Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
Am J Pathol. 2011 Jul;179(1):104-15. doi: 10.1016/j.ajpath.2011.03.032. Epub 2011 May 14.
IL-33 and its soluble receptor and cell-associated receptor (ST2L) are all increased in clinical and experimental asthma. The present study addressed the hypothesis that ST2L impairs the therapeutic effects of CpG in a fungal model of asthma. C57BL/6 mice were sensitized to Aspergillus fumigatus and challenged via i.t. instillation with live A. fumigatus conidia. Mice were treated with IgG alone, anti-ST2L monoclonal antibody (mAb) alone, CpG alone, IgG plus CpG, or anti-ST2L mAb plus CpG every other day from day 14 to day 28 and investigated on day 28 after conidia. Lung ST2L and toll-like receptor 9 protein expression levels concomitantly increased in a time-dependent manner during fungal asthma. Therapeutic blockade of ST2L with an mAb attenuated key pathological features of this model. At subtherapeutic doses, neither anti-ST2L mAb nor CpG alone affected fungal asthma severity. However, airway hyperresponsiveness, mucus cell metaplasia, peribronchial fibrosis, and fungus retention were markedly reduced in asthmatic mice treated with the combination of both. Whole lung CXCL9 levels were significantly elevated in the combination group but not in the controls. Furthermore, in asthmatic mice treated with the combination therapy, dendritic cells generated significantly greater IL-12p70 with CpG in vitro compared with control dendritic cells. The combination of anti-ST2L mAb with CpG significantly attenuated experimental asthma, suggesting that targeting ST2L might enhance the therapeutic efficacy of CpG during allergic inflammation.
IL-33 及其可溶性受体和细胞相关受体（ST2L）在临床和实验性哮喘中均增加。本研究旨在验证 ST2L 是否会损害 CpG 在真菌性哮喘模型中的治疗效果这一假设。C57BL/6 小鼠用烟曲霉致敏，并通过 i.t. 滴注活烟曲霉孢子进行攻击。小鼠从第 14 天到第 28 天每隔一天接受 IgG 单独、抗 ST2L 单克隆抗体（mAb）单独、CpG 单独、IgG 加 CpG 或抗 ST2L mAb 加 CpG 治疗，并在孢子接种后第 28 天进行研究。在真菌性哮喘中，肺 ST2L 和 Toll 样受体 9 蛋白表达水平随时间呈时间依赖性增加。用 mAb 阻断 ST2L 可减轻该模型的关键病理特征。在亚治疗剂量下，抗 ST2L mAb 或 CpG 单独使用均不会影响真菌性哮喘的严重程度。然而，在联合使用两种药物的哮喘小鼠中，气道高反应性、粘液细胞化生、支气管周围纤维化和真菌保留明显减少。组合组的整个肺 CXCL9 水平显著升高，但对照组没有。此外，在联合治疗的哮喘小鼠中，与对照树突状细胞相比，CpG 体外产生的树突状细胞产生的 IL-12p70 明显增加。抗 ST2L mAb 与 CpG 的联合使用显著减轻了实验性哮喘，表明靶向 ST2L 可能增强 CpG 在过敏炎症期间的治疗效果。
