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2013 Fiscal Year Final Research Report

Immune mechanisms involved in the development of fatal autoimmune hepatitis in mice

Research Project

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Project/Area Number 23590973
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionKyoto University

Principal Investigator

WATANABE Norihiko  京都大学, 医学(系)研究科(研究院), 非常勤講師 (50419446)

Project Period (FY) 2011 – 2013
Keywords内科学 / 肝臓病学 / 免疫学 / 劇症肝炎 / 自己免疫性肝炎 / 消化管免疫 / サイトカイン / ケモカイン
Research Abstract

Some of the patients with autoimmune hepatitis (AIH) manifest liver failure at initial presentation. However, it is unknown how the progression to fulminant hepatitis occurs. We developed a mouse model of fulminant AIH by inducing a concurrent loss of Foxp3+ regulatory T cells and PD-1-mediated signaling. During AIH progression in these mice, T-bet together with IFN-gamma and CXCR3 were highly expressed in the inflamed liver, and T cells in the spleen and inflamed liver dominantly expressed CXCR3. Expression of one CXCR3 ligand, CXCL9, was elevated in the liver; in vivo administration of anti-CXCL9 suppressed AIH progression. In addition, serum levels of IL-18 were elevated during progression, and dendritic cells in the spleen and liver highly produced IL-18. In vivo administration of anti-IL-18R suppressed the increase of splenic CXCR3+ T cells and the fatal progression of hepatitis. These data suggest that in our model, IL-18 is critical for the progression to fulminant hepatitis.

  • Research Products

    (27 results)

All 2014 2013 2012 2011

All Journal Article (11 results) (of which Peer Reviewed: 11 results) Presentation (16 results)

  • [Journal Article] Progression of autoimmune hepatitis is mediated by IL-18- producing dendritic cells and hepatic CXCL9 expression in mice2014

    • Author(s)
      Ikeda A, Aoki N, Kido M, Iwamoto S, Nishiura H, Maruoka R, Chiba T, Watanabe N
    • Journal Title

      Hepatology

      Volume: (Epub ahead of print)

    • DOI

      10.1002/hep.27087

    • Peer Reviewed
  • [Journal Article] Splenectomy prolongs the effects of corticosteroids in mouse models of autoimmune hepatitis2013

    • Author(s)
      Maruoka R, Aoki N, Kido M, Iwamoto S, Nishiura H, Ikeda A, Chiba T, Watanabe N
    • Journal Title

      Gastroenterology

      Volume: 145 Pages: 209-220

    • DOI

      10.1053/j.gastro.2013.03.011

    • Peer Reviewed
  • [Journal Article] Interleukin-21 and TNF-αare critical for the development of autoimmune gastritis in mice2013

    • Author(s)
      Nishiura H, Iwamoto S, Kido M, Aoki N, Maruoka R, Ikeda A, Chiba T, Watanabe N
    • Journal Title

      J Gastroenterol Hepatol

      Volume: 28 Pages: 982-991

    • DOI

      10.1111/jgh.12144

    • Peer Reviewed
  • [Journal Article] TNF-αis essential in the induction of fatal autoimmune hepatitis in mice through upregulation of hepatic CCL20 expression2013

    • Author(s)
      Iwamoto S, Kido M, Aoki N, Nishiura H, Maruoka R, Ikeda A, Okazaki T, Chiba T, Watanabe N
    • Journal Title

      Clin Immunol

      Volume: 146 Pages: 15-25

    • DOI

      10.1016/j.clim.2012.10.008

    • Peer Reviewed
  • [Journal Article] Langerhans cells are critical in epicutaneous sensitization with protein antigen via TSLP receptor signaling2012

    • Author(s)
      Nakajima S, Igyarto B, Honda T, Egawa G, Otsuka A, Hara-Chikuma M, Watanabe N, Ziegler SF, Tomura M, Miyachi Y, Kaplan DH, Kabashima K
    • Journal Title

      J Allergy Clin Immunol

      Volume: 129 Pages: 1048-1055

    • DOI

      10.1016/j.jaci.2012.01.063

    • Peer Reviewed
  • [Journal Article] Increased susceptibility to autoimmune gastritis in thymic stromal lymphopoietin receptor- deficient mice2012

    • Author(s)
      Nishiura H, Kido M, Aoki N, Iwamoto S, Maruoka R, Ikeda A, Chiba T,Ziegler SF, Watanabe N
    • Journal Title

