Differential Effects of Rapamycin and Dexamethasone in Mouse Models of Established Allergic Asthma

The mammalian target of rapamycin (mTOR) plays an important role in cell growth/differentiation, integrating environmental cues, and regulating immune responses. Our lab previously demonstrated that inhibition of mTOR with rapamycin prevented house dust mite (HDM)-induced allergic asthma in mice. Here, we utilized two treatment protocols to investigate whether rapamycin, compared to the steroid, dexamethasone, could inhibit allergic responses during the later stages of the disease process, namely allergen re-exposure and/or during progression of chronic allergic disease. In protocol 1, BALB/c mice were sensitized to HDM (three i.p. injections) and administered two intranasal HDM exposures. After 6 weeks of rest/recovery, mice were re-exposed to HDM while being treated with rapamycin or dexamethasone. In protocol 2, mice were exposed to HDM for 3 or 6 weeks and treated with rapamycin or dexamethasone during weeks 4–6. Characteristic features of allergic asthma, including IgE, goblet cells, airway hyperreactivity (AHR), inflammatory cells, cytokines/chemokines, and T cell responses were assessed. In protocol 1, both rapamycin and dexamethasone suppressed goblet cells and total CD4+ T cells including activated, effector, and regulatory T cells in the lung tissue, with no effect on AHR or total inflammatory cell numbers in the bronchoalveolar lavage fluid. Rapamycin also suppressed IgE, although IL-4 and eotaxin 1 levels were augmented. In protocol 2, both drugs suppressed total CD4+ T cells, including activated, effector, and regulatory T cells and IgE levels. IL-4, eotaxin, and inflammatory cell numbers were increased after rapamycin and no effect on AHR was observed. Dexamethasone suppressed inflammatory cell numbers, especially eosinophils, but had limited effects on AHR. We conclude that while mTOR signaling is critical during the early phases of allergic asthma, its role is much more limited once disease is established.雷帕霉素靶蛋白（mammalian target of rapamycin, mTOR）在细胞生长与分化、整合环境信号以及调控免疫应答过程中发挥关键作用。本课题组此前已证实，采用雷帕霉素抑制mTOR信号通路，可预防屋尘螨（house dust mite, HDM）诱导的小鼠过敏性哮喘。本研究采用两种给药方案，旨在对比雷帕霉素与糖皮质激素地塞米松，在过敏性哮喘进程后期——即过敏原再次暴露阶段或慢性过敏性疾病进展阶段——对过敏反应的抑制效果。 方案1中，BALB/c小鼠经屋尘螨致敏（三次腹腔注射），并接受两次鼻内屋尘螨暴露。静置恢复6周后，再次对小鼠予以屋尘螨暴露，同时给予雷帕霉素或地塞米松干预。方案2中，小鼠接受屋尘螨暴露3周或6周，并在第4至6周期间予以雷帕霉素或地塞米松处理。 本研究对过敏性哮喘的典型特征进行了评估，涵盖免疫球蛋白E（IgE）、杯状细胞、气道高反应性（airway hyperreactivity, AHR）、炎症细胞、细胞因子/趋化因子以及T细胞应答。 在方案1中，雷帕霉素与地塞米松均可抑制肺组织内的杯状细胞及总CD4+ T细胞（涵盖活化T细胞、效应T细胞与调节性T细胞），但对气道高反应性或支气管肺泡灌洗液（bronchoalveolar lavage fluid）中的总炎症细胞数量无显著影响。雷帕霉素亦可降低IgE水平，但白细胞介素-4（IL-4）及嗜酸性粒细胞趋化因子1的表达水平却出现上调。 方案2中，两种药物均可抑制总CD4+ T细胞（涵盖活化T细胞、效应T细胞与调节性T细胞）及IgE水平。经雷帕霉素处理后，IL-4、趋化因子及炎症细胞数量均有所升高，且未对气道高反应性产生影响。地塞米松则可抑制炎症细胞数量，尤其是嗜酸性粒细胞，但对气道高反应性的影响较为有限。 综上，尽管mTOR信号通路在过敏性哮喘的早期阶段至关重要，但一旦疾病确立，其发挥的调控作用则极为有限。