Investigation and therapeutic application of ICOS and ICOSL in systemic sclerosis

ICOS和ICOSL在系统性硬化症中的研究和治疗应用

• 批准号: 21591456
• 负责人: HASEGAWA Minoru
• 金额: $ 2.91万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21591456/
• 关键词: 強皮症; 線維化; ICOS; ICOSL; ブレオマイシン; 皮膚; 肺; サイトカイン; ICOS ligand; マウス

We assessed the roles of ICOS and ICOSL in tissue fibrosis by administering bleomycin intratracheally or intradermally into ICOS and/or ICOSL-deficient mice. The loss of ICOS attenuated fibrosis of lungs and skin, whereas deficiency of ICOSL aggravated it. Mice deficient in both ICOS and ICOSL also exhibited accelerated fibrosis, reflecting a dominant role for ICOSL over ICOS in this model. ICOSL expression on macrophages and B cells in bronchoalveolar fluids was significantly elevated in ICOS-deficient mice compared to wild type mice during this process. Thus, ICOSL expression levels on B cells and macrophages were inversely associated with the severity of tissue fibrosis. Our results indicate that ICOSL expression on antigen presenting cells plays a previously unknown regulatory role during the development of bleomycin-induced tissue fibrosis which is independent of the ICOS-ICOSL pathway.

我们通过给ICOS和/或ICOSL缺陷小鼠气管内或皮内注射博莱霉素来评估ICOS和ICOSL在组织纤维化中的作用。ICOS的缺失减轻了肺和皮肤的纤维化，而ICOSL的缺失则加重了肺和皮肤的纤维化。同时缺乏ICOS和ICOSL的小鼠也表现出加速的纤维化，反映了ICOSL在该模型中的主导作用。在此过程中，ICOS缺陷小鼠的巨噬细胞和支气管肺泡液中B细胞的ICOSL表达显著高于野生型小鼠。因此，B细胞和巨噬细胞上ICOSL的表达水平与组织纤维化的严重程度呈负相关。我们的结果表明，在博莱霉素诱导的组织纤维化过程中，抗原提呈细胞上ICOSL的表达起着先前未知的调节作用，这种作用不依赖于ICOS-ICOSL通路。

项目成果

Augmented ICOS-ICOS ligand signaling axis in patients with early diffuse cutaneous systemic sclerosis

早期弥漫性皮肤系统性硬化症患者增强的 ICOS-ICOS 配体信号轴

• 发表时间: 2011
• 作者: Hasegawa M;Matsushita T;Hamaguchi Y;Fujimoto M;Takehara K
• 通讯作者: Takehara K

Serum chemokine and cytokine levels as indicators of disease activity in patients with systemic sclerosis

• DOI: 10.1007/s10067-010-1610-4
• 发表时间: 2011-02-01
• 期刊: CLINICAL RHEUMATOLOGY
• 影响因子: 3.4
• 作者: Hasegawa, Minoru;Fujimoto, Manabu;Sato, Shinichi
• 通讯作者: Sato, Shinichi

Dermoscopy findings of nail fold capillaries in connective tissue diseases

• DOI: 10.1111/j.1346-8138.2010.01092.x
• 发表时间: 2011-01-01
• 期刊: JOURNAL OF DERMATOLOGY
• 影响因子: 3.1
• 作者: Hasegawa, Minoru

A Novel Inhibitor of Smad-Dependent Transcriptional Activation Suppresses Tissue Fibrosis in Mouse Models of Systemic Sclerosis

• DOI: 10.1002/art.24934
• 发表时间: 2009-11-01
• 期刊: ARTHRITIS AND RHEUMATISM
• 作者: Hasegawa, Minoru;Matsushita, Yukiyo;Sato, Shinichi
• 通讯作者: Sato, Shinichi

Reduced red blood cell velocity in nail-fold capillaries as a sensitive and specific indicator of microcirculation injury in systemic sclerosis

• DOI: 10.1093/rheumatology/kep066
• 发表时间: 2009-06-01
• 期刊: RHEUMATOLOGY
• 影响因子: 5.5
• 作者: Mugii, Naoki;Hasegawa, Minoru;Takehara, Kazuhiko
• 通讯作者: Takehara, Kazuhiko