Critical role for OX40 ligand in the development of pathogenic Th2 cells in a murine model of asthma
Critical role for OX40 ligand in the development of pathogenic Th2 cells in a murine model of asthma
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DOI：
10.1002/eji.200323455
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发表时间：
2003-04-01
影响因子：
5.4
通讯作者：
Okumura, K
中科院分区：
文献类型：
--
作者：
Hoshino, A;Tanaka, Y;Okumura, K
支气管哮喘的特点是嗜酸性粒细胞大量浸润和气道高反应性 (AHR)，这是由过敏原特异性 T 细胞过度产生 Th2 细胞因子（IL-4、IL-5 和 IL-13）引起的。我们最近证明了 OX40 配体 (OX40L) 对 Th2 介导的实验性利什曼病的发展做出了关键贡献。在这项研究中，我们通过在小鼠哮喘模型中利用 OX40L 缺陷小鼠和中和性抗 OX40L mAb，研究了 OX40L 在 Th2 介导的肺部炎症发展中的作用。野生型 BALB/c 小鼠中卵清蛋白致敏和气道激发诱发了典型的过敏性哮喘，其特征为 AHR、嗜酸性粒细胞积聚、粘液产生增加以及肺部 Th2 细胞因子水平高。所有这些哮喘反应均未在 OX40L 缺陷的 BALB/c 小鼠中诱导。在致敏期间对野生型 BALB/c 小鼠施用中和抗 OX40L mAb 也消除了哮喘反应的诱导。相反，在攻击期间施用抗OX40L mAb并没有抑制哮喘反应。这些结果表明 OX40L 在诱导期发挥关键作用，诱导期导致致病性 Th2 细胞的发育，但在效应期则不然，效应期包括致病性 Th2 细胞在肺中的迁移和激活。
Bronchial asthma is characterized by massive infiltration of eosinophils and airway hyperreactivity (AHR), which are caused by overproduction of Th2 cytokines (IL-4, IL-5, and IL-13) by allergen-specific T cells. We recently demonstrated a critical contribution of OX40 ligand (OX40L) to the development of Th2-mediated experimental leishmaniasis. In this study, we have examined the role of OX40L in the development of Th2-mediated pulmonary inflammation by utilizing OX40L-deficient mice and a neutralizing anti-OX40L mAb in a murine model of asthma. Sensitization and airway challenge with ovalbumin in wild-type BALB/c mice induced a typical allergic asthma characterized by AHR, accumulation of eosinophils, increased mucus production, and high levels of Th2 cytokines in the lung. All these asthmatic responses were not induced in OX40L-deficient BALB/c mice. Administration of neutralizing anti-OX40L mAb in wild-type BALB/c mice during the sensitization period also abolished the induction of asthmatic responses. In contrast, administration of anti-OX40L mAb during the challenge period did not inhibit the asthmatic responses. These results indicate a critical role for OX40L in the induction phase, which leads to the development of pathogenic Th2 cells, but not in the effector phase, which includes migration and activation of pathogenic Th2 cells in the lung.