      J Immunol

      Volume: 188 Pages: 190-197

    • DOI

      10.4049/jimmunol.1003787

    • Peer Reviewed
  • [Journal Article] IFN-αis reciprocally involved in the concurrent development of organ-specific autoimmunity in the liver and stomach2012

    • Author(s)
      Iwamoto S, Kido M, Aoki N, Nishiura H, Maruoka R, Ikeda A, Okazaki T,Chiba T, Watanabe N
    • Journal Title

      Autoimmunity

      Volume: 45 Pages: 186-198

    • DOI

      10.3109/08916934.2011.616559

    • Peer Reviewed
  • [Journal Article] Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori : a multicentre cohort follow-up study of 420 patients in Japan2012

    • Author(s)
      Nakamura S, Sugiyama T, Matsumoto T, Iijima K, Ono S, Tajika M, TariA, Kitadai Y, Matsumoto H, Nagaya T, Kamoshida T, Watanabe N, Chiba T, Origasa H, Asaka M; for the JAPAN GAST Study Group
    • Journal Title

      Gut

      Volume: 61 Pages: 507-513

    • DOI

      10.1136/gutjnl-2011-300495

    • Peer Reviewed
  • [Journal Article] Dual roles of CagA protein in Helicobacter pylori-induced chronic gastritis in mice2011

    • Author(s)
      Kido M, Watanabe N, Aoki N, Iwamoto S, Nishiura H, Maruoka R, IkedaA, Azuma T, Chiba T
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 412 Pages: 266-272

    • DOI

      10.1016/j.bbrc.2011.07.081

    • Peer Reviewed
  • [Journal Article] Acute airway obstruction in a patient with achalasia2011

    • Author(s)
      Miyamoto S, Konda Y, Matsui M, Sawada K, Ikeda K, Watanabe N, Kawanami C, Chiba T
    • Journal Title

      Intern Med

      Volume: 50 Pages: 2333-2336

    • URL

      https://www.jstage.jst.go.jp/article/internalmedicine/50/20/50_20_2333/_article

    • Peer Reviewed
  • [Journal Article] Primary gastrointestinal follicular lymphoma involving the duodenal second portion is a distinct entity : a multicenter, retrospective analysis in Japan2011

    • Author(s)
      Takata K, Okada H, Ohmiya N, Nakamura S, Kitadai Y, Tari A, Akamatsu T, Kawai H, Tanaka S, Araki H, Yoshida T, Okumura H, Nishisaki H, Sagawa T, Watanabe N, Arima N, Takatsu N, Nakamura M, Yanai S, Kaya H, Morito T, Sato Y, Moriwaki H, Sakamoto C, Niwa Y, Goto H, Chiba T, Matsumoto T, Ennishi D, Kinoshita T, Yoshino T
    • Journal Title

      Cancer Sci

      Volume: 102 Pages: 1532-1536

    • DOI

      10.1111/j.1349-7006.2011.01980

    • Peer Reviewed
  • [Presentation] 新たに確立した動物モデルを用いた自己免疫性肝炎の病態解明と新規治療法の開発難治性疾患等克服研究事業(難治性疾患克服研究事業)「難治性の肝・胆道疾患に関する調査研究」班2013

    • Author(s)
      渡部則彦
    • Organizer
      平成25年度第2回総会
    • Place of Presentation
      東京ステーションコンファレンス
    • Year and Date
      2013-12-19
  • [Presentation] 慢性から劇症まで多様な病態を呈する自己免疫性肝炎(AIH)モデルでの病態解析2013

    • Author(s)
      渡部則彦、丸岡隆太郎、池田亜希
    • Organizer
      JDDW 2013 (第55回日本消化器病学会大会)
    • Place of Presentation
      グランドプリンスホテル新高輪 東京
    • Year and Date
      2013-10-09
  • [Presentation] 自己免疫性肝炎モデルではマウスの系統の違いから同一の免疫機構の破綻によって慢性肝炎から劇症肝炎まで発症する2013

    • Author(s)
      渡部則彦、丸岡隆太郎、青木信裕、木戸正博、池田亜希、岩本諭、西浦尚代、千葉勉
    • Organizer
      第24回The Meeting of Liver and Immunology
    • Place of Presentation
      京都国際ホテル 京都
    • Year and Date
      2013-09-07
  • [Presentation] 慢性から劇症まで多様な病態を呈する自己免疫性肝炎モデルを用いたAIH病態形成機構の解明2013

