Pathogenesis and regulation mechanisms for Th1- and Th2-dependent allergic airway inflammation

为了克服1型/ 2型免疫平衡被破坏所导致的各种免疫疾病，我们建立了Th1依赖性或th2依赖性免疫疾病模型。本课题通过抗原特异性Th1或Th2细胞过继转移后吸入抗原，建立变应性气道炎症小鼠模型，研究其发病机制中的精确细胞调控和分子机制。在目前的模型中，Th1细胞的转移引起致命的气道高反应性（AHR），并伴有严重的嗜中性粒细胞增多，而Th2细胞的转移引起肺嗜酸性粒细胞增多。与th2转移模型相比，Th1转移模型中与气道上皮粘液高分泌相关的MUC5AC和Gob5 mRNA表达水平极低。由此可见，th1诱导的AHR不依赖于这种粘液分泌过高，而粘液分泌过高是th2介导哮喘中AHR升高的必要条件。在th2转移模型中，我们发现，在体内注射TLR9配体时，CpG通过阻断th2细胞向肺的迁移而显著抑制了症状。为了研究其机制，我们使用IFN-γ敲除小鼠和中和I型细胞因子（如IFN-α， β和IL-12）的抗体。结果表明，CpG对th2细胞迁移的抑制作用不需要IFN-γ，而需要IFN-α、β和IL-12。这些发现对于阐明th2细胞在效应期向肺迁移的下调介导的抑制机制具有很高的价值，这表明CpG有望成为th2依赖性哮喘临床应用的工具。此外，我们评估了乳酸菌（LAB）对th2依赖性哮喘的抑制作用，乳酸菌容易激活1型免疫。结果提示，口服乳酸菌对诱导期变应性炎症的预防作用大于对效应期变应性炎症的治疗作用。本研究结果将有助于阐明过敏性气道炎症的发病机制和适当调节的发展。少

To overcome various immune diseases induced by disruption of type1/type2 immune balance, we have established Th1- or Th2-dependent immune diseases models. In the present project, we established allergic airway inflammation mouse models by adoptive transfer of antigen-specific Th1 or Th2 cells followed by the antigen inhalation and investigated precise cellular regulation and molecular mechanisms in the pathogenesis. In the present models, transfer of Th1 cells induced fatal airway hyperresponsiveness (AHR) associated with severe neutrophilia, whereas the cased of Th2 cells caused eosinophilia in the lung. Compared to the Th2-transferred model, mRNA expression levels of MUC5AC and Gob5, related to mucus hypersecretion in airway epithelium, were extremely lower in the Th1 -transferred model. Thus, it was demonstrated that the Th1-induced AHR was independent on such mucus hypersecretion, which was essential for elevation of AHR in Th2-mediated asthma. In the Th2-transferred model, we foun … More d that in vivo injection of TLR9 ligand, CpG remarkably suppressed the symptoms by blocking of Th2-cell migration into lung. To investigate the mechanism, we used IFN-γ knockout mice and neutralizing antibodies against type I cytokines such as IFN-α, β, and IL-12. As the results, IFN-α, β, and IL-12, but not IFN-γ, were required for the inhibitory effect of CpG on Th2-cell migration. These findings were highly valued for elucidation of the suppression mechanism mediated by down-regulation of Th2-cell migration into lung even at effector phase, suggesting that CpG would be expected as a tool for clinical application in Th2-dependent asthma.Furthermore, we evaluated inhibitory effects of lactic acid bacterium (LAB), which easily activate type1 immunity, on Th2-dependent asthma. As the results, it was suggested that oral intake of LAB may have preventative effects on the allergic inflammation at induction phase rather than therapeutic effects at effector phase. The present findings will contribute to elucidation of the pathogenesis and development of the proper regulation in allergic airway inflammation. Less