Gajewska Beata U, Tafuri Anna, Swirski Filip K, Walker Tina, Johnson Jill R, Shea Theresa, Shahinian Arda, Goncharova Susanna, Mak Tak W, Stämpfli Martin R, Jordana Manel
Department of Pathology and Molecular Medicine, and Division of Respiratory Diseases and Allergy, Centre For Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
J Immunol. 2005 Mar 1;174(5):3000-5. doi: 10.4049/jimmunol.174.5.3000.
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.
最近描述的ICOS-B7RP-1共刺激途径与效应性Th2反应的产生有关，因此已成为过敏性疾病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在黏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存在的情况下，将B7RP-1基因敲除小鼠暴露于雾化的OVA会导致气道嗜酸性粒细胞炎症。这种反应持续时间长，因为用相同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的显著表达以及Th2相关细胞因子（IL-5、IL-4和IL-13）和免疫球蛋白（IgE和IgG1）的产生确凿地证明了在没有B7RP-1的情况下Th2反应的产生。此外，两种主要的Th2相关共刺激分子CD28和ICOS的表达表明在没有B7RP-1信号的情况下T细胞被激活。最后，如肺部持续的嗜酸性粒细胞增多和IL-5产生所示，B7RP-1基因敲除小鼠对吸入耐受的诱导具有抗性。总之，我们的结果表明，在黏膜过敏性致敏模型中，ICOS-B7RP-1途径对于Th2反应的产生是多余的，但对于吸入耐受的诱导是必不可少的。
