Establishment of screening system to develop therapeutic compound for allergic disease

随着经济的高速发展，花粉症、哮喘和特应性皮炎等过敏性疾病已成为日本城市地区的严重社会问题，虽然目前常用类固醇和免疫抑制剂治疗过敏性疾病，但这些治疗在某些情况下会产生有害的副作用，因此，开发新的治疗策略，以发挥更大的作用，而不是副作用，将是必要的，在未来。过敏性患者的血清中含有大量的免疫球蛋白E抗体（IgB），与过敏原反应。IgE在免疫球蛋白基因的类别转换后从血浆B细胞分泌，而Th 2衍生的细胞因子IL-4调节该类别转换过程。IL-4通过其受体的信号通路控制B细胞中Th 2的分化和Ig B类别转换。因此，JL-4受体介导的信号通路可能成为治疗变态反应性疾病的有效靶点。 ...更多信息 监测酪氨酸磷酸化STAT 6与IL-4受体或酪氨酸磷酸化STAT 6同二聚体之间相互作用的系统，我们筛选了干扰这些相互作用的化合物。我们证实了这些化合物的抑制作用是对IgB的类别转换和STAT 6介导的CD 23启动子活性的激活的作用。细胞因子信号传导（SOCS）蛋白的抑制子是由于它们作为细胞因子信号的负调节剂的作用，涉及决定Th 1和Th 2分化的方向。我们最近发现SOCS 3和SOCS 5分别主要在Th 2和Th 1细胞中表达，由于SOCS 3通过与IL-12受体β 2结合来抑制IL-12介导的信号传导，我们建立了一个筛选系统来监测SOCS 3与IL-12受体β 2胞浆区的相互作用，但其准确性和灵敏度仍是一个有待解决的问题。少

After the advanced economic growth, allergic disease, such as pollinosis, asthma and Atopic dermatitis, seriously become social problem in urban area of Japan.Although a steroid and immunosuppressant agent are so far commonly used for the therapeutic treatment of allergic patients, these treatment carried on the harmful side effect in some case, thus the development of novel therapeutic strategy to function more than the side effect would be necessary in the future.The serum of allergic patient contains large quantities of an immunoglobulin E antibody(IgB)reacting with allergen.IgE is secreted from plasma B cells after the class switch of the immunoglobulin gene, and Th2 derived cytokine, IL-4 regulates this class switch process.IL-4 controls the differentiation of Th2 and the IgB class switching in B cells by the signal pathway through its receptor.Therefore, JL-4 receptor mediated signaling pathway would be useful therapeutic target for allergic disease.We established the two hybrid … More system that monitor the interaction either between tyrosine-phosphorylated STAT6 and IL-4 receptor or homodimer of tyrosine-Phosphorylated STAT6, and using this system, we screen the compound to interfere these interaction.We confirmed the inhibitory effect of these compounds as an effect on the class switch of IgB and the activation of STAT6 mediated CD23 promoter activity.As a result of these extensive screening of 10000 compound, 2 compounds are found as candidates.The suppressors of the cytokine signaling(SOCS)protein are due to their action as a negative regulator of the cytokine signal, implicated in the determination of direction for Th1 and Th2 differentiation.We recently found that SOCS3 and SOCS5 are predominantly expressed in Th2 and Th1 cells, respectively, and they reciprocally inhibit the Th1 and Th2 differentiation processes.Since SOCS3 inhibits IL-12 mediated signaling through the binding with IL-12 receptor beta 2, we generate the screening system to monitor the interaction between SOCS3 and cytoplasmic region of IL-12 receptor beta 2.However, accuracy and sensitivity remain to be unresolved problem. Less