The role of the ICOS/B7RP‐1 T cell costimulatory pathway in murine experimental autoimmune uveoretinitis
The role of the ICOS/B7RP‐1 T cell costimulatory pathway in murine experimental autoimmune uveoretinitis
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DOI：
10.1002/eji.200636138
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发表时间：
2006-11
影响因子：
5.4
通讯作者：
Y. Usui;H. Akiba;M. Takeuchi;T. Kezuka;A. Takeuchi;T. Hattori;Y. Okunuki;Tomohide Yamazaki;H. Yagita;M. Usui;K. Okumura
中科院分区：
文献类型：
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作者：
Y. Usui;H. Akiba;M. Takeuchi;T. Kezuka;A. Takeuchi;T. Hattori;Y. Okunuki;Tomohide Yamazaki;H. Yagita;M. Usui;K. Okumura
ICOS/B7 RP-1是CD 28/B7共刺激分子家族的新成员，在自身免疫性疾病中发挥不同的作用。在这项研究中，我们研究了ICOS/B7 RP-1通路在小鼠实验性自身免疫性葡萄膜视网膜炎（EAU）发病机制中的作用，EAU是人类自身免疫性葡萄膜炎的动物模型。在EAU诱导的小鼠中，在视网膜区域的浸润性CD 4 + T细胞上发现ICOS表达。抗B7 RP-1单克隆抗体（mAb）治疗或ICOS缺陷小鼠显示疾病评分大幅降低。在效应期阻断ICOS/B7 RP-1相互作用可改善疾病，而在诱导期阻断ICOS/B7 RP-1相互作用则无显著效果。此外，施用抗B7 RP-1 mAb有效地改善了由致病性T细胞的过继转移诱导的疾病。抗B7 RP-1 mAb处理抑制致病性T细胞的扩增和/或效应子功能，因为在体外用抗原肽再刺激后，淋巴结细胞的增殖反应和IFN-γ产生减少。这些结果表明，ICOS/B7 RP-1相互作用在葡萄膜炎的发病机制中起着关键作用。我们还表明，ICOS介导的共刺激在EAU和实验性自身免疫性脑脊髓炎中发挥不同的作用，实验性自身免疫性脑脊髓炎也是一种以与EAU相同的方式诱导的Th 1疾病。
ICOS/B7RP‐1 is a new member of the CD28/B7 family of costimulatory molecules and plays differential roles in autoimmune diseases. In this study, we examined the role of ICOS/B7RP‐1 pathway in the pathogenesis of mouse experimental autoimmune uveoretinitis (EAU), an animal model of human autoimmune uveitis. ICOS expression was found on infiltrating CD4+ T cells in the region of the retina in EAU‐induced mice. The anti‐B7RP‐1 monoclonal antibody (mAb)‐treated or ICOS‐deficient mice showed a substantial reduction of disease scores. Blockade of ICOS/B7RP‐1 interaction during the effector phase ameliorated the disease, whereas its blockade during the induction phase exhibited no significant effect. Moreover, administration of anti‐B7RP‐1 mAb effectively ameliorated the disease induced by adoptive transfer of pathogenic T cells. The anti‐B7RP‐1 mAb treatment inhibited the expansion and/or effector function of pathogenic T cells, given that proliferative response and IFN‐γ production by lymph node cells were reduced upon restimulation with the antigen peptide in vitro. These results suggest that the ICOS/B7RP‐1 interaction plays a critical role in the pathogenesis of uveitis. We also indicated that ICOS‐mediated costimulation plays differential roles in EAU and experimental autoimmune encephalomyelitis, which is also a Th1 disease induced in the same manner as EAU.