Adaptation of therapeutic agents for Th1 cell dependent severe asthma using asthmatic murine model

• Project/Area Number: 20K17436
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• 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: Kouyama SatoshiSatoshi 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)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: T細胞 / 気管支喘息 / アレルギー反応 / アレルギー / 喘息 / サイトカイン / Th細胞

Outline of Research at the Start

我々は、マウスから多数のT細胞クローン株を樹立し、喘息反応との因果関係を解析してきた。重症性とステロイド抵抗を示すT細胞クローン株がTh1型であり、従来の知見に基づくTh2ターゲットの治療とは異なるアプローチが求められることに着目し、この研究を計画した。そこで近年開発が加速し、新たな治療ターゲットとして期待されている分子標的治療薬の投与効果を検証する。喘息の機序に特異性の高い分子標的治療薬の中には、白血病など他分野で治験が進められているものから承認済みのものまで多数存在するが、アレルギー疾患への適応は多くが未開である。T細胞クローンとその動物モデルから治療効果を調査し、治験の足掛かりを目指す。

Outline of Final Research Achievements

Drug candidates were selected from known investigational and approved molecular targeted drugs. Inhibition of activity was observed in T-cell clones that induce late asthmatic response and in T-cell clones that induce eosinophilic inflammation. These were found to have additive inhibitory effects with glucocorticoids. As a cellular diagnosis in animal models, Th2 eosinophil infiltration in the alveoli was greatly suppressed. However, inhibition of neutrophil infiltration of Th1 clones was very limited. None of the Th1-transfected mouse models showed significant improvement in respiratory indices.
As a result, the effect on cellular and respiratory indices is limited.
In addition, we observed that Th1, which is not dependent on antigen presentation, exhibited very high survival in response to steroids and molecularly targeted therapies. Thus, these findings suggest that Th1's antigen presentation-independent viability may be responsible for its refractoriness in asthma.

Academic Significance and Societal Importance of the Research Achievements

我が国において、成人人口の3～4％の有病率とされる喘息は、新たな治療薬やガイドラインの改定が奏功しつつある一方、依然、年間おそよ2000人の死者をもたらす重大な疾患である。一方で、我が国で承認された新薬の15％は腫瘍用薬とその他の代謝性医薬品すなわちがん治療の医薬である。抗腫瘍の分子標的治療薬には、喘息と機序の一部を共通する細胞表面および細胞内シグナル経路ターゲットを持つものも含まれる。
我々は、複合的な喘息の病因・病態の中でもTh1細胞がマウス喘息モデルで難治性かつ重症化する性質を報告している。動物モデルから喘息治療への有効性を明らかにし、重症喘息治療への適応の足掛かりとなることが期待できる。

Research Products

• [Journal Article] Steroid resistance of severe asthma — mechanisms and therapeutic targets (2022)
  • Author(s): 森 晶夫, 神山 智, 大友 暁美, 山口 美也子, 組谷 智恵美, 岩本 圭右, 矢野 光一, 藤田 教寛, 岩田 真紀, 永山 貴紗子, 劉 楷, 中村 祐人, 濱田 祐斗, 渡井 健太郎, 上出 庸介, 福富 友馬, 関谷 潔史, 松元 幸一郎, 谷本 安, 小林 信之, 大友 隆之, 神沼 修
  • Journal Title: Folia Pharmacologica Japonica Volume: 157 Issue: 5 Pages: 293-298
  • DOI: 10.1254/fpj.22027
  • ISSN: 0015-5691, 1347-8397
• [Presentation] Biochemical analysis of T cell dependent bronchoconstriction (2023)
  • Author(s): Kouyama S, Ohtomo-Abe A, Tawasaki Y, Iwata M, Nakamura Y, Hamada Y, Kamide Y, Sekiya K, Fukutomi Y, Ohtomo T, Kaminuma O, Mori A
  • Organizer: American Academy of Allergy Asthma & Immunology Annual Meeting 2023
  • Int'l Joint Research
• [Presentation] Biochemical characterization of T cell derived bronchoconstrictor (2023)
  • Author(s): Kouyama S, Ohtomo-Abe A, Kawasai Y, Iwata M, Nakamura Y, Hamada Y, Kamide Y, Sekiya K, Fukutomi Y, Ohtomo T, Kaminuma O, Mori A
  • Organizer: European Academy of Allergy and Clinical Immunology Hybrid Congress 2023
  • Int'l Joint Research
• [Presentation] Biological and biochemical analysis of T cell derived bronchoconstriction (2023)
  • Author(s): Kouyama S, Ohtomo-Abe A, Kawasaki Y, Iwata M, Nakamura Y, Hamada Y, Kamide Y, Sekiya K, Fukutomi Y, Ohtomo T, Kaminuma O, Mori A
  • Organizer: European Respiratory Society 2023 International Congress
  • Int'l Joint Research
• [Presentation] Cellular Analysis of T cell-dependent steroid-resistant asthma (2023)
  • Author(s): Kouyama S, Ohtomo-Abe A, Kawasaki Y, Nakamura Y, Kamide Y, Sekiya K, Ohtomo T, Kaminuma O, Mori A
  • Organizer: Asia Pacific Association of Allergy, Asthma and Clinical Immunology International Conference 2023
  • Int'l Joint Research
• [Presentation] Cellular and molecular analysis of T cell-dependent steