Preferential development of Th2 cells and its therapeutic regulation in bronchial asthma

支气管哮喘中Th2细胞的优先发育及其治疗调控支气管哮喘是I型变态反应的代表疾病，过敏原特异性Th2细胞优先分化，在IgE应答、器官高反应性和变应性炎症的形成中起核心作用。在这项研究中，什么决定因素可能对这种T细胞分化负责，以及是否通过操纵Th2细胞因子来调节Th2细胞的分化导致I型过敏性疾病的发展受到抑制。研究了可能导致Th2优先分化的细胞因子表达和候选基因多态性。在高IgE状态下，外周血单核细胞过量产生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，这些细胞因子可能是Th2发育的负调控细胞因子。对5'IL-4调控区、IL-4受体或β -肾上腺素受体外显子基因多态性的分析表明，每种多态性本身可能与特应性疾病无关。然而，基因多态性的组合可能与疾病的发病有关，目前正在进行中。为了发现具有抑制IL-4功能的化合物，在小鼠IgE合成系统中筛选了许多化合物。发现化合物#8921特异性抑制IgE抗体反应，以及Th2细胞分化。在小鼠哮喘模型中，经支气管肺泡灌洗检测，它能抑制血清IgE抗体水平和肺内炎症细胞（尤其是嗜酸性粒细胞）的浸润。目前正在对化合物8921的作用进行详细分析。

Preferential development of Th2 cells and its therapeutic regulation in bronchial asthmaIn bronchial asthma, a representative disease of type I allergy, allergen specific Th2 cells are preferentially differentiated and play central roles on the formation of IgE responses, organ hyper-reactivity and allergic inflammation.In this study what determinates might be responsible for such T cell differentiation and whether regulation of differentiation of Th2 cells through the manipulation of the Th2 cytokines caused an inhibition of development of type I allergic diseases were asked.The expression of cytokine and polymorphisms of candidate genes, which might lead to Th2 preferential differentiation was examined.In hyper IgE status, 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 might be negative regulatory cytokines in the Th2 development.Analyses of gene polymorphisms including 5'IL-4 regulatory region, IL-4 receptor or 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.In order to find out compounds with the inhibitory activity of IL-4 function, many chemical compounds were screened in murine IgE synthesis system.And compound #8921 was found to suppress specifically IgE antibody responses, as well as Th2 cell differentiation.In murine asthma model, it suppressed serum IgE antibody levels and the infiltration of inflammatory cells, especially eosinophils, in the lung as assessed by broncho alveolar lavage.Detailed analysis of the action of compound #8921 is under progress.