Active induction of allergen specific Th1 cells for atopic asthma

在1型变态反应性疾病中，变应原特异性Th2细胞被分化，并在IgE反应性、器官高反应性和过敏性炎症的形成中起核心作用。本研究探讨了导致这种分化的决定因素，以及通过主动免疫诱导变应原特异性Th1细胞是否能抑制1型变态反应性疾病的发展。检测了细胞因子的表达和候选基因的多态性，这可能导致Th2的优先分化。在特应性皮炎患者中，发现外周血单核细胞过度产生IL-6，血清IL-18水平升高。为了揭示这些细胞因子是否在T细胞分化中起作用，我们对这些细胞因子进行了检测采用IL-6基因敲除小鼠或特应性皮炎模型小鼠。结果表明，这些细胞因子是Th2发育过程中的负性调节细胞因子。对IL-4调控区、IL-4受体和β2肾上腺素能受体外显子基因的基因多态性分析表明，每个基因多态性本身可能与特应性疾病无关。但这些基因多态的组合可能与特应性疾病的发生有关，目前正在进行筛查。经过筛选，发现一种小分子非肽化合物能抑制IL-4信号转导，如IL-4诱导的Th2分化和IL-4诱导的人和小鼠淋巴细胞的IgE合成。即使在体内，该化合物也能抑制哮喘模型小鼠体内IgE的合成和嗜酸性粒细胞的数量。因此，它是一种新的抗过敏化合物。

In type 1 allergic diseases, allergen specific Th2 cells are differentiated and play central roles on the formation of IgE responsiveness, organ hyper-reactivity and allergic inflammation.In this study what determinants might be responsible for such differentiation and whether induction of allergen specific Th1 cells through active immunization caused an inhibition of development of type 1 allergic diseases was asked.The expression of cytokine and polymorphisms of candidate genes, which might lead to preferential Th2 differentiation were examined.In the patients with atopic dermatitis it was found that IL-6 was over-produced by peripheral monocytes and serum level of IL-18 was elevated.To reveal whether or not these cytokines would function in the T cell differentiation, IL-6 gene knock-out mice or atopic dermatitis-model mice was employed.The results indicate that these cytokines are negative regulatory cytokines in the Th2 development.Analyses of gene polymorphisms including 5" IL-4 regulatory region, IL-4 receptor and beta2-adrenoceptor exon genes showed that each polymorphism by itself might not be related to atopic diseases.However, it is possible that the combination of gene polymorphisms relate to the onset of the diseases, which are now in progress.After screening, one low molecular weight non-peptide compound was found to inhibit IL-4 signalling such as IL-4-induced Th2 differentiation and IL-4-induced IgE synthesis by mouse and human lymphocytes.Even in vivo, an administration of this one suppressed IgE synthesis and eosinophil number in BALE in asthmatic model mice.Thus it was a novel anti-allergic compound.NC/Nga mice, spontaneously developed atopic dermatitis model mice, were sensitized with House Dust (HD) mite.Whether active induction of HD mite-specific Th1 cells in vivo before the clinical onset of the disease lead to suppression of the development of dermatitis and of IgE elevation is now tested.