Toll-like receptor 4 agonists adsorbed to aluminium hydroxide adjuvant attenuate ovalbumin-specific allergic airway disease:: role of MyD88 adaptor molecule and interleukin-12/interferon-γ axis
Toll-like receptor 4 agonists adsorbed to aluminium hydroxide adjuvant attenuate ovalbumin-specific allergic airway disease:: role of MyD88 adaptor molecule and interleukin-12/interferon-γ axis
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DOI：
10.1111/j.1365-2222.2008.03036.x
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发表时间：
2008-10-01
影响因子：
6.1
通讯作者：
Russo, M.
中科院分区：
文献类型：
--
作者：
Bortolatto, J.;Borducchi, E.;Russo, M.
背景流行病学和实验数据表明细菌脂多糖（LPS）可以预防或加剧过敏性哮喘。脂多糖通过 Toll 样受体 4 (TLR4) 触发免疫反应，进而通过 MyD88 或 TRIF 衔接蛋白激活两条主要信号传导途径。 LPS 是一种亲 1 型 T 辅助细胞 (Th 1) 佐剂，而氢氧化铝（明矾）是一种强效 2 型 T 辅助细胞 (Th2) 佐剂，但两种佐剂混合对肺过敏发展的影响尚未研究。 目的 我们确定吸附在明矾佐剂上的天然 (LPS) 或合成 (ER-803022) TLR4 激动剂是否会影响过敏原致敏和气道过敏性疾病的发展。为了剖析 LPS 诱导的分子途径，我们使用了 TLR4-、MyD88-、TRIF- 或 IL-12/IFN-gamma 缺陷型小鼠。 方法 通过皮下注射卵清蛋白 (OVA) 致敏小鼠，无论是否含有共吸附在明矾上的 TLR4 激动剂，并用 OVA 鼻内攻击。最后一次 OVA 攻击后 24 小时评估过敏性肺病的发展。结果 OVA 加 LPS 共吸附到明矾上的致敏作用以剂量依赖性方式受损，OVA 诱导的 Th2 介导的过敏反应，如气道嗜酸性粒细胞增多、2 型细胞因子分泌、气道高反应性、粘液过度产生和 IgE 或 IgG1 过敏性抗体的血清水平。尽管 Th1 相关同种型 IgG2a 的水平有所增加，但对肺部特异性效应的研究表明，LPS 不会诱导 Th1 模式的炎症。脂多糖损害 Th2 免疫的发展，通过 TLR4 和 MyD88 分子以及 IL-12/IFN-gamma 轴发出信号，但不通过 TRIF 途径。此外，合成的 TLR4 激动剂被证明比 LPS 具有更少的全身炎症反应，也可以防止过敏性哮喘的发生。 结论 Toll 样受体 4 激动剂与明矾上的过敏原共吸附，可下调过敏性肺病并预防极化 T 细胞介导的气道炎症的发生。
Background Epidemiological and experimental data suggest that bacteria] lipopolysaccharides (LPS) can either protect from or exacerbate allergic asthma. Lipopolysaccharides trigger immune responses through toll-like receptor 4 (TLR4) that in turn activates two major signalling pathways via either MyD88 or TRIF adaptor proteins. The LPS is a pro-Type 1 T helper cells (Th 1) adjuvant while aluminium hydroxide (alum) is a strong Type 2 T helper cells (Th2) adjuvant, but the effect of the mixing of both adjuvants on the development of lung allergy has not been investigated.Objective We determined whether natural (LPS) or synthetic (ER-803022) TLR4 agonists adsorbed onto alum adjuvant affect allergen sensitization and development of airway allergic disease. To dissect LPS-induced molecular pathways, we used TLR4-, MyD88-, TRIF-, or IL-12/IFN-gamma-deficient mice.Methods Mice were sensitized with subcutaneous injections of ovalbumin (OVA) with or without TLR4 agonists co-adsorbed onto alum and challenged with intranasally with OVA. The development of allergic lung disease was evaluated 24 h after last OVA challenge.Results Sensitization with OVA plus LPS co-adsorbed onto alum impaired in dose-dependent manner OVA-induced Th2-mediated allergic responses such as airway eosinophilia, type-2 cytokines secretion, airway hyper-reactivity, mucus hyper production and serum levels of IgE or IgG1 anaphylactic antibodies. Although the levels of IgG2a, Th1 -affiliated isotype increased, investigation into the lung-specific effects revealed that LPS did not induce a Th1 pattern of inflammation. Lipopolysaccharides impaired the development of Th2 immunity, signaling via TLR4 and MyD88 molecules and via the IL-12/IFN-gamma axis, but not through TRIF pathway. Moreover, the synthetic TLR4 agonists that proved to have a less systemic inflammatory response than LPS also protected against allergic asthma development.Conclusion Toll-like receptor 4 agonists co-adsorbed with allergen onto alum down-modulate allergic lung disease and prevent the development of polarized T cell-mediated airway inflammation.