Interleukin-21 and tumor necrosis factor-α are critical for the development of autoimmune gastritis in mice

Authors

  • Hisayo Nishiura,

    1. Department of Gastroenterology and Hepatology, Kyoto University, Sakyo-ku, Kyoto, Japan
    2. Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
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  • Satoru Iwamoto,

    1. Department of Gastroenterology and Hepatology, Kyoto University, Sakyo-ku, Kyoto, Japan
    2. Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
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  • Masahiro Kido,

    1. Department of Gastroenterology and Hepatology, Kyoto University, Sakyo-ku, Kyoto, Japan
    2. Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
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  • Nobuhiro Aoki,

    1. Department of Gastroenterology and Hepatology, Kyoto University, Sakyo-ku, Kyoto, Japan
    2. Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
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  • Ryutaro Maruoka,

    1. Department of Gastroenterology and Hepatology, Kyoto University, Sakyo-ku, Kyoto, Japan
    2. Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
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  • Aki Ikeda,

    1. Department of Gastroenterology and Hepatology, Kyoto University, Sakyo-ku, Kyoto, Japan
    2. Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
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  • Tsutomu Chiba,

    1. Department of Gastroenterology and Hepatology, Kyoto University, Sakyo-ku, Kyoto, Japan
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  • Norihiko Watanabe

    Corresponding author
    1. Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
    • Department of Gastroenterology and Hepatology, Kyoto University, Sakyo-ku, Kyoto, Japan
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  • The Center for Innovation in Immunoregulative Technology and Therapeutics is supported in part by the Special Coordination Funds for Promoting Science and Technology of the Japanese Government and in part by Astellas Pharma Inc. in the Formation of Innovation Center for Fusion of Advanced Technologies Program. This work is partially supported by Grants-in-aid for Scientific Research 20390207, 21229009, 23590973 from Japan Society for the Promotion of Science (JSPS), a Health and Labour Sciences Research Grant on Intractable Diseases from the Ministry of Health, Labour and Welfare, Japan, Grants-in-Aid for Research by the Japanese Society of Gastroenterology, The Kato Memorial Trust for Nambyo Research, and The Waksman Foundation of Japan.

Correspondence

Dr Norihiko Watanabe, Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. Email: norihiko@kuhp.kyoto-u.ac.jp

Abstract

Background and Aim

Autoimmune gastritis (AIG), an organ-specific autoimmune disease, is accompanied by achlorhydria, pernicious anemia, gastric carcinoid tumors, and gastric cancer. Patients with AIG initially respond to corticosteroids but have a great potential to relapse after treatment is withdrawn. This study examines the roles of cytokines in order to identify potential therapeutic options for AIG patients.

Methods

Using a mouse model of AIG, we monitored disease progression and administered antibodies in vivo to block cytokines.

Results

We developed a mouse model of AIG with early onset and rapid progression in which neonatal thymectomy (NTx) was performed on programmed cell death 1-deficient (PD-1−/−) mice on the BALB/c background. Using NTx–PD-1−/− mice, we found that in AIG lesions, interferon-γ, and tumor necrosis factor (TNF)-α together with interleukin-21 (IL-21) were highly expressed in the inflamed gastric mucosa. In addition, as with the injection of dexamethasone, in vivo administration of either anti-TNF-α or anti-IL-21 suppressed the development of AIG in NTx–PD-1−/− mice.

Conclusions

These data reveal the essential role of IL-21 in the development of AIG and suggest that in addition to corticosteroids, anti-TNF-α as well as anti-IL-21 have the potential to induce the remission of AIG, offering additional therapeutic options for AIG patients.

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