Role of Immune co-signals in the pathogenesis and development of new treatment of refractory uveoretinitis

免疫协同信号在难治性葡萄膜视网膜炎发病机制和新疗法开发中的作用

• 批准号: 21791715
• 负责人: USUI Yoshihiko
• 金额: $ 2.75万
• 依托单位: Tokyo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21791715/
• 关键词: ぶどう膜網膜炎; 補助シグナル分子; CD4T細胞; Th1反応; Th17反応; 眼ベーチェット; ICOS; サイトカイン; CD4陽性T細胞; 眼ベーチェット病

Endogenous uveitis such as Behcet's disease (BD) is a potentially blinding disease in humans and is responsible for 10-15% of the acquired blindness in Japan. Although endogenous uveitis covers a spectrum of clinical entities, all forms are believed to share immunohistological similarities characterized by the infiltration of mainly CD4 T cells. It is well known that CD4 T cell activation requires the integration of at least two distinct signals. Signal one results from antigen-specific T cell receptor engagement by MHC class 2-bound peptide presented by antigen presenting cells (APC). Signal two results from engagement of costimulatory molecules expressed by APC and T cell. The CD28 homolog inducible costimulator (ICOS) has recently been identified as a novel member of the CD28 costimulator family, and is expressed by activated T cells in both humans and mice. The ICOS ligand, B7-related protein (B7RP-1), also known as B7 homologous protein (B7h), is constitutively expressed by APC. As the result of microarray analysis, ICOS in PBMCs showed the greatest difference in expression in BD patients with uveitis compared to healthy controls. ICOS expression on CD4 T cells in BD patients with uveitis was significantly higher than that in healthy individuals both before and after Con A stimulation. Among BD patients, ICOS expression on CD4 T cells was significantly higher in those with active uveitis than in those with remitted uveitis. Blockade of ICOS/B7-related protein-1 interaction by anti-ICOS mAb significantly decreased IFN-γ and IL-17 production by PBMCs when stimulated with Con A or IRBP in BD with active uveitis. In conclusion, our data provide additional evidence for the potential utility of ICOS expression on CD4 T cells as a marker to determine disease activity and that ICOS represents a promising therapeutic target for ocular BD by inhibiting Th1 and Th17 cytokines.

内源性葡萄膜炎如白塞氏病（BD）是一种潜在的致盲疾病，在日本占获得性失明的10-15%。虽然内源性葡萄膜炎涵盖了一系列临床实体，但所有形式的葡萄膜炎被认为具有免疫组织学上的相似性，其特征主要是CD4 T细胞的浸润。众所周知，CD4 T细胞激活需要整合至少两种不同的信号。信号一来自抗原呈递细胞（APC）呈递的MHC 2类结合肽与抗原特异性T细胞受体的结合。信号二是APC和T细胞表达的共刺激分子相互作用的结果。CD28同源诱导共刺激因子（ICOS）最近被确定为CD28共刺激因子家族的新成员，并在人和小鼠的活化T细胞中表达。ICOS配体B7相关蛋白（B7RP-1），又称B7同源蛋白（B7h），由APC组成性表达。微阵列分析结果显示，与健康对照组相比，伴有葡萄膜炎的BD患者中PBMCs中ICOS的表达差异最大。在Con A刺激前后，伴有葡萄膜炎的BD患者CD4 T细胞上的ICOS表达均显著高于健康人。在BD患者中，活动性葡萄膜炎患者CD4 T细胞上的ICOS表达明显高于缓解性葡萄膜炎患者。通过抗ICOS单抗阻断ICOS/ b7相关蛋白-1相互作用，可显著降低在伴有活动性葡萄膜炎的BD中，受Con A或IRBP刺激的PBMCs产生的IFN-γ和IL-17。总之，我们的数据为ICOS在CD4 T细胞上的表达作为确定疾病活动性的标志物的潜在应用提供了额外的证据，并且ICOS通过抑制Th1和Th17细胞因子代表了一个有希望的眼部BD治疗靶点。

项目成果

色素性眼内腫瘍の良悪性鑑別を目的とした液性因子測定の意義

体液因子测定对区分良恶性眼内色素瘤的意义

• 发表时间: 2010
• 作者: 臼井嘉彦;他
• 通讯作者: 他

Arch of corneal opacity.

角膜拱形混浊。

• 期刊: Arch Ophthalmol in press
• 作者: Miyake T;Usui Y;Goto H.
• 通讯作者: Goto H.

感染性ぶどう膜炎診療における最近のトピックと問題点

感染性葡萄膜炎治疗的最新主题和问题

• 发表时间: 2010
• 作者: Ikeda K;Nakano R;Uraoka M;Nakagawa Y;Koide M;Katsume A;Minamino K;Yamada E;Yamada H;Quertermous T;Matsubara H;臼井嘉彦
• 通讯作者: 臼井嘉彦

眼免疫疾患における補助シグナル分子の免疫制御

眼部免疫疾病中辅助信号分子的免疫调节

• 发表时间: 2010
• 作者: Levinson RD;Okada AA;Ashouri E;Keino H;Rajalingam R.;臼井嘉彦
• 通讯作者: 臼井嘉彦

Increased levels of 8-hydroxydeoxyguanosine in the vitreous of patients with diabetic retinopathy.

糖尿病视网膜病变患者玻璃体中 8-羟基脱氧鸟苷水平升高。

• 发表时间: 2010
• 期刊: Diabetes Res Clin Pract 89
• 作者: Usui Y;Wakabayashi Y;et al.
• 通讯作者: et al.