Exacerbated Th2-mediated airway inflammation and hyperresponsiveness in autoimmune diabetes-prone NOD mice: a critical role for CD1d-dependent NKT cells
Exacerbated Th2-mediated airway inflammation and hyperresponsiveness in autoimmune diabetes-prone NOD mice: a critical role for CD1d-dependent NKT cells
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DOI：
10.1002/eji.200324151
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发表时间：
2004-02-01
影响因子：
5.4
通讯作者：
Herbelin, A
中科院分区：
文献类型：
--
作者：
Araujo, LM;Lefort, J;Herbelin, A
NOD小鼠已被证明是胰岛素依赖型糖尿病的相关模型，与人类疾病非常相似。然而，目前尚不清楚该毒株是否表现出对Th1介导的自身免疫的普遍偏见，或者仍然能够建立完整的Th2介导的反应。在这里，我们表明NOD小鼠有能力发展成一种典型的Th2介导的疾病，即实验性过敏性哮喘。与预期相反的是，他们甚至比BALB/c小鼠发展出更强的Th2介导的肺部炎症反应，在这个模型中，这种菌株显示出典型的Th2偏向。因此，在过敏原致敏和鼻内激发后，NOD小鼠实验性哮喘的典型特征加剧，包括增强的支气管肺反应性、粘液产生和肺部嗜酸性炎症以及血清中特异性IgE滴度。与BALB/c小鼠相比，过敏性哮喘的这些特征与肺中IL-4、IL-5、IL-13和嗜酸性粒细胞趋化素的产生增加有关。尽管NOD小鼠的数量和功能存在缺陷，但依赖CD1d的NKT细胞加剧了疾病的恶化，因为在OVA免疫的CD1d(-/-)NOD小鼠中，这一特定T细胞亚群的缺陷，与NOD小鼠相比，呼吸道嗜酸性粒细胞明显减少。这是第一个证据表明，易患糖尿病的自身免疫性NOD小鼠也可以引起Th2介导的反应增强，从而可能为研究常见的遗传和细胞成分提供一个有用的模型，包括导致哮喘和1型糖尿病的NKT细胞。
The NOD mouse has proved to be a relevant model of insulin-dependent diabetes mellitus, closely resembling the human disease. However, it is unknown whether this strain presents a general bias toward Th1-mediated autoimmunity or remains capable of mounting complete Th2-mediated responses. Here, we show that NOD mice have the capacity to develop a typical Th2-mediated disease, namely experimental allergic-asthma. In contrast to what might have been expected, they even developed a stronger Th2-mediated pulmonary inflammatory response than BALB/c mice, a strain that shows a typical Th2 bias in this model. Thus, after allergen sensitization and intra-nasal challenge, the typical features of experimental asthma were exacerbated in NOD mice, including enhanced bronchopulmonary responsiveness, mucus production and eosinophilic inflammation in the lungs as well as specific IgE titers in serum. These hallmarks of allergic asthma were associated with increased IL-4 IL-5, IL-13 and eotaxin production in the lungs, as compared with BALB/c mice. Notwithstanding their quantitative and functional defect in NOD mice, CD1d-dependent NKT cells contribute to aggravate the disease, since in OVA-immunized CD1d(-/-) NOD mice, which are deficient in this particular T cell subset, airway eosinophilia was clearly diminished relative to NOD littermates. This is the first evidence that autoimmune diabetes-prone NOD mice can also give rise to enhanced Th2-mediated responses and might thus provide a useful model for the study of common genetic and cellular components, including NKT cells that contribute to both asthma and type 1 diabetes.