-inducible genes and defensin-α3. We have also established new receptor inhibitor of IL-6 (NRI) which is feasible to gene therapy.We have identified several candidate molecules which play pathological roles in these autoimmune diseases. The in vivo functions of them are being studied.

我们已经证实了抗白细胞介素-6 （IL-6）受体抗体tocilizumab治疗类风湿性关节炎（RA）和系统性发作的青少年特发性关节炎（soJIA）的疗效。IL-6阻断可提高血清雄激素水平，对RA有抗炎作用。IL-6阻断也延缓了关节损伤的进展，并且在托珠单抗开始后的前3个月，通过血清MMP-3、CRP和PIIANP的降低可以预测长期疗效。在soJIA患者中，对mRNA表达的详尽DNA微阵列分析显示，与健康供者相比，有24个分子的表达存在差异。其中包括与先天免疫、信号转导和细胞生长有关的分子。基因本体和网络、通路分析也揭示了IFN-γ、TNF在soJIA和多关节JIA中的级联刺激。ATP合成相关基因仅在soJIA中下调。这些分子可能在soJIA中起病理作用。我们现在正在研究与IL-6相关的病理作用。在系统性红斑狼疮（SLE）中，DNA微阵列分析鉴定出24个分子，其中包括9个IFN-α-诱导基因和防御素-α3。我们还建立了新的可用于基因治疗的IL-6受体抑制剂（NRI）。我们已经确定了几个候选分子在这些自身免疫性疾病中起病理作用。它们的体内功能正在研究中。

项目成果

Imaging of lesions in a murine rheumatoid arthritis model with a humanized anti-interleukin-6 receptor antibody.

使用人源化抗白细胞介素 6 受体抗体对小鼠类风湿性关节炎模型中的病变进行成像。

• 发表时间: 2005
• 期刊: Ann Nucl Med 19
• 作者: Sugimoto K;Nishimoto N;Yoshizaki K;Nishimura T 他1名.
• 通讯作者: Nishimura T 他1名.

Serum protein in systemic-onset juvenile idiopathic arthritis differentiates response versus nonresponse to therapy. : 2005

全身性幼年特发性关节炎中的血清蛋白可区分对治疗的反应与无反应。

• 发表时间: 2005
• 期刊: Arthritis Res. & Therapy 7
• 作者: Miyamae T;Malehorn DE;Lemster B;et al.
• 通讯作者: et al.

Clinical study in patients with Castleman's desease, Crohn's disease and rheumatoid arthritis in Japan.

日本卡斯尔曼病、克罗恩病和类风湿性关节炎患者的临床研究。

• 发表时间: 2005
• 期刊: Clin. Rev. in Allegy and Immunol. 28
• 作者: Adachi Y;Aoki C;Yoshio-Hoshino N;Takayama K;Curiel DT;Nishimoto N.;Nishimoto N.
• 通讯作者: Nishimoto N.

Effect of anti-mouse interleukin-6 receptor antibody in autoimmune mouse models. In Monoclonal Antibodies Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman's disease.

抗小鼠白介素 6 受体抗体在自身免疫小鼠模型中的作用。

• 发表时间: 2005
• 期刊: New Research(Edited by Simmons MA)(Nova Science Publishers, Inc.)
• 作者: Mihara M;Nishimoto N;Ohsugi Y
• 通讯作者: Ohsugi Y

Therapeutic efficacy of humanized recombinant anti-IL 6-receptor antibody for children with systemic-onset juvenile idiopathic arthritis.

人源化重组抗IL 6受体抗体对全身性幼年特发性关节炎儿童的治疗效果。

• 发表时间: 2005
• 期刊: Arthritis Rheum. 52
• 作者: Yokota S;et al.
• 通讯作者: et al.