B7RP-1 is not required for the generation of Th2 responses in a model of allergic airway inflammation but is essential for the induction of inhalation tolerance
B7RP-1 is not required for the generation of Th2 responses in a model of allergic airway inflammation but is essential for the induction of inhalation tolerance
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DOI：
10.4049/jimmunol.174.5.3000
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发表时间：
2005-03-01
影响因子：
4.4
通讯作者：
Jordana, M
中科院分区：
文献类型：
--
作者：
Gajewska, BU;Tafuri, A;Jordana, M
最近描述的 ICOS-B7RP-1 共刺激途径与效应 Th2 反应的产生有关，因此已成为过敏性疾病的有吸引力的治疗靶点。在本研究中，我们使用 B7RP-1 缺陷小鼠来研究 B7RP-1 在粘膜过敏性气道炎症模型中 Th2 反应的产生和维持中的作用。我们发现，在 GM-CSF 背景下，将 B7RP-1 敲除小鼠暴露于雾化 OVA 会导致气道嗜酸性粒细胞炎症。这种反应是持久的，因为用相同的抗原再次攻击小鼠会重现气道嗜酸性粒细胞增多。此外，T 细胞上 T1/ST2 的显着表达以及 Th2 相关细胞因子（IL-5、IL-4 和 IL-13）和 Igs（IgE 和 IgG1）的产生最终证明了在不存在 B7RP-1 的情况下产生了 Th2 应答。此外，两种主要的 Th2 相关共刺激分子 CD28 和 ICOS 的表达表明在 B7RP-1 信号传导缺失的情况下 T 细胞被激活。最后，B7RP-1 敲除小鼠对吸入耐受的诱导具有抵抗力，如肺部持续嗜酸性粒细胞增多和 IL-5 产生所示。总之，我们的结果表明，在粘膜过敏致敏模型中，ICOS-B7RP-1 途径对于 Th2 反应的产生是多余的，但对于诱导吸入耐受性至关重要。
The recently described ICOS-B7RP-1 costimulatory pathway has been implicated in the generation of effector Th2 responses and, hence, has become an attractive therapeutic target for allergic diseases. In the present study, we used B7RP-1-deficient mice to investigate the role of B7RP-1 in the generation and maintenance of Th2 responses in a model of mucosal allergic airway inflammation. We found that exposure of B7RP-1 knockout mice to aerosolized OVA in the context of GM-CSF leads to airway eosinophilic inflammation. This response was long lasting because rechallenge of mice with the same Ag recapitulated airway eosinophilia. Moreover, significant expression of T1/ST2 on T cells and production of Th2-affiliated cytokines (IL-5, IL-4, and IL-13) and Igs (IgE and IgG1) conclusively demonstrate the generation of a Th2 response in the absence of B7RP-1. In addition, expression of two major Th2-associated costimulatory molecules-CD28 and ICOS-indicates T cell activation in the absence of B7RP-1 signaling. Finally, B7RP-1 knockout mice are resistant to the induction of inhalation tolerance as indicated by the sustained eosinophilia in the lung and IL-5 production. In summary, our results demonstrate that in a model of mucosal allergic sensitization, the ICOS-B7RP-1 pathway is redundant for the generation of Th2 responses but essential for the induction of inhalation tolerance.