Sel Serdar, Wegmann Michael, Sel Sarper, Bauer Stefan, Garn Holger, Alber Gottfried, Renz Harald
Department of Clinical Chemistry and Molecular Diagnostics, Hans-Meerwein-Strasse, 35033 Marburg, Germany.
J Immunol. 2007 Jun 15;178(12):7805-13. doi: 10.4049/jimmunol.178.12.7805.
Based on epidemiological data, the hygiene hypothesis associates poor hygienic living conditions during childhood with a lower risk for the development of allergic diseases such as bronchial asthma. The role of viral infections, and especially of viral TLR ligands, within this context remains to be clarified. Viral TLR ligands involve dsRNA and ssRNA which are recognized by TLR-3 or TLR-7, respectively. In this study, we evaluated the impact of TLR-3 or TLR-7 activation on experimental asthma in mice. Systemic application of the synthetic TLR-3 or TLR-7 ligands polycytidylic-polyinosinic acid (p(I:C)) or R-848, respectively, during the sensitization phase prevented the production of OVA-specific IgE and IgG1 Abs and subsequently abolished all features of experimental asthma including airway hyperresponsiveness and allergic airway inflammation. Furthermore, administration of p(I:C) or R-848 to animals with already established primary allergic responses revealed a markedly reduced secondary response following allergen aerosol rechallenges. In contrast to wild-type animals, application of p(I:C) or R-848 to IL-12p35(-/-) mice had no effect on airway inflammation, goblet cell hyperplasia, and airway hyperresponsiveness. However, in the absence of IL-12, the numbers of eosinophils and lymphocytes in bronchoalveolar lavage fluids were still significantly reduced. These partial effects could also be abolished by neutralizing anti-IL-10 Abs in IL-12p35(-/-) mice. These data indicate that TLR-3 or TLR-7 activation by viral TLR ligands has both preventive as well as suppressive effects on experimental asthma which is mediated by the additive effects of IL-12 and IL-10.
基于流行病学数据，卫生假说认为儿童时期卫生条件差与支气管哮喘等过敏性疾病的低发病风险相关。在这种情况下，病毒感染尤其是病毒Toll样受体（TLR）配体的作用仍有待阐明。病毒TLR配体包括双链RNA（dsRNA）和单链RNA（ssRNA），它们分别被TLR-3或TLR-7识别。在本研究中，我们评估了TLR-3或TLR-7激活对小鼠实验性哮喘的影响。在致敏阶段分别全身应用合成的TLR-3或TLR-7配体聚肌苷酸-聚胞苷酸（p(I:C)）或R-848，可防止卵清蛋白（OVA）特异性IgE和IgG1抗体的产生，并随后消除实验性哮喘的所有特征，包括气道高反应性和过敏性气道炎症。此外，对已经建立原发性过敏反应的动物给予p(I:C)或R-848，发现过敏原气溶胶再次激发后的二次反应明显降低。与野生型动物相反，对白细胞介素12p35基因敲除（IL-12p35(-/-)）小鼠应用p(I:C)或R-848对气道炎症、杯状细胞增生和气道高反应性没有影响。然而，在缺乏白细胞介素12的情况下，支气管肺泡灌洗液中的嗜酸性粒细胞和淋巴细胞数量仍显著减少。在IL-12p35(-/-)小鼠中，通过中和抗白细胞介素10抗体也可消除这些部分效应。这些数据表明，病毒TLR配体激活TLR-3或TLR-7对实验性哮喘具有预防和抑制作用，这是由白细胞介素12和白细胞介素10的累加效应介导的。
