A study for atopic dermatitis controlledby Caspase-1 and IL-18

我们建立了两个转基因小鼠（皮肤特异性caspase-1和IL-18过表达小鼠），这些小鼠发生了类似于人类特应性皮炎（AD）的持续性皮炎。这些小鼠的皮肤和全身免疫系统为变应性类型，转变为Th 2条件，分泌IL-18、IL-4、IL-5和IL-10。皮肤肥大细胞增多症和高组胺血症导致作为特应性皮炎特征模型的密集抓挠行为，以及血清IgE水平的显著升高。IgE-/-Caspase-1 Tg持续AD型皮肤病变，但IL-18的清除完全抑制了皮肤病变的发展，这强烈支持这种皮炎的IL-18依赖性。由于这些病变是独立于外源性过敏原，我们提出了一个新的概念，作为先天型过敏症的过敏原依赖IgE介导的过敏症。我们成功地治疗了皮肤表现的半胱天冬酶-1Tg使用卡介苗接种抑制IL-18的生产。我们还开发了Stat 6-/-半胱天冬酶-1Tg，其发展为类似脓疱性银屑病的皮肤病变，而没有Th 2漂移。这些研究揭示了经皮IL-18分泌在Th 2型AD和Th 1型银屑病中的重要性。

We have established two transgenic mice (skin specifically caspase-1 and IL-18 overexpressed mice), and these mice developed persistent dermatitis similar to the human atopic dermatitis (AD). The skin and systemic immune systems of these mice were allergic type shifted to Th2 conditions, secreting IL-18, IL-4, IL-5 and IL-10. Dermal mastocytosis and hyper histaminemia resulted in intensive scratching behaviour as a characteristic model for atopic dermatitis, and significant elevation of serum IgE levels. IgE-/-Caspase-1Tg persisted AD type skin lesions, but extermination of IL-18 completely suppressed development of the skin lesions, which strongly supported IL-18 dependency of this dermatitis. Because these lesions were independent from the exogenous allergens, we proposed a new concept as innate type atopy in contrast to the allergen dependent IgE mediated atopy. We successfully treated the skin manifestations of the caspase-1Tg using BCG vaccination with suppressed IL-18 production. We also developed Stat6-/-caspase-1Tg, which developed skin lesions mimic pustular psoriasis without Th2 shift. These studies revealed importance of the percutaneous IL-18secretion in both of Th2 type AD and Th1 type psoriasis.