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Role of the aryl hydrocarbon receptor in establishing oral tolerance

芳烃受体在建立口服耐受中的作用

基本信息

批准号：
221398890
负责人：
Professorin Dr. Charlotte Esser
金额：
--
依托单位：
Leibniz-Institut für umweltmedizinische Forschung (IUF)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/221398890?language=en
关键词：
Role aryl hydrocarbon receptor establishing

项目摘要

In this project the role of the aryl hydrocarbon receptor in oral tolerance will be analysed in mouse models. Oral tolerance is a vital function of the immune system, ensuring that no immune response is raised against harmless food proteins. Our previous work has demonstrated that feeding mice with the man-made environmental pollutant 2,3,7,8-Tetrachlordibenzo-p-dioxin (TCDD) destabilizes oral tolerance. TCDD is a strong activator of the intracellular transcription factor aryl hydrocarbon receptor (AhR). Underlying causes of TCDD-impaired oral tolerance were changes in the cytokine secretion of gut draining dendritic cells, correlated to changes in the balance of regulatory T cells and inflammatory T cells. For mice, which lack the AhR , i.e. the sensor for substances like TCDD, oral tolerance was also impaired, albeit mechanisms differed. In AhR-deficient mice gut lymphocytes involved in regulatory functions were significantly reduced. Many edible plants contain compounds, which bind and activate the AhR similar to TCDD. However, it is unknown whether such compounds, e.g. indoles or polyphenols, affect or impair oral tolerance. Many plant-derived potential AhR ligands, such as indol-3-carbinol, quercetin oder epigallo-catechingallate are marketed as nutritional complements. We want to analyse whether also plant-derived AhR-ligands affect oral tolerance, and whether this influences food allergies. In a second part the underlying mechanisms of AhR-dependent disturbances of oral tolerance shall be dissected using conditional AhR-deficient mouse models. Thereby we want to identify the cells and potential factors such as cytokines, which are involved. We expect our data to contribute to a better understanding of the role of AhR in the gut immune system. Moreover, the data will be prerequisite for any therapeutic or preventive use of AhR-ligands in oral tolerance or food allergy.

在本项目中，将在小鼠模型中分析芳烃受体在口服耐受性中的作用。口服耐受性是免疫系统的重要功能，确保不会对无害的食物蛋白产生免疫反应。我们以前的工作已经证明，用人造环境污染物2，3，7，8-四氯二苯并对二恶英（TCDD）喂养小鼠会破坏口服耐受性。TCDD是细胞内转录因子芳烃受体（AhR）的强激活剂。TCDD口服耐受性受损的根本原因是肠道引流树突状细胞细胞因子分泌的变化，与调节性T细胞和炎性T细胞平衡的变化相关。对于缺乏AhR的小鼠，即TCDD等物质的传感器，口服耐受性也受到损害，尽管机制不同。在AhR缺陷的小鼠肠道淋巴细胞参与调节功能显着减少。许多可食用植物含有与TCDD类似的化合物，可以结合并激活AhR。然而，尚不清楚此类化合物，例如吲哚或多酚，是否影响或损害口服耐受性。许多植物来源的潜在AhR配体，如吲哚-3-甲醇、槲皮素或表没食子儿茶素没食子酸酯作为营养补充剂销售。我们想分析植物来源的AhR配体是否也会影响口服耐受性，以及这是否会影响食物过敏。在第二部分中，将使用条件性AhR缺陷小鼠模型剖析AhR依赖性口服耐受性紊乱的潜在机制。因此，我们希望识别参与的细胞和潜在因子，如细胞因子。我们希望我们的数据有助于更好地了解AhR在肠道免疫系统中的作用。此外，这些数据将是AhR配体在口服耐受或食物过敏中的任何治疗或预防用途的先决条件。