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Establishment of gene therapy for the regulation of IgE and Chemokine production in patients with nasal allergy

建立调节鼻过敏患者 IgE 和趋化因子产生的基因疗法

基本信息

批准号：
13470359
负责人：
FUJIEDA Shigeharu
金额：
$ 9.09万
依托单位：
福井医科大学
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Nasal fibroblasts stimulated by cytokines released the chemokine and play a key role in pathogenesis of allergic rhinitis.Syk proteins were expressed in human nasal fibroblasts, but the expression level varied.There were positive correlation between the level of Syk expression and RANTES production by LPS.Over expression of wild-type Syk by gene transfer enhanced RANTES production.Administration of Syk-antisense inhibited RANTES production. JNK1 and p38 MAP kinase are important for RANTES production. Four types of dominant positive mutant Ras were made and transfected into nasal fibroblast. When PI3kinase pathway was activated by Ras mutant, nasal fibroblast produced the largest amount of RANTES.Double strand RNA(dsRNA) also induced RANTES production by nasal fibroblast.The addition of IFNg enhanced RANTES production by dsRNA, while IL4 had no effect to enhance RANTES production.Eotaxin was not induced by dsRNA. However, IL-4 and deRNA had syngergistic effect to induce Eotaxin production by nasal fibroblst. Nasal fibroblast expressed CCR3, which is a regand to RANTES and Eotaxin.The treatment of RANTES increased CCR 3 expression on nasal fibroblast and induced cell growth in the manner of autocrine.CD45 molecules regulated IgE class switching on B cells via JNK pathway.The new method to quantify IgE class swithing was established.Human IgG-IgE chimeric protein inhibit IgE class switch recombination by co-aggregating B cell CD32 and CD23.This protein directly inhibited germline transcription, subsequent class switching to and IgE production.

鼻成纤维细胞在细胞因子的刺激下释放趋化因子，在变应性鼻炎的发病中起重要作用。Syk蛋白在人鼻成纤维细胞中有表达，但表达水平不同。Syk蛋白表达水平与LPS诱导RANTES的产生呈正相关。通过基因转移过表达野生型Syk可促进RANTES的产生，而Syk反义核酸可抑制RANTES的产生。JNK 1和p38 MAP激酶对RANTES的产生是重要的。制备了四种显性阳性突变型Ras，并转染鼻成纤维细胞。Ras突变体激活PI 3激酶通路后，鼻成纤维细胞产生最多的RANTES，双链RNA（dsRNA）也能诱导鼻成纤维细胞产生RANTES，IFNg的加入能促进dsRNA产生RANTES，而IL 4对RANTES的产生无促进作用，dsRNA不诱导Eotaxin的产生。而IL-4和deRNA对鼻成纤维细胞Eotaxin的产生有协同作用。鼻成纤维细胞表达CCR 3，建立了一种新的定量IgE类转换的方法，人IgG-IgE嵌合蛋白通过与人IgG-IgE嵌合蛋白共表达抑制IgE类转换，并通过与人IgG-IgE嵌合蛋白共表达抑制IgE类转换，从而抑制IgE类转换。聚集B细胞CD 32和CD 23。该蛋白直接抑制生殖系转录、随后的类转换和IgE的产生。