Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice.
Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice.
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DOI：
10.4049/jimmunol.161.12.7054
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发表时间：
1998-12
影响因子：
4.4
通讯作者：
D. Broide;J. Schwarze;H. Tighe;Tim Gifford;M. Nguyen;S. Malek;J. V. Van Uden;E. Martín-Orozco;E. Gelfand;E. Raz
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文献类型：
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作者：
D. Broide;J. Schwarze;H. Tighe;Tim Gifford;M. Nguyen;S. Malek;J. V. Van Uden;E. Martín-Orozco;E. Gelfand;E. Raz
我们使用过敏原诱导的气道高反应性小鼠模型来证明含有 CpG DNA 基序的免疫刺激 DNA 序列 (ISS) 可以显着抑制气道嗜酸性粒细胞增多并降低对吸入乙酰甲胆碱的反应性。 ISS不仅抑制气道（93%）和肺实质（91%）的嗜酸性粒细胞增多，而且还显着抑制血液嗜酸性粒细胞增多（86%），表明ISS对骨髓嗜酸性粒细胞的产生有显着影响。骨髓中嗜酸性粒细胞的产生被抑制了 58%，这与 T 细胞衍生的细胞因子生成（IL-5、粒细胞-巨噬细胞 CSF 和 IL-3）的显着抑制有关。 ISS 通过刺激单核细胞/巨噬细胞和 NK 细胞产生 IL-12 和 IFN，间接对 T 细胞细胞因子产生产生抑制作用。 ISS 减少组织嗜酸性粒细胞数量的作用是立即的（给药 1 天内）和持续的（持续 6 天），并且不是由于 ISS 直接诱导嗜酸性粒细胞凋亡。当全身（腹腔注射）或粘膜（即鼻内或气管内）给药时，ISS 可有效抑制嗜酸性气道炎症。有趣的是，单剂量 ISS 抑制气道嗜酸性粒细胞增多的效果与每日注射皮质类固醇 7 天一样有效。此外，虽然 ISS 和皮质类固醇都能抑制 IL-5 的产生，但只有 ISS 能够诱导过敏原特异性 IFN-γ 的产生，并将免疫系统转向 Th1 反应。因此，在过敏原暴露之前全身或粘膜施用 ISS 可以为过敏性疾病提供一种新形式的主动免疫疗法。
We have used a mouse model of allergen-induced airway hyperresponsiveness to demonstrate that immunostimulatory DNA sequences (ISS) containing a CpG DNA motif significantly inhibit airway eosinophilia and reduce responsiveness to inhaled methacholine. ISS not only inhibited eosinophilia of the airway (by 93%) and lung parenchyma (91%), but also significantly inhibited blood eosinophilia (86%), suggesting that ISS was exerting a significant effect on the bone marrow production of eosinophils. The inhibition of the bone marrow production of eosinophils by 58% was associated with a significant inhibition of T cell-derived cytokine generation (IL-5, granulocyte-macrophage CSF, and IL-3). ISS exerted this inhibitory effect on T cell cytokine production indirectly by stimulating monocytes/macrophages and NK cells to generate IL-12 and IFNs. The onset of the ISS effect on reducing the number of tissue eosinophils was both immediate (within 1 day of administration) and sustained (lasted 6 days), and was not due to ISS directly inducing eosinophil apoptosis. ISS was effective in inhibiting eosinophilic airway inflammation when administered either systemically (i.p.), or mucosally (i.e., intranasally or intratracheally). Interestingly, a single dose of ISS inhibited airway eosinophilia as effectively as daily injections of corticosteroids for 7 days. Moreover, while both ISS and corticosteroids inhibited IL-5 generation, only ISS was able to induce allergen-specific IFN-gamma production and redirect the immune system toward a Th1 response. Thus, systemic or mucosal administration of ISS before allergen exposure could provide a novel form of active immunotherapy in allergic diseases.