Role of the aryl hydrocarbon receptor in establishing oral tolerance

在这个项目中，芳烃受体在口服耐受中的作用将在小鼠模型中进行分析。口服耐受是免疫系统的重要功能，确保不会对无害的食物蛋白质产生免疫反应。我们之前的研究表明，给小鼠喂食人造环境污染物2,3,7,8-四氯二苯并-对二恶英（TCDD）会破坏小鼠的口服耐受能力。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细胞平衡的变化有关。对于缺乏AhR（即TCDD等物质的传感器）的小鼠，尽管机制不同，但口服耐受性也受到损害。ahr缺陷小鼠参与调节功能的肠道淋巴细胞显著减少。许多可食用植物含有类似TCDD的化合物，可以结合并激活AhR。然而，目前尚不清楚这些化合物，例如吲哚或多酚，是否会影响或损害口腔耐受性。许多植物衍生的潜在AhR配体，如吲哚-3-甲醇、槲皮素和表没食子儿茶儿茶酸酯，都被作为营养补充剂销售。我们想分析植物源性ahr配体是否也会影响口腔耐受性，以及这是否会影响食物过敏。在第二部分中，ahr依赖性口服耐受障碍的潜在机制将使用条件ahr缺陷小鼠模型进行剖析。因此，我们想要确定细胞和潜在的因素，如细胞因子，其中涉及。我们希望我们的数据有助于更好地理解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使用的先决条件。

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.