Analysis of helper T cell subset in severe asthma for the development of new immunotherapy

2011 Fiscal Year Final Research Report

• Project/Area Number: 21390255
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Chiba University
• Principal Investigator: NAKAJIMA Hiroshi 千葉大学, 大学院・医学研究院, 教授 (00322024)
• Co-Investigator(Kenkyū-buntansha): KAGAMI Shin-ichiro 千葉大学, 医学部附属病院, 助教 (30375654) ; HIROSE Koichi 千葉大学, 医学部附属病院, 講師 (90400887) ; WATANABE Norihiko 千葉大学, 大学院・医学研究院, 准教授 (20375653) ; SUTO Akira 千葉大学, 大学院・医学研究院, 助教 (50447306)
• Project Period (FY): 2009 – 2011
• Keywords: 喘息 / IL-22 / IL-21 / c-Maf / T細胞 / 免疫療法

Research Abstract

Asthma is chronic airway inflammation characterized by eosinophil infiltration, mucus hypersecretion, and airway hyperresponsiveness (AHR) to a variety of stimuli. These characteristics are mainly mediated by antigen-specific Th2 cells and their cytokines including IL-4, IL-5, and IL-13. Moreover, we and others have shown that Th17 cells induce neutrophilc airway inflammation in part through the production of IL-17A. More recently, IL-22, one of Th17 cell-derived cytokines with both proinflammatory and anti-inflammatory properties, has been shown to be detected in the airways in a murine model of asthma. However, the role of IL-22 in the regulation of allergic airway inflammation remains largely unknown.
In this study, we found that IL-22 was produced by CD4^+ T cells infiltrating in the airways upon antigen challenge, that the neutralization of IL-22 by anti-IL-22 antibody in the effector phase enhanced antigen-induced eosinophil recruitment into the airways, and that intranasal administration of recombinant IL-22 inhibited antigen-induced eosinophil recruitment into the airways. We also found that anti-IL-22 antibody enhanced antigen-induced IL-25 production in the airways, which is known to enhance Th2-type immune responses in the airways, and indeed co-injection of anti-IL-25 antibody reversed the enhancing effect of anti-IL-22 antibody on antigen-induced eosinophil recruitment into the airways. Finally, we found that IL-22 inhibited IL-13-mediated enhancement of IL-25 expression in LPS-stimulated lung epithelial cell line MLE-15 cells. Our results suggest that IL-22 attenuates antigen-induced airway inflammation in part by inhibiting the expression of IL-25 in lung epithelial cells.

