Study On The Genes Mediating Oral Tolerance In A Murine Model Of Allergic Asthma
Date Issued
2007
Date
2007
Author(s)
Yu, Shih-Yi
DOI
zh-TW
Abstract
Oral tolerance is defined as a state of immunological unresponsiveness to a specific antigen after exposure to that antigen via the enteric route. This characteristic phenomenon might be used as a potential treatment for allergic diseases such as asthma. Asthma is usually regarded as a hyper-responsive airway disease involving chronic inflammation. First, we established an animal model using OVA-T-cell receptor (OVA-TCR) transgenic mice with airway hyperresponsiveness, antigen-specific IgE production, and eosinophilia. The OVA-TCR can recognize the 323-339 peptide fragment of ovalbumin (OVA). In this study, oral tolerance was induced by tube-feeding transgenic mice with 0.5mg/day OVA protein daily, simultaneously sensitized by OVA protein with aluminum hydroxide. Oral-administered OVA protein (0.5mg/day for 5 or 10 consecutive days) resulted in significant lowered airway hypersensitivity as well as reduced inflammative cells infiltration, titer of serum OVA-specific IgE, IL-5 secretion in bronchoalveolar lavage fluid(BALF), and IL-4 secretion in splenocyte. Furthermore, the proliferation of OVA-specific splenocyte was inhibited by oral-administered OVA protein. Taken together, oral administration of low-dose OVA protein induced oral tolerance, inhibited both local and systemic type II helper T cell (Th2) response, and significantly relieved airway allergic hypersensitivity.
The second goal of the present study was to evaluate the Peyer's Patch (PP) gene expression in OVA-TCR transgenic mice after oral administration of OVA protein to induce specific immune tolerance. PP gene expression patterns were examined with Affymetrix Mouse GeneChip and further confirmed by real-time PCR. We detected the gene expression level on PP tissues, mesenteric lymph nodes (MLN), and CD4+CD25+ T cells derived from spleen after oral feeding of OVA protein (200mg/day, 20mg/day, and 0.5mg/day for 5 consecutive days). The results showed that transcription factor-associated genes, including foxp3, crem, and satb1, were highly expressed by the PP of the OVA-fed mice, and the growth suppression- and anergy- associated genes rbm10 and mterfd1 were elevated both in PP and CD4+CD25+ T cells derived from spleen after oral feeding of OVA protein. In addition to these genes, cd226 and crip3 were also up-regulated on PP and MLN upon OVA protein administration. Interestingly, most of these genes were mainly expressed in the B cells of PP. Moreover, as shown in some studies, naïve B cells are ineffective antigen-presenting cells (APC) and considered unable to activate naïve T cells, and even induced regulatory T cells inhibiting priming of fresh T cells in a contact-dependent manner in vitro. These results suggested that genes mediating oral tolerance were highly expressed in B cells of PP and may have a special mechanism to regulate immune tolerance.
Subjects
口服耐受
腸道黏膜免疫
皮耶式體
腸繫膜淋巴
調控型T細胞
oral tolerance
mucosal immune system
mesenteric lymph nodes
regulatory T cell
Type
other
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