Department of Toxicology, Institute for Risk Assessment Sciences, Utrecht University, 3508 TD Utrecht, The Netherlands.
Toxicol Sci. 2011 Oct;123(2):491-500. doi: 10.1093/toxsci/kfr175. Epub 2011 Jul 29.
Food allergy is an increasing health problem in Western countries. Previously, it has been shown that the intensity of food allergic reactions can be regulated by regulatory T (T(reg)) cells. In addition, it has been shown that activation of the aryl hydrocarbon receptor (AhR) regulates T-cell responses by induction of T(reg) cells. Therefore, we hypothesized that activation of the AhR pathway can suppress development of food allergic responses through the induction of T(reg) cells. This was investigated by using a mouse model for peanut allergy. C3H/HeOuJ mice (AhR(b)(-2)) were sensitized to peanut by administering peanut extract (PE) by gavage in the presence of cholera toxin and were treated with the prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.6, 1.7, 5, and 15 μg/kg body weight) on days 3 and 11 orally. The functional role of CD4(+)CD25(+)Foxp3(+) T(reg) cells was investigated by depleting these cells with anti-CD25 mAb during sensitization to PE. TCDD treatment dose dependently suppressed sensitization to peanut (PE-specific IgE, IgG1, and IgG2a and PE-induced IL-5, IL-10, and IL-13, respectively). The percentage, but not the number, of CD4(+)CD25(+)Foxp3(+) T(reg) cells dose dependently increased by AhR activation in both spleen and mesenteric lymph nodes. Depletion of CD4(+)CD25(+)Foxp3(+) T(reg) cells markedly reversed the suppressive effect of TCDD on PE-specific antibody levels and PE-induced IL-5, IL-10, and IL-13 cytokine production. Present data demonstrate for the first time that activation of the AhR by TCDD suppressed the development of Th2-mediated food allergic responses. A functional shift within the CD4(+) cell population toward CD4(+)CD25(+)Foxp3(+) T(reg) cells appeared to underlie this effect. This suggests that the AhR pathway might provide potential therapeutic targets to treat food allergic diseases.
食物过敏是西方国家日益严重的健康问题。此前已经表明，调节性 T（Treg）细胞可以调节食物过敏反应的强度。此外，已经表明芳香烃受体（AhR）的激活通过诱导 Treg 细胞来调节 T 细胞反应。因此，我们假设 AhR 途径的激活可以通过诱导 Treg 细胞来抑制食物过敏反应的发展。通过使用花生过敏的小鼠模型对此进行了研究。C3H/HeOuJ 小鼠（AhR(b)(-2)）通过给予含有霍乱毒素的花生提取物（PE）经口致敏，并在致敏时用原型 AhR 配体 2,3,7,8-四氯二苯并-p-二恶英（TCDD）（0.6、1.7、5 和 15μg/kg 体重）进行口服治疗第 3 和 11 天。通过在致敏期间用抗 CD25 mAb 耗竭这些细胞，研究了 CD4(+)CD25(+)Foxp3(+)Treg 细胞的功能作用。TCDD 处理剂量依赖性地抑制了对花生的致敏（PE 特异性 IgE、IgG1 和 IgG2a 以及 PE 诱导的 IL-5、IL-10 和 IL-13）。在脾脏和肠系膜淋巴结中，AhR 激活后 CD4(+)CD25(+)Foxp3(+)Treg 细胞的百分比而非数量均剂量依赖性地增加。CD4(+)CD25(+)Foxp3(+)Treg 细胞的耗竭显着逆转了 TCDD 对 PE 特异性抗体水平和 PE 诱导的 IL-5、IL-10 和 IL-13 细胞因子产生的抑制作用。目前的数据首次表明，TCDD 激活 AhR 可抑制 Th2 介导的食物过敏反应的发展。CD4(+)细胞群向 CD4(+)CD25(+)Foxp3(+)Treg 细胞的功能转变似乎是这种作用的基础。这表明 AhR 途径可能为治疗食物过敏疾病提供潜在的治疗靶点。
