Active induction of allergen specific Th1 cells for atopic asthma

在1型过敏性疾病中，过敏原特异性Th 2细胞分化并在IgE反应性的形成中发挥中心作用，器官超在这项研究中，询问了什么决定因素可能负责这种分化，以及通过主动免疫诱导过敏原特异性Th 1细胞是否导致抑制1型过敏性疾病的发展。检测了可能导致优先Th 2分化的候选基因的多态性。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，本研究采用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在Th 2细胞发育中是负调节性细胞因子，对IL-4基因5 ′调控区、IL-4受体和β 2-肾上腺素能受体外显子基因的多态性本身可能与特应性疾病无关，但基因多态性的组合可能与疾病的发生有关，目前正在进行中，经筛选，发现一种低分子量非肽化合物抑制IL-4信号传导，例如小鼠和人淋巴细胞的IL-4诱导的Th 2分化和IL-4诱导的IgE合成。即使在体内，该化合物的给药抑制哮喘模型小鼠BALE中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。NC/Nga小鼠，用屋尘（HD）螨致敏自发发展的特应性皮炎模型小鼠。现在测试在疾病临床发作之前体内HD螨特异性Th 1细胞的主动诱导是否导致皮炎发展和IgE升高的抑制。

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.