    • Author(s)
      渡部則彦, 池田亜希, 丸岡隆太郎, 西浦尚代, 岩本諭, 青木信裕, 木戸正博, 千葉勉
    • Organizer
      第50回日本消化器免疫学会総会
    • Place of Presentation
      ホテルグランドヒル市谷 東京
    • Year and Date
      2013-08-01
  • [Presentation] 新たに確立した動物モデルを用いた自己免疫性肝炎の病態解明と新規治療法の開発難治性疾患等克服研究事業(難治性疾患克服研究事業)「難治性の肝・胆道疾患に関する調査研究」班2013

    • Author(s)
      渡部則彦
    • Organizer
      平成25年度第1回総会
    • Place of Presentation
      東京ステーションコンファレンス 東京
    • Year and Date
      2013-06-27
  • [Presentation] 自然発症型自己免疫性肝炎モデルを用いたステロイド治療にかわる新規治療法の探索2012

    • Author(s)
      渡部則彦,丸岡隆太郎、青木信裕
    • Organizer
      第49回日本消化器免疫学会総会
    • Place of Presentation
      城山観光ホテル 鹿児島
    • Year and Date
      2012-07-05
  • [Presentation] 自己免疫性肝炎(AIH)新規モデルマウスの病態から重症・難治性AIHの治療をさぐる2012

    • Author(s)
      青木信裕、丸岡隆太郎、渡部則彦
    • Organizer
      第48回日本肝臓学会総会
    • Place of Presentation
      ANAクラウンプラザホテル金沢 金沢
    • Year and Date
      2012-06-07
  • [Presentation] Splenectomy overcomes therapeutic insufficiency of corticosteroids and induces prolonged remission2012

    • Author(s)
      Maruoka R, Aoki N, Watanabe N
    • Organizer
      DDW2012
    • Place of Presentation
      San Diego, USA
    • Year and Date
      2012-05-21
  • [Presentation] 新規致死性自己免疫性肝炎(AIH)モデルにおけるAIH劇症化機序の解明2012

    • Author(s)
      青木信裕、木戸政博、渡部則彦
    • Organizer
      第98回日本消化器病学会総会
    • Place of Presentation
      京王プラザホテル 東京
    • Year and Date
      2012-04-20
  • [Presentation] Fatal immune-mediated liver injury is triggered by dysregulated follicular-helper T cells in the spleen of mice―Splenectomy overcomes therapeutic insufficiency of corticosteroids and induces remission2012

    • Author(s)
      Watanabe N
    • Organizer
      EASL Monothematic Conference : Immune Mediated Liver Injury
    • Place of Presentation
      Stratford-Upon-Avon, United Kingdom
    • Year and Date
      2012-01-20
  • [Presentation] 致死性自己免疫性肝炎マウスモデルの発症における脾臓TFH細胞の関与2011

    • Author(s)
      青木信裕、渡部則彦
    • Organizer
      第40回日本免疫学会学術集会
    • Place of Presentation
      幕張メッセ 千葉
    • Year and Date
      2011-11-28
  • [Presentation] Mechanisms involved in fatal progression of autoimmune hepatitis in mice2011

    • Author(s)
      Aoki N, Watanabe N
    • Organizer
      AASLD The Liver Meeting 2011
    • Place of Presentation
      San Francisco, USA
    • Year and Date
      2011-11-07
  • [Presentation] Mechanisms involved in fatal progression of autoimmune hepatitis in mice2011

    • Author(s)
      Aoki N, Watanabe N
    • Organizer
      UEGW Stockholm 2011
    • Place of Presentation
      Stockholm, Sweden
    • Year and Date
      2011-10-24
  • [Presentation] 新規自己免疫性肝炎(AIH)モデルにおけるAIH劇症化機構の解明2011

    • Author(s)
      青木信裕、渡部則彦
    • Organizer
      第19回日本消化器関連学会週間
    • Place of Presentation
      福岡国際会議場 福岡
    • Year and Date
      2011-10-20
  • [Presentation] 新規致死性自己免疫性肝炎(AIH)モデルにおける発症機構の解明と新たな免疫療法の開発2011

    • Author(s)
      青木信裕、渡部則彦
    • Organizer
      第48回日本消化器免疫学会総会
    • Place of Presentation
      金沢エクセル東急 石川
    • Year and Date
      2011-07-21
  • [Presentation] 新規モデルマウスを用いた自己免疫性肝炎(AIH)発症機序の解明2011

    • Author(s)
      青木信裕、渡部則彦
    • Organizer
      第47回日本肝臓病学会総会
    • Place of Presentation
      ホテルグランパシフィックLE DAIBA 東京
    • Year and Date
      2011-06-03

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Published: 2015-07-16  

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