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Analysis of allergic rhinitis by nano level and development of novel therapy

纳米级过敏性鼻炎分析及新疗法开发

基本信息

批准号：
17390458
负责人：
FUJIEDA Shigeharu
金额：
$ 10.58万
依托单位：
University of Fukui
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

We proposed that fibroblasts are not passive players in the immune system. Incubation with poly(I:C) enhanced the secretion of RANTES and IL-8 from human nasal fibroblasts. However, eotaxin, IL-1β, TNF-α, IFNα, IFNγ and IL-12 were not secreted. The JNK inhibitor SP600125 and PI3-kinase inhibitor LY294002 significantly blocked the poly(I:C)-induced release RANTES and IL-8, whereas the p38 MAP kinase inhibitor SB203580 suppressed poly(I:C)-induced secretion of IL-8, but not RANTES. Eotaxin production by IL-4 is correlated with expression of SOCS5 in nasal fibroblast via PI3-kinase pathway. B lymphocyte stimulator protein (BLyS) was induced by poly(I:C). BLyS induced IgE class switching. Secretion of BLyS is associated with Rho, Syk, Vav, c-Src, TRAF6, p-Selectin.Plasmacytoid dendritic cells (pDC) produce a large amount of IFNα, through the ligation of TLR9 unmethylated CpG motifs. CpG DNA enhanced the NF-KB subunits p65/p50 activity, which collaborated with p38 MAPK to up-regulate the expression of IRF-7, CXCL10 and CCL3 in a manner independent of type I IFN signaling. Type I IFN induced the expression of IRF-7, but not of IFNα, in a NF-KB -independent way. CpG DNA enabled the type I IFN-treated pDC to express IFNα in the presence of NF-KB/p38 MAPK inhibitor, and chloroquine abrogated this effect. With CpG DNA, IRF-7, both constitutively and newly expressed, moved to the nuclei independent of NF-KB/p38 MAPK.Sublingeal immunotherapy (SLIT) was performed for seasonal allergic rhinitis in Japan. We found 8 proteins that increased in serum after SLIT. The amount of proteins is correlated with clinical outcome. Of 48,000 transcripts, 32-gene expression is increased in PBMC in patients received with SLIT.

我们提出成纤维细胞不是免疫系统中的被动参与者。poly（I:C）培养可增强人鼻成纤维细胞RANTES和IL-8的分泌。而eotaxin、IL-1β、TNF-α、IFNα、IFNγ和IL-12均无分泌。JNK抑制剂SP600125和pi3激酶抑制剂LY294002显著阻断poly（I:C）诱导的释放RANTES和IL-8，而p38 MAP激酶抑制剂SB203580抑制poly（I:C）诱导的IL-8分泌，但不抑制RANTES。IL-4通过pi3激酶途径与鼻成纤维细胞中SOCS5的表达相关。聚（I:C）诱导B淋巴细胞刺激蛋白（BLyS）的产生。BLyS诱导IgE类转换。BLyS的分泌与Rho、Syk、Vav、c-Src、TRAF6、p-Selectin有关。浆细胞样树突状细胞（pDC）通过连接TLR9未甲基化的CpG基序产生大量IFNα。CpG DNA增强NF-KB亚基p65/p50活性，与p38 MAPK协同上调IRF-7、CXCL10和CCL3的表达，且不依赖于I型IFN信号传导。I型IFN以不依赖NF-KB的方式诱导IRF-7的表达，但不诱导IFNα的表达。CpG DNA使I型ifn处理的pDC在NF-KB/p38 MAPK抑制剂存在的情况下表达IFNα，氯喹消除了这一作用。在CpG DNA中，IRF-7，无论是组成性的还是新表达的，都独立于NF-KB/p38 MAPK转移到细胞核中。在日本进行季节性变应性鼻炎的鼻下免疫治疗（SLIT）。我们发现8种蛋白在SLIT后血清中升高。蛋白质的数量与临床结果相关。在48000个转录本中，接受SLIT治疗的患者PBMC中32个基因表达增加。