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

在经济高速增长后，花粉症、哮喘和特应性皮炎等过敏性疾病严重成为日本城市地区的社会问题。尽管类固醇和免疫抑制剂目前普遍用于过敏患者的治疗，但这些治疗在某些情况下会产生有害的副作用，因此未来有必要开发新的治疗策略，以发挥更多的作用而不是副作用。我们关注Th2的发育过程，作为治疗变态反应性疾病的靶点。在受限的细胞因子环境中，通过T细胞抗原受体(TCR)的初始激活信号是辅助T(Th)细胞发育的关键。细胞因子通过改变染色质构象来调节关键转录因子T-bet和GATA-3的表达，从而指导Th1和Th2分化的方向。在这项研究中，我们研究了IL-4介导的信号在转基因小鼠EXP…中的动力学。在小鼠IL-4受体缺乏的背景下，更多地研究了人IL-4受体(hIL-4R TG)。这些实验表明，在TCR介导的T细胞活化的早期阶段，IL-4基因座内保守的非编码序列(CNS)-1和-2中的染色质结构的变化需要IL-4信号来支持Th2的谱系承诺。在从初始的CD4T细胞向效应的Th2细胞分化的过程中，Th2基因座染色质结构的表观遗传学变化与细胞因子表达谱密切相关。利用转基因方法，我们研究了II4基因座上相当保守的非编码序列的顺式作用活性。位于II4基因下游的Th2特异性重塑位点CNS-2调控CD62L、LO、GT、CD44、LT、Hi、GT；记忆样T细胞产生IL-4。CNS-2调节的T细胞耗尽导致Th2分化完全丧失。该CNS-2含有RBP-J的可能结合位点，RBP-J是Notch信号的关键调节器。CD4T细胞特异性RBP-J缺陷小鼠表现出从记忆样T细胞产生的初级IL-4减少和Th2的发育。因此，Notch/RBP-J信号介导的CNS-2调节在Th2分化过程中对原代IL-4的产生起着至关重要的作用。较少

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