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Oral vaccine from daily lactic acid bacteria! -Development of new vaccine adjuvants-

每日乳酸菌口服疫苗！

基本信息

批准号：
13556018
负责人：
KITAZAWA Haruki
金额：
$ 8.83万
依托单位：
Tohoku University
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

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13556018/
关键词：
Lactic acid bacteria Immunobiotics L.gasseri DNA Peyer's patch TLR9 Transfectant Cytokine L.gasseri 腸管膜リンパ節 L. bularicus トランスフェクタン S.thermophilus CpG motif 腸管クローニング

项目摘要

Domestic animals are very important for food production. However, it becomes very severe problem that they have chronic intestinal diseases resulted in loss of food production and overadministration of antibiotics. In this study, the final goal is development of a novel oral vaccine adjuvant by using dairy lactic and bacterial DNA. In order to go ahead to the final goal, we first tried to find the active DNA motifs from lactic and bacteria (LAB) and develop a new immunoassay system with swine TLR9 transfectant and finally elucidate the mechanisms of the immunostimulation by the LAB DNA in the gut. We found several immunostimulatory DNA motifs including a novel one from the LAB. We cloned Toll-like receptor 9 (TLR9) from swine peyer's patch, which is expected for human model, and successfully developed a swine TLR9 transfectant. The transfectant was useful for the evaluation of active DNA from the LAB. The DNA motifs augmented an induction of Th1 type cytokine (IL-6, IL-12, IFNγ) mRNA in peyer's patches. The swine TLR9 gene was preferentially expressed peyer's patches (Pps) and mesenteric lymph nodes (MLNs), of which their degrees were approximately three times higher than that of spleens but weak in the other tissues. We firstly showed that high express (TLR9^+) cells were formed in Pps and MLNs. In addition, TLR9^+ cells existed not only in immune cells such as dendritic cells and B cells but also in membranous cells (M cells), belonging to follicle-associated epithelia (FAE) in Pps. These results suggest that Pps and MLNs provide the host defense with the ability to respond to a variety of bioactive oligonucleotides (ODNs) from bacteria at a conductive site of initial immune responses. From these results, immunostimulatory DNA motif from the LAB exerted the cytokine induction in the gut via TLR9 suggesting that the LAB DNA is a good candidate of an oral vaccine adjuvant.

家畜对粮食生产非常重要。然而，它成为非常严重的问题，他们有慢性肠道疾病，导致粮食生产的损失和抗生素的过度使用。本研究的最终目标是利用乳乳酸菌和细菌DNA开发一种新型口服疫苗佐剂。为了进一步实现这一目标，我们首先尝试从乳酸菌中寻找具有活性的DNA基序，并利用猪TLR 9基因构建了一种新的免疫检测系统，最后阐明乳酸菌DNA在肠道中的免疫刺激机制。我们发现了几个免疫刺激DNA基序，包括一个新的LAB。我们从猪派伊尔斑中克隆了Toll样受体9（TLR 9），并成功构建了猪TLR 9的转染子。该转染子可用于活性DNA的评价。DNA基序增强了派伊尔斑中Th 1型细胞因子（IL-6、IL-12、IFNγ）mRNA的诱导。猪TLR 9基因在脾淋巴结（Pps）和肠系膜淋巴结（MLNs）中优先表达，其表达程度约为脾的3倍，但在其他组织中表达较弱。我们首次发现在Pps和MLNs中形成了高表达（TLR 9 ^+）的细胞。此外，Pps中TLR 9 ^+细胞不仅存在于树突状细胞、B细胞等免疫细胞中，还存在于卵泡相关上皮（FAE）的膜细胞（M细胞）中。这些结果表明，Pps和MLNs提供宿主防御的能力，以响应各种生物活性的寡核苷酸（ODNs）从细菌在一个导电网站的初始免疫反应。根据这些结果，来自LAB的免疫刺激DNA基序通过TLR 9在肠道中发挥细胞因子诱导作用，表明LAB DNA是口服疫苗佐剂的良好候选物。