Orally administered TGF-β is biologically active in the intestinal mucosa and enhances oral tolerance
Orally administered TGF-β is biologically active in the intestinal mucosa and enhances oral tolerance
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DOI：
10.1016/j.jaci.2007.05.023
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发表时间：
2007-10-01
影响因子：
14.2
通讯作者：
Nakao, Atsuhito
中科院分区：
文献类型：
--
作者：
Ando, Takashi;Hatsushika, Kyosuke;Nakao, Atsuhito
背景：流行病学研究表明，母乳中的TGF-β在婴儿期对过敏性疾病提供保护。然而，目前尚不清楚口服施用的TGF-β，如人乳中的TGF-β，是否在肠粘膜中保留和发挥其活性，并可影响对饮食抗原的免疫应答（耐受性）。目的：我们试图确定口服TGF-β是否在肠粘膜中具有生物活性并影响口服耐受性。研究方法：通过用表达Smad应答报告构建体的转基因小鼠（SBE-luc小鼠）进行体内成像，通过用抗磷酸化Smad 2抗体进行免疫组织化学染色，以及通过TGF-β和Smad 7 mRNA表达的实时RT-PCR分析，评价经口施用的TGF-β在肠粘膜中的活性。在通过高剂量卵清蛋白（OVA）喂养耐受的小鼠中评估口服施用TGF-β对口服耐受诱导的影响。结果如下：TGF-β的口服给药增加了SBE-luc小鼠肠道中Smad反应性报告基因活性，并诱导了BALB/c小鼠肠道中Smad 2磷酸化以及TGF-β和Smad 7 mRNA表达。口服TGF-β后，血清TGF-β水平也升高。与单独经口给予OVA的小鼠相比，经口给予OVA和TGF-β的BALB/c小鼠表现出OVA特异性IgE和IgG 1抗体、T细胞反应性和速发型皮肤反应的降低。结论：口服TGF-β在肠粘膜中保留了足够的生物活性，并增强了口服耐受性。临床意义：口服TGF-β可能成为预防过敏性疾病（如食物过敏）的潜在策略。
Background: Epidemiologic studies suggest that TGF-beta in breast milk provides protection against allergic disease during infancy. However, it is unclear whether orally administered TGF-beta, such as TGF-beta in human milk, retains and exerts its activity in the intestinal mucosa and can affect immune response (tolerance) to dietary antigens. Objective: We sought to determine whether orally administered TGF-beta is biologically active in intestinal mucosa and affects oral tolerance. Methods: Activity of orally administered TGF-beta in the intestinal mucosa was evaluated by means of in vivo imaging with transgenic mice expressing a Smad-responsive reporter construct (SBE-luc mice), by means of immunohistochemical staining with anti-phosphorylated Smad2 antibody, and by means of real-time RT-PCR analysis of TGF-beta and Smad7 mRNA expression. The effects of orally administered TGF-beta on oral tolerance induction were assessed in mice tolerized by means of high-dose ovalbumin (OVA) feeding. Results: The oral administration of TGF-beta increased Smad-responsive reporter activity in the intestines of SBE-luc mice and induced Smad2 phosphorylation and TGF-beta and Smad7 mRNA expression in the intestines of BALB/c mice. Serum TGF-beta levels were also increased after oral administration of TGF-beta. BALB/c mice treated orally with OVA and TGF-beta showed augmented reduction of OVA-specific IgE and IgG1 antibodies, T-cell reactivity, and immediate-type skin reactions when compared with the mice treated orally with OVA alone. Conclusions: Orally administered TGF-beta retains sufficient biologic activity in intestinal mucosa and enhances oral tolerance. Clinical implications: Oral administration of TGF-beta might become a potential strategy to prevent allergic diseases, such as food allergy.