Development of therapeutic strategy for allergic disorder on the basis of genome informations

随着经济的高速发展，花粉症、哮喘、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。虽然类固醇和免疫抑制剂迄今为止常用于过敏性患者的治疗性治疗，但这些治疗在某些情况下会产生有害的副作用，因此未来需要开发新的治疗策略以发挥超过副作用的作用。Th 2细胞的发育过程是过敏性疾病治疗的靶点，T细胞抗原受体（TCR）在限制性细胞因子环境中的初始激活信号对辅助性T（Th）细胞发育的启动至关重要。细胞因子通过染色质构象的变化调节关键转录因子T-bet和加塔-3的表达，其指导Th 1和Th 2分化的方向。在这项研究中，我们研究了IL-4介导的信号转导在转基因小鼠中的动力学， 关于我们 在小鼠IL-4受体缺陷背景上强调人IL-4受体（hIL-4 R Tg）。这些实验证明，在TCR介导的T细胞活化的早期阶段需要IL-4信号以使谱系定型为Th 2，沿着染色质的结构变化，在IL-1内的保守非编码序列（CNS）-1和-2中，Th 2基因座的染色质结构的表观遗传变化与从幼稚CD 4 T细胞分化过程中的细胞因子表达谱密切相关。Th 2细胞的作用。利用转基因的方法，我们研究了Ⅱ 4基因座上相当保守的非编码序列的顺式作用活性。CNS-2对应于II 4基因下游的Th 2特异性重塑位点，调节CD 62 L、<lo>CD 44 ^<hi>记忆样CD 4 ^+ T细胞中IL-4的初级产生。CNS-2调节的T细胞的耗竭导致Th 2分化的完全丧失。该CNS-2含有RBP-J的推定结合位点，RBP-J是Notch信号传导的关键调节剂。CD 4 T细胞特异性RBP-J缺陷小鼠显示记忆样T细胞和Th 2发育的初级IL-4产生的消除。因此，Notch/RBP-J信号传导介导的CNS-2调节对于Th 2分化中的初级IL-4产生至关重要。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. We focus on Th2 developmental process as therapeutic target for allergic disease.An initial activation signal via the T cell antigen receptor(TCR) in a restricted cytokine environment is critical for the onset of helper T(Th) cell development. Cytokines regulate the expression of key transcriptional factors, T-bet and GATA-3,which instruct the direction of Th1 and Th2 differentiation, through changes in chromatin conformation. In this study, we investigated the kinetics of IL-4-mediated signaling in a transgenic mouse, exp … More ressing human IL-4 receptor (hIL-4R Tg) on a mouse IL-4 receptor deficient background. These experiments demonstrated that an IL-4 signal was required at the early stage of TCR mediated T cell activation for lineage commitment to Th2, along with structural change in chromatin, in conserved non-coding sequences (CNS)-1 and -2 within the IL-4 locus.Epigenetic changes in the chromatin structure of the Th2 locus tightly associate with cytokine expression profile during the differentiation process from naive CD4 T cells to effecter Th2 cells. Using a transgenic approach, we studied cis-acting activity of considerable conservation of noncording sequences on II4 locus. CNS-2 corresponding to Th2 specific-remodeling site located at downstream of II4 gene, regulated the primary IL-4 production in CD62L^<lo> CD44^<hi> memory like CD4^+ T cells. The depletion of the CNS-2-regulated T cells resulted complete loss of Th2 differentiation. This CNS-2 contains putative binding site for RBP-J, which is a critical modulator for Notch signaling. CD4 T cell specific RBP-J deficient mice showed abrogation of primary IL-4 production from the memory like T cells and Th2 development. Therefore, Notch/RBP-J signaling mediated CNS-2 regulation is a crucial for primary IL-4 production in Th2 differentiation. Less