Contribution of regulatory T cells to alleviation of experimental allergic asthma after specific immunotherapy
Contribution of regulatory T cells to alleviation of experimental allergic asthma after specific immunotherapy
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DOI：
10.1111/j.1365-2222.2012.04064.x
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发表时间：
2012-10-01
影响因子：
6.1
通讯作者：
van Oosterhout, A. J. M.
中科院分区：
文献类型：
--
作者：
Maazi, H.;Shirinbak, S.;van Oosterhout, A. J. M.
背景变态反应原特异性免疫疗法(SIT)自1911年开始应用以来，其作用机制尚不清楚。有证据表明，在过敏患者的SIT过程中可以诱导出CD4+FOXP3+调节性T细胞(Treg细胞)。然而，这些细胞在体内对SIT的贡献还没有得到评估。目的探讨(I)SIT过程中的CD4+CD25+T细胞和(Ii)SIT诱导的FOXP3+Treg细胞在SIT介导的哮喘抑制中的作用。方法在经典卵清蛋白致敏的实验性哮喘模型基础上，建立SIT小鼠模型。SIT处理24、96h后，用流式细胞仪检测Treg细胞的数量。我们在SIT治疗前去除了CD4+CD25+T细胞，并在过敏原激发前去除了CD4+FOXP3+T细胞，以研究它们在SIT治疗中对抑制过敏表现的作用。结果SIT治疗时，CD4+CD25+T细胞的耗尽逆转了对气道高反应性(AHR)的抑制，但不能逆转气道嗜酸性粒细胞增多和血清中特异性IgE水平。有趣的是，在脾和血液中SIT后，CD4+CD25+FOXP3+T细胞的数量会短暂增加，这表明在治疗过程中会产生可诱导的、可能是过敏原特异性的Treg细胞。SIT治疗后去除CD4+FOXP3+Treg细胞可部分逆转SIT诱导的气道嗜酸性粒细胞抑制，但不能逆转AHR和血清特异性IgE水平。结论和临床相关性我们得出结论，SIT介导的对AHR的耐受诱导需要在注射变应原时使用CD4+CD25+T细胞。此外，SIT产生的CD4+CD25+FOXP3+T细胞有助于抑制过敏原攻击时的呼吸道嗜酸性粒细胞增多。因此，在SIT中和SIT后增加Treg细胞数量或其活性可能对提高SIT的疗效具有临床意义。
Background Allergen-specific immunotherapy (SIT) has been used since 1911, yet its mechanism of action remains to be elucidated. There is evidence indicating that CD4+FOXP3+ regulatory T cells (Treg cells) are induced during SIT in allergic patients. However, the contribution of these cells to SIT has not been evaluated in vivo. Objective To evaluate the in vivo contribution of (i) CD4+ CD25+ T cells during SIT and of (ii) SIT-generated inducible FOXP3+ Treg cells during allergen exposure to SIT-mediated suppression of asthmatic manifestations. Methods We used a mouse model of SIT based on the classical OVA-driven experimental asthma. Treg cells were quantified by flow cytometry 24 and 96h post SIT treatment. We depleted CD4+CD25+ T cells prior to SIT, and CD4+FOXP3+ T cells prior to allergen challenges to study their contribution to the suppression of allergic manifestations by SIT treatment. Results Our data show that depletion of CD4+CD25+ T cells at the time of SIT treatment reverses the suppression of airway hyperresponsiveness (AHR), but not of airway eosinophilia and specific IgE levels in serum. Interestingly, the number of CD4+CD25+FOXP3+ T cells is transiently increased after SIT in the spleen and blood, suggesting the generation of inducible and presumably allergen-specific Treg cells during treatment. Depletion of CD4+FOXP3+ Treg cells after SIT treatment partially reverses the SIT-induced suppression of airway eosinophilia, but not of AHR and serum levels of specific IgE. Conclusion and clinical relevance We conclude that SIT-mediated tolerance induction towards AHR requires CD4+CD25+ T cells at the time of allergen injections. In addition, SIT generates CD4+CD25+FOXP3+ T cells that contribute to the suppression of airway eosinophilia upon allergen challenges. Therefore, enhancing Treg cell number or their activity during and after SIT could be of clinical relevance to improve the therapeutic effects of SIT.