Research Products

• [Journal Article] Tumor suppressor p53 functions as a negative regulator in IgE-mediated mast cell activation (2011)
  • Author(s): Suzuki K, Murphy SH, Xia Y, Yokota M, Nakagomi D, Liu F, Verma IM, Nakajima H
  • Journal Title: PLoS One Volume: 6 Pages: e25412
  • DOI: DOI:10.1371/journal.pone.0025412
  • Peer Reviewed
• [Journal Article] IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation. (2011)
  • Author(s): Takahashi K, Hirose K, Kawashima S, Niwa Y, Wakashin H, Iwata A, Tokoyoda K, Renauld JC, Iwamoto I, Nakayama T, Nakajima H
  • Journal Title: J. Allergy Clin. Immunol Volume: 128 Pages: 1067-76
  • DOI: DOI:10.1016/j.jaci.2011.06.018
  • Peer Reviewed
• [Journal Article] STAT4 is required for IFN-β-induced MCP-1 mRNA expression in murine mast cells (2011)
  • Author(s): Iida K, Suzuki K, Yokota M, Nakagomi D, Wakashin H, Iwata A, Kawashima H, Takatori H, Nakajima H
  • Journal Title: Int. Arch. Allergy Immunol Volume: 155 Pages: s71-76
  • DOI: DOI:10.1159/000327300
  • Peer Reviewed
• [Journal Article] A functional polymorphism in B and T lymphocyte attenuator is associated with susceptibility to rheumatoid arthritis (2011)
  • Author(s): Oki M, Watanabe N, Owada T, Oya Y, Ikeda K, Saito Y, Matsumura R, Seto Y, Iwamoto I, Nakajima H
  • Journal Title: Clin. Dev. Immunol Pages: 305656
  • DOI: DOI:10.1155/2011/305656
  • Peer Reviewed
• [Journal Article] Lack of B and T lymphocyte attenuator exacerbates autoimmune disorders and induces Fas-independent liver injury in MRL-lpr/lpr mice (2011)
  • Author(s): Oya Y, Watanabe N, Owada T, Oki M, Ikeda K, Suto A, Kagami S-I, Hirose K, Kishimoto T, Nakajima H
  • Journal Title: Int. Immunol Volume: 23 Pages: 335-44
  • DOI: DOI:10.1093/intimm/dxr017
  • Peer Reviewed
• [Journal Article] B and T lymphocyte attenuator suppresses IL-21 production from follicular helper T cells and subsequent humoral immune responses (2010)
  • Author(s): Kashiwakuma D, Suto A, Hiramatsu Y, Ikeda K, Takatori H, Suzuki K, Kagami S, Hirose K, Watanabe N, Iwamoto I, Nakajima H
  • Journal Title: J. Immunol Volume: 185 Pages: 2730-2736
  • DOI: DOI:10.4049/jimmunol.0903839
  • Peer Reviewed
• [Journal Article] Role of Th2 cells in IgG4-related lacrimal gland enlargement (2010)
  • Author(s): Kanari H, Kagami S, Kashiwakuma D, Oya Y, Furuta S, Ikeda K, Suto A, Suzuki K, Hirose K, Watanabe N, Okamoto Y, Yamamoto S, Iwamoto I, Nakajima H
  • Journal Title: Int. Arch. Allergy Immunol Volume: 152 Pages: s47-53
  • DOI: DOI:10.1159/000312125
  • Peer Reviewed
• [Journal Article] c-Maf activates the promoter and enhancer of IL-21 gene while TGF-β inhibits c-Maf-induced IL-21expression in CD4^+ T cells (2010)
  • Author(s): Hiramatsu Y, Suto A, Kashiwakuma D, Kanari H, Kagami S, Ikeda K, Hirose K, Watanabe N, Grusby MJ, Iwamoto I, Nakajima H
  • Journal Title: J. Leukoc. Biol Volume: 87 Pages: 703-712
  • DOI: DOI:10.1189/jlb.0909639
  • Peer Reviewed
• [Journal Article] Activation-induced accumulation of B and T lymphocyte attenuator at the immunological synapse in CD4^+ T cells (2010)
  • Author(s): Owada T, Watanabe N, Oki M, Oya Y, Saito Y, Saito T, Iwamoto I, Murphy TL, Murphy KM, Nakajima H
  • Journal Title: J. Leukoc. Biol Volume: 87 Pages: 425-432
  • DOI: DOI:10.1189/jlb.0309138
  • Peer Reviewed
• [Journal Article] Color-coded real-time cellular imaging of T lymphocyte accumulation and focus formation in mouse asthma model (2010)
  • Author(s): Hasegawa A, Hayashi K, Kishimoto H, Yang M, Tofukuji S, Suzuki K, Nakajima H, Hoffman RM, Shirai M, Nakayama T
  • Journal Title: J. Allergy Clin. Immunol Volume: 125 Pages: 461-468
  • DOI: DOI:10.1016/j.jaci.2009.09.016
  • Peer Reviewed
• [Journal Article] Protective roles of B and T lymphocyte attenuator (BTLA) in NKT cell-mediated experimental hepatitis (2010)
  • Author(s): Iwata A, Watanabe N, Oya Y, Owada T, Ikeda K, Suto A, Kagami S, Hirose K, Kanari H, Kawashima S, Nakayama T, Taniguchi M, Iwamoto I, Nakajima H
  • Journal Title: J. Immunol Volume: 184 Pages: 127-133
  • DOI: DOI:10.4049/jimmunol.0900389
  • Peer Reviewed
• [Journal Article] STAT6 Inhibits T-bet-independent Th1 cell differentiation (2009)
  • Author(s): Tamachi T, Takatori H, Fujiwara M, Hirose K, Maezawa Y, Kagami S, Suto A, Watanabe N, Iwamoto I, Nakajima H
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 382 Pages: 751-755
  • DOI: DOI:10.1016/j.bbrc.2009.03.101
  • Peer Reviewed
• [Journal Article] Protein geranylgeranylation regulates the balance between Th17 cells and Foxp3^+ regulatory T cells (2009)
  • Author(s): Kagami S, Owada T, Kanari H, Saito Y, Suto A, Ikeda K, Hirose K, Watanabe N, Iwamoto I, Nakajima H
  • Journal Title: Int. Immunol Volume: 21 Pages: 679-689
  • DOI: DOI:10.1093/intimm/dxp037
  • Peer Reviewed
• [Presentation] 胚中心反応と濾胞ヘルパーT細胞に関する最近の話題 (2012)
  • Author(s): 中島裕史
  • Organizer: 第61回日本アレルギー学会秋季学術大会
  • Place of Presentation: 東京
  • Year and Date: 2012-11-10
• [Remarks]
  • URL: http://www.m.chiba-u.jp/class/gene/index.html
• [Patent(Industrial Property Rights)] 関節リウマチに対する抗IL-6受容体抗体療法の有効性の予測方法 (2011)
  • Inventor(s): 中島裕史, 池田啓, 加々美新一郎, 鈴木快枝, 中山俊憲, 岩本逸夫, 古田俊介, 小原收, 野中謙, 山下政克, 的場亮
  • Industrial Property Rights Holder: 千葉大学
  • Industrial Property Number: 特願2011-156921
  • Filing Date: 2011-07-15