Investigation on steroid resistant airway inflammation

• Project/Area Number: 18K08422
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Clinical Research Center for Allergy and Rheumatology, National Hospital Organization, Sagamihara National Hospital
• Principal Investigator: MORI AKIO 独立行政法人国立病院機構(相模原病院臨床研究センター), 先端技術開発研究部, 部長 (80251247)
• Co-Investigator(Kenkyū-buntansha): 神山 智 独立行政法人国立病院機構(相模原病院臨床研究センター), 先端技術開発研究部, 研究員 (20626783) ; 神沼 修 広島大学, 原爆放射線医科学研究所, 教授 (80342921) ; 大友 隆之 東京薬科大学, 薬学部, 助教 (90463108)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ステロイド抵抗性 / 気管支喘息 / T細胞 / 炎症 / 喘息

Outline of Final Research Achievements

Severe asthma is characterized by steroid resistance. In order to analyze the cellular and molecular mechanisms of steroid resistance expressed in Th cells, steroid sensitive (SS)/resistant (SR) Th clones were established from DO11.10 transgenic for OVA-specific T cell receptor. When SS/SR Th clones were transferred to naive mice, SS/SR eosinophilic inflammation of the lung was induced upon OVA challenge. Several cytokines and molecules were differentially expressed and controlled by dexamethasone between SS and SR Th clones. Among some kinases, agent A, a T cell-selective kinase inhibitor, inhibited proliferation of SR Th clones in vitro, and SR eosinophilic inflammation in vivo. SS eosinophilic inflammation was also synergistically inhibited by the same agent in the presence of dexamethasone. Thorough discovery molecules responsible for steroid resistance will help our understanding and overcoming severe inflammatory disorders.

Academic Significance and Societal Importance of the Research Achievements

わが国の重症喘息の特徴は、1) 成人発症、2) 非アトピー型、3) T細胞レベルのステロイ
ド抵抗性である。本研究においては、T細胞レベルのステロイド抵抗性喘息モデルを活用し、オミックス解析、種々のシグナル伝達阻害剤を応用して、共シグナルの下流に位置するステロイド抵抗性を担うシグナル伝達分子、経路を解析した。低分子のステロイド抵抗性制御薬が実現すれば、アレルギー分野にとどまらず、重症炎症性疾患に共通の画期的な成果となる。本研究を進展することで、現時点では未だ解明されていないステロイド薬の抗炎症作用機序が同定できる可能性がある。

Research Products

• [Journal Article] T Cell-Mediated Nasal Hyperresponsiveness in Allergic Rhinitis (2020)
  • Author(s): Osamu Kaminuma, Tomoe Nishimura, Mayumi Saeki, Akio Mori, Takachika Hiroi
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 43 Issue: 1 Pages: 36-40
  • DOI: 10.1248/bpb.b18-01021
  • NAID: 130007779207
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2020-01-01
  • Peer Reviewed / Open Access
• [Journal Article] 専門医のためのアレルギー学講座 38.アレルギー性肺疾患（類縁疾患）の基本から最新情報まで 2.好酸球性多発血管炎性肉芽腫症 (2020)
  • Author(s): 谷口正実、関谷潔史、上出庸介、福冨友馬、渡井健太郎、濱田祐斗、中村祐人、劉 楷、藤田教寛、矢野光一、岩田真紀、永山貴紗子、森 晶夫
  • Journal Title: アレルギー Volume: 69 Pages: 293-303
• [Journal Article] 特集Ⅱ 皮膚アレルギー研究最前線 皮膚アレルギー研究に役立つ新しいマウスモデル (2020)
  • Author(s): 神沼 修、吉川日出雄、森 晶夫
  • Journal Title: 臨床免疫・アレルギー科 Volume: 73 Pages: 506-512
• [Journal Article] The serum CXCL9 is a potential marker of T1 inflammation in eosinophilic asthma (2019)
  • Author(s): . Hasegawa, T., Okazawa, T., Yabusaki, M., Uga, H., Kurata, H., and Mori, A.
  • Journal Title: Allergy Volume: 74 Issue: 12 Pages: 2515-2518
  • DOI: 10.1111/all.13924
  • Peer Reviewed
• [Journal Article] Advances in asthma, asthma-COPD overlap, and related biologics in 2018 (2019)
  • Author(s): Bacharier, L. B., Mori, A., and Kita, H.
  • Journal Title: J Allergy Clin Immunol. Volume: 144 Pages: 906-919
  • Peer Reviewed
• [Journal Article] Thrombospondin 1-mediated suppression of mast cell degranulation is involved in the efficacy of sublingual immunotherapy (2019)
  • Author(s): Kaminuma O, Kitamura N, Gotoh M, Shindo M, Watanabe N, Saeki M, Nishimura T, Mori A, Nemoto S, Tatsumi H, Okubo K, Hiroi T.
  • Journal Title: Allergology International Volume: 68 Issue: Supplement.1 Pages: S9-S10
  • DOI: 10.1016/j.alit.2019.03.007
  • NAID: 130007709743
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Potential mechanisms of T cell-mediated and eosinophil-independent bronchial hyperresponsiveness. (2019)
  • Author(s): Saeki M, Kaminuma O, Nishimura T, Kitamura N, Mori A, Hiroi T.
  • Journal Title: Int J Mol Sci. Volume: 20 Issue: 12 Pages: 2980-2981
  • DOI: 10.3390/ijms20122980
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] T Cell-Mediated Nasal Hyperresponsiveness in Allergic Rhinitis (2019)
  • Author(s): Kaminuma, O., Nishimura, T., Saeki, M., Mori, A., and Hiroi, T.
  • Journal Title: Biol. Pharm. Bull. Volume: 43 Pages: 36-40
  • NAID: 130007779207
  • Peer Reviewed
• [Journal Article] Downregulation of NFAT3 Due to Lack of T-Box Transcription Factor TBX5 Is Crucial for Cytokine Expression in T Cells (2018)
  • Author(s): Kaminuma Osamu、Kitamura Noriko、Nishito Yasumasa、Nemoto Soichi、Tatsumi Hideki、Mori Akio、Hiroi Takachika
  • Journal Title: The Journal of Immunology Volume: 200 Issue: 1 Pages: 92-100
  • DOI: 10.4049/jimmunol.1602113
  • Open Access
• [Journal Article] Contribution of neuraminidase 3 to the differentiation of induced regulatory T cells (2018)
  • Author(s): Kaminuma Osamu、Katoh Shigeki、Miyagi Taeko、Watanabe Nobumasa、Kitamura Noriko、Nishimura Tomoe、Saeki Mayumi、Mori Akio、Hiroi Takachika
  • Journal Title: Genes to Cells Volume: 23 Issue: 2 Pages: 112-116
  • DOI: 10.1111/gtc.12553
  • Peer Reviewed / Open Access
• [Journal Article] Effects of anti-allergic drugs on T cell-mediated nasal hyperresponsiveness in a murine model of allergic rhinitis (2018)
  • Author(s): Nishimura Tomoe、Kaminuma Osamu、Saeki Mayumi、Kitamura Noriko、Gotoh Minoru、Mori Akio、Hiroi Takachika
  • Journal Title: Allergology International Volume: 67 Issue: Supplement.1 Pages: S25-S31
  • DOI: 10.1016/j.alit.2018.05.002
  • NAID: 130007485137
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Presentation] Pharmacological analysis of helper T cell-dependent, steroid-resistant asthma (2020)
  • Author(s): Mori, A., Kouyama, S., Yamaguchi, M., Kumitani, C., Ohtomo-Abe, A., Fujita, N., Iwata, M., Nagayama, K., Ryu, K., Nakamura, Y., Hamada, Y., Hayashi, H., Watai, K., Kamide, Y., Sekiya, K., Fukutomi, Y., Taniguchi, M., Ohtomo, T., Kaminuma, O.
  • Organizer: European Academy of Allergy and Clinical Immunology Congress 2020
  • Int'l Joint Research
• [Presentation] Pharmacological analysis of T cell-dependent steroid-resistant asthma (2020)
  • Author(s): Mori, A., Kouyama, S., Yamaguchi, M., Kumitani, C., Ohtomo-Abe, A., Yano, K., Fujita, N., Iwata, M., Nagayama, K., Ryu, K., Nakamura, Y., Hamada, Y., Hayashi, H., Watai, K., Kamide, Y., Sekiya, K., Fukutomi, Y., Taniguchi, Ohtomo, T., and Kaminuma, O.
  • Organizer: European Respiratory Society 2020 International Congress
  • Int'l Joint Research
• [Presentation] The contribution of L-type amino acid transporter 1 in activated Th2 cells for the development of atopic dermatitis (2020)
  • Author(s): Kaminuma, O., Hayashi, K., Nishimura, T., Saeki, M., Hiroi, T., Iwata, Y., Sugiura, K., Mori, A.
  • Organizer: JSA/WAO XXVII World Allergy Congress (WAC 2020) conjoint with the APAPARI 2020 Congress
  • Int'l Joint Research
• [Presentation] An inhibitory factor for mast cell degranulation induces by sublingual immunotherapy (2020)
  • Author(s): Kaminuma, O., Gotoh, M., Kitamura, N., Shindo, M., Watanabe, N., Saeki, M., Nishimura, T., Mori, A., Nemoto, S., Tatsumi, H., Okubo, K., Hiroi, T.
  • Organizer: JSA/WAO XXVII World Allergy Congress (WAC 2020) conjoint with the APAPARI 2020 Congress
  • Int'l Joint Research
• [Presentation] The effectiveness of mepolizumab for peripheral neurological symptoms in eosinophilic granulamatosis with polyangiitis (2020)
  • Author(s): Nakamura, Y., Fukutomi, Y., Kawasaki, Y., Fujita, N., Iwata, M., Nagayama, K., Yano, K., Hamada, Y., Watai, K., Ryu, K., Hayashi, H., Kamide, Y., Mori, A., Taniguchi, M., Sekiya, K.
  • Organizer: JSA/WAO XXVII World Allergy Congress (WAC 2020) conjoint with the APAPARI 2020 Congress
  • Int'l Joint Research
• [Presentation] Elevated serum levels of galectin-10 in active eosinophilic granulomatosis with polyangiitis (2020)
  • Author(s): Kamide, Y., Ueki, S., Fukuchi, M., Fujita, N., Iwata, M., Nagayama, K., Nakamura, Y., Yano, K., Watai, K., Hamada, Y., Ryu, K., Hayashi, H., Fukutomi, Y., Sekiya, K., Mori, A., Taniguchi, M.
  • Organizer: JSA/WAO XXVII World Allergy Congress (WAC 2020) conjoint with the APAPARI 2020 Congress
  • Int'l Joint Research
• [Presentation] Synergistic suppression of T cell-induced eosinophilia by glucocorticoid and CTLA4-Ig (2019)
  • Author(s): Mori, A., Kouyama, S., Yamaguchi, M., Kumitani, C., Ohtomo-Abe, A., Fujita, N., Iwata, M., Nagayama, K., Ryu, K., Nakamura, Y., Tomita, Y., Hamada, Y., Hayashi, H., Watai, K., Kamide, Y., Sekiya, K., Fukutomi, Y., T., Taniguchi, M., Ohtomo, T., Kaminuma, O.
  • Organizer: American Academy of Allergy Asthma & Immunology Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] CD28 signal blockade as a treatment for steroid resistant asthma (2019)
  • Author(s): Mori, A., Kouyama, S., Yamaguchi, M., Kumitani, C., Ohtomo-Abe, A., Fujita, N., Iwata, M., Nagayama, K., Ryu, K., Nakamura, Y., Tomita, Y., Hamada, Y., Hayashi, H., Watai, K., Kamide, Y., Sekiya, K., Fukutomi, Y., T., Taniguchi, M., Ohtomo, T., Kaminuma, O.
  • Organizer: 17th International Congress of Immunology
  • Int'l Joint Research
• [Presentation] Control of steroid resistance by blocking costimulatory signal (2019)
  • Author(s): Mori, A., Kouyama, S., Yamaguchi, M., Kumitani, C., Ohtomo-Abe, A., Fujita, N., Iwata, M., Nagayama, K., Ryu, K., Nakamura, Y., Tomita, Y., Hamada, Y., Hayashi, H., Watai, K., Kamide, Y., Sekiya, K., Fukutomi, Y., T., Taniguchi, M., Ohtomo, T., Kaminuma, O.
  • Organizer: WAO International Scientific Conference 2019
  • Int'l Joint Research
• [Presentation] Comprehensive analysis of sputum and serum biomarkers in adult asthma (2018)
  • Author(s): Mori, A., Kouyama, S., Yamaguchi, M., Kumitani, C., Fujita, N., Iwata, M., Nagayama, K., Ryu, K., Nakamura, Y., Tomita, Y., Hamada, Y., Hayashi, H., Watai, K., Kamide, Y., Sekiya, K., Fukutomi, Y., T., Taniguchi, M., Shimoda, T., Odashima, H., Motomura, C., Fujisawa, T., Nagao, M., Shoji, S., Oshima, S., et al.
  • Organizer: Joint Congress of Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI) and Asia Pacific Association of Pediatric Allergy, Respirology & Immunology (APAPARI) 2018
  • Int'l Joint Research
• [Presentation] T cell-induced bronchoconstriction in mice (2018)
  • Author(s): Kouyama, S., Ohtomo, T., Kaminuma, O., and Mori, A.
  • Organizer: American College of Allergy and Immunology 2018
  • Int'l Joint Research
• [Presentation] Mechanisms of nonatopic, T cell-induced bronchoconstriction. (2018)
  • Author(s): Mori, A., Kouyama, S., Yamaguchi, M., Kumitani, C., Ohtomo-Abe, A., Fujita, N., Iwata, M., Nagayama, K., Ryu, K., Nakamura, Y., Tomita, Y., Hamada, Y., Hayashi, H., Watai, K., Kamide, Y., Sekiya, K., Fukutomi, Y., T., Taniguchi, M., Ohtomo, T., Kaminuma, O.
  • Organizer: WAO International Scientific Conference 2018
  • Int'l Joint Research
• [Presentation] New sensitization to Aspergillus fumigatus in adult asthma over a 10-year observation period (2018)
  • Author(s): Watai, K., Fukutomi, Y., Hayashi, H., Iwata, M., Nagayama, K., Nakamura, Y., Tanaka, J., Hamada, Y., Ryu, K., Tomita, Y., Mitsui, C., Kamide, Y., Sekiya, K., Mori, A., Asano, K., and Taniguchi, M.
  • Organizer: European Respiratory Society 2018 International Congress
  • Int'l Joint Research
• [Presentation] Pharmacological characterization of T cell-induced broncho-constriction in vitro and in vivo. (2018)
  • Author(s): Mori, A., Kouyama, S., Yamaguchi, M., Kumitani, C., Fujita, N., Iwata, M., Nagayama, K., Ryu, K., Nakamura, Y., Tomita, Y., Hamada, Y., Hayashi, H., Watai, K., Kamide, Y., Sekiya, K., Fukutomi, Y., T., Taniguchi, M., Ohtomo, T., Kaminuma, O.
  • Organizer: European Respiratory Society 2018 International Congress
  • Int'l Joint Research
• [Funded Workshop] WAO International Scientific Conference 2019 (2019)