Hyperexpression of inducible costimulator and its contribution on lamina propria T cells in inflammatory bowel disease
Hyperexpression of inducible costimulator and its contribution on lamina propria T cells in inflammatory bowel disease
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DOI：
10.1053/j.gastro.2003.12.011
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发表时间：
2004-03-01
期刊：
影响因子：
29.4
通讯作者：
Hibi, T
中科院分区：
文献类型：
--
作者：
Sato, T;Kanai, T;Hibi, T
背景与目的：为了研究CD28家族的新成员ICOS在t细胞活化和慢性肠道炎症调控中的作用，我们评估了ICOS在炎症性肠病患者中的表达和功能作用（11313）。方法：采用流式细胞术和免疫组织化学检测溃疡性结肠炎（UC）、克罗恩病（CID）和正常人肠固有层单核细胞（LPMC）中ICOS、CD28和细胞毒性t淋巴细胞抗原（CTLA） 4的表达。用流式细胞术检测ICOS配体B7h在肠黏膜固有层B细胞、巨噬细胞和上皮细胞（EC）上的表达。通过增殖反应和细胞因子的产生来评估ICOS对LPMC的功能性共刺激作用。结果：11313例患者炎症黏膜中表达ICOS的CD4(+) LPMC显著升高，而在炎症对照组和正常对照组中无明显升高。IBD患者炎症黏膜的B细胞、巨噬细胞和EC中B7h的表达也显著上调。与单独使用抗cd3单克隆抗体（mAb）相比，抗cd3 /ICOS共刺激的增殖反应显著提高。三组间UC抗cw / icos刺激lpmc分泌的白细胞介素(IL)-5显著增加。相反，在IL-12存在的情况下，cd3 / icos刺激的CD - lpmc分泌的干扰素(IFN)- γ显著增加。结论：激活后高表达的ICOS。11313例患者CD4+ LPMC参与IBD免疫反应失调。由于ICOS高表达仅限于IBD患者的炎症部位，ICOS将成为治疗IBD的可行治疗靶点。
Background &Aims: To investigate the role of inducible costimulator (ICOS), a new member of the CD28 family involved in regulation of T-cell activation and chronic intestinal inflammation, we assessed its expression and functional role in patients with inflammatory bowel disease (11313). Methods: Expression of ICOS, CD28, and cytotoxic T-lymphocyte antigen (CTLA) 4 on intestinal lamina propria mononuclear cells (LPMC) from patients with ulcerative colitis (UC), Crohn's disease (CID), and normal controls was determined using flow cytometry and immunohistochemistry. Expressions of the ICOS ligand, B7h, on lamina propria B cells, macrophages, and epithelial cells (EC) in the intestinal mucosa were also determined using flow cytometry. The functional costimulatory effect of ICOS on LPMC was assessed by the proliferative response and cytokine production. Results: CD4(+) LPMC expressing ICOS was significantly increased in the inflamed mucosa of 11313 patients but not in inflammatory or normal controls. B7h was also significantly up-regulated on B cells, macrophages, and EC in inflamed mucosa of IBD patients. Proliferative responses of anti-CD3/ICOS costimulation were significantly higher compared with those of anti-CD3 monoclonal antibody (mAb) alone. Anti-CW/ICOS-stimulated-LPMC from UC secreted significantly increased amounts of interleukin (IL)-5 among the 3 groups. In contrast, anti-CD3/ICOS-stimulated-LPMC from CD secreted significantly increased amounts of interferon (IFN)-gamma in the presence of IL-12. Conclusions: Highly expressed ICOS in activated. CD4+ LPMC of 11313 patients contributes to the dysregulated immune responses in IBD. Because ICOS hyperexpression was limited to inflammatory sites in IBD patients, ICOS would be a feasible therapeutic target for the treatment of IBD.