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APPROACHES FOR CONTROLLING INFECTION BY GENE THERAPY

通过基因治疗控制感染的方法

基本信息

批准号：
10044299
负责人：
ASANO Yoshihiro
金额：
$ 4.86万
依托单位：
EHIME UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10044299/
关键词：
infection immunity innate immunity T cell subset IL-12 p40 macrophage function

项目摘要

Successful development of Th2 cells requires both differentiation and expansion processes, and depends on the activation levels of IL-4 receptor (IL-4R) -mediated signaling. Among signaling molecules downstream of IL-4R, STAT6 activation is thought to be critical for differentiation process, and phosphorylation of IRS-2 is important for proliferation. The activation of Ras/MAPK cascade appears to act on Jak1 kinase to enhance its kinase activity and improve IL-4R function. The activation of CN in naive CD4 T cells induces transcriptional upregulation of Jak3. STAT5 is found to be physically and functionally associated with IL-4 receptor complex in the anti-TCR-activated naive T cells and established cloned Th2 cells. The IL-4-induced activation of STAT5 appears to play an important role in the expansion process of the developing Th2 cells. Thus, the recruitment of Jak3 and STAT5 molecules to functional IL-4R complex in developing Th2 cells appears to be crucial for Th2 cell development.We demonstrated that the splenomegaly associated with Salmonella-infection, a host-defensive response, was caused by the migration of Mac-1^+ cells into the infected spleen. We tried to generate murine bone marrow-derived DC lines by using a helper-free and replication-defective recombinant retrovirus encoding the SV40 early antigens, and obtained several DC lines that can cytokine-independently grow.We established the mutant Listeria monocytogenes which expressed ply118 gene product when virulence genes are activated. We tried to establish the gene transduction system using this mutant Listeria.

Th 2细胞的成功发育需要分化和扩增过程，并且取决于IL-4受体（IL-4 R）介导的信号传导的活化水平。在IL-4 R下游的信号分子中，STAT 6的活化被认为是分化过程的关键，IRS-2的磷酸化对于增殖是重要的。Ras/MAPK级联的激活似乎作用于Jak 1激酶，以增强其激酶活性并改善IL-4 R功能。初始CD 4 T细胞中CN的活化诱导Jak 3的转录上调。在抗TCR活化的初始T细胞和已建立的克隆化Th 2细胞中，发现STAT 5与IL-4受体复合物在物理和功能上相关。IL-4诱导的STAT 5活化在Th 2细胞的扩增过程中起重要作用。因此，在Th 2细胞发育过程中，Jak 3和STAT 5分子与IL-4 R功能复合物的募集似乎对Th 2细胞的发育至关重要。我们证明了沙门氏菌感染相关的脾肿大（一种宿主防御反应）是由Mac-1^+细胞迁移到受感染的脾中引起的。我们尝试用编码SV 40早期抗原的无辅助因子、复制缺陷型重组逆转录病毒构建小鼠骨髓来源的DC细胞系，获得了几株能独立生长的DC细胞系，并建立了能在毒力基因激活时表达SV 40 118基因产物的突变型单核细胞增多性李斯特菌。我们尝试利用该突变株建立基因转导系统。