Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pharmacol Ther. May 6, 2016; 7(2): 242-253
Published online May 6, 2016. doi: 10.4292/wjgpt.v7.i2.242
Oral tolerance is inducible during active dextran sulfate sodium-induced colitis
Satoshi Ino, Chikara Kohda, Kosuke Takeshima, Hiroki Ishikawa, Tomoko Norose, Toshiko Yamochi, Masafumi Takimoto, Hiroshi Takahashi, Kazuo Tanaka
Satoshi Ino, Chikara Kohda, Kosuke Takeshima, Hiroki Ishikawa, Kazuo Tanaka, Department of Microbiology and Immunology, School of Medicine, Showa University, Tokyo 142-8555, Japan
Tomoko Norose, Toshiko Yamochi, Masafumi Takimoto, Department of Pathology and Laboratory Medicine, School of Medicine, Showa University, Tokyo 142-8555, Japan
Hiroshi Takahashi, Division of Gastroenterology, Department of Internal Medicine, Showa University, Yokohama 227-8501, Japan
Author contributions: Ino S, Kohda C and Takeshima K performed the majority of experiments and analyzed the data; Norose T, Yamochi T and Takimoto M contributed pathological analysis; Kohda C, Ishikawa H, Takahashi H and Tanaka K designed and coordinated the research; Ino S and Kohda C wrote the paper.
Institutional review board statement: All procedures involving experimental animals were approved by the Institutional Animal Care and Use Committee of Showa University (Permit Number: 04127) and complied with the Guide for the Care and Use of Laboratory Animals (7th and 8th edition, ILAR-NRC). In our facility, the Animal Care and Use Committee of Showa University also functions as an Institutional Review Board for animal experiments.
Institutional animal care and use committee statement: All procedures involving experimental animals were approved by the Institutional Animal Care and Use Committee of Showa University (Permit Number: 04127) and complied with the Guide for the Care and Use of Laboratory Animals (7th and 8th edition, ILAR-NRC).
Conflict-of-interest statement: To the best of our knowledge, no conflict of interest exists.
Data sharing statement: A technical appendix, statistical code, and dataset are available from the corresponding author at kohda@med.showa-u.ac.jp. All participants provided informed consent for data sharing.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Chikara Kohda, PhD, Assistant Professor, Department of Microbiology and Immunology, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. kohda@med.showa-u.ac.jp
Telephone: +81-3-37848131 Fax: +81-3-37843069
Received: November 27, 2015
Peer-review started: November 28, 2015
First decision: December 24, 2015
Revised: January 20, 2016
Accepted: February 16, 2016
Article in press: February 17, 2016
Published online: May 6, 2016
Abstract

AIM: To investigate whether oral tolerance is inducible during the active phase of dextran sulfate sodium (DSS)-induced colitis.

METHODS: Colitis was induced in 6- to 8-wk-old female BALB/c mice by the administration of 2% DSS. To induce oral tolerance, mice that received water with DSS [DSS (+)] and mice that received autoclaved water [DSS (-)] were intragastrically (i.g.) administered ovalbumin (OVA) as a tolerogen before systemic challenge with OVA. Following this, serum levels of OVA-specific IgE antibodies were measured. In mice with active colitis, CD4+CD25+Foxp3+ cell and B10 cell frequencies were evaluated using flow cytometry. Cytokine mRNA expression profiles were evaluated by reverse transcription real-time polymerase chain reaction.

RESULTS: Regardless of the presence of DSS colitis, OVA-specific immunoglobulin E concentrations were significantly reduced in mice that were i.g. administered OVA compared to mice that were i.g. administered PBS [DSS (+): 4.4 (4.2-9.5) ng/mL vs 83.9 (66.1-123.2) ng/mL, P < 0.01; DSS (-): 27.7 (0.1-54.5) ng/mL vs 116.5 (80.6-213.6) ng/mL, P < 0.01]. These results demonstrated that oral tolerance was induced in both the presence and absence of colitis. In the spleen and mesenteric lymph nodes (MLN), the frequencies of CD4+CD25+Foxp3+ cells and B10 cells, both of which are associated with oral tolerance, did not significantly change. In the spleen, interferon-γ mRNA expression significantly decreased in mice with colitis [DSS (+): 0.42 (0.31-0.53) vs DSS (-): 1.00 (0.84-1.39), P < 0.01]. The expression levels of other cytokines did not significantly change.

CONCLUSION: Oral tolerance is inducible during active DSS colitis. The stability of regulatory cell populations in the spleen and MLN in colitis might correlate with these results.

Keywords: Cytokine, Dextran sulfate sodium colitis, Oral tolerance, Regulatory T cell, Regulatory B cell

Core tip: Our study is the first to demonstrate that oral tolerance is inducible during the active phase of dextran sulfate sodium (DSS)-induced colitis. Lymphocytic infiltration into the large intestine mucosa associated with epithelial defects did not influence oral tolerance. In DSS colitis, the frequencies of CD4+CD25+Foxp3+ T cells and B10 cells in the spleen and mesenteric lymph nodes remained stable. This stability might have led to the induction of oral tolerance in DSS colitis. Accordingly, if an appropriate antigen is chosen, then oral immunotherapy may be applicable for the treatment of ulcerative colitis.