Targeting ST2L potentiates CpG-mediated therapeutic effects in a chronic fungal asthma model.
Targeting ST2L potentiates CpG-mediated therapeutic effects in a chronic fungal asthma model.
复制标题
DOI：
10.1016/j.ajpath.2011.03.032
复制
发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
Hemanth Ramaprakash;T. Shibata;K. Duffy;U. Ismailoglu;Rachel M Bredernitz;A. Moreira;A. Coelho;Anuk M. Das;Natalie Fursov;G. Chupp;C. Hogaboam
中科院分区：
文献类型：
--
作者：
Hemanth Ramaprakash;T. Shibata;K. Duffy;U. Ismailoglu;Rachel M Bredernitz;A. Moreira;A. Coelho;Anuk M. Das;Natalie Fursov;G. Chupp;C. Hogaboam
IL-33及其可溶性受体和细胞相关受体（ST 2L）在临床和实验性哮喘中均升高。本研究提出了ST 2L在哮喘真菌模型中损害CpG治疗效果的假设。C57 BL/6小鼠对烟曲霉菌致敏，经i.t.用liveA滴注。烟曲霉孢子从第14天至第28天，每隔一天用单独的IgG、单独的抗ST 2L单克隆抗体（mAb）、单独的CpG、IgG加CpG或抗ST 2L mAb加CpG处理小鼠，并在分生孢子后第28天进行研究。在真菌性哮喘期间，肺ST 2L和Toll样受体9蛋白表达水平以时间依赖性方式伴随增加。用mAb治疗性阻断ST 2L减弱了该模型的关键病理学特征。在亚治疗剂量下，单独使用抗ST 2L mAb或CpG均不影响真菌性哮喘的严重程度。然而，哮喘小鼠的气道高反应性、粘液细胞化生、支气管周围纤维化和真菌潴留在两种药物联合治疗后均显著降低。全肺CXCL 9水平在组合组中显著升高，但在对照组中没有。此外，与对照树突状细胞相比，在联合治疗的哮喘小鼠中，树突状细胞与CpG体外产生显著更高的IL-12 p70。抗ST 2L单克隆抗体与CpG联用可显著减轻实验性哮喘，提示靶向ST 2L可能增强CpG在过敏性炎症中的治疗效果。
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 toAspergillus fumigatusand challenged via i.t. instillation with liveA. fumigatusconidia. 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 CpGin vitrocompared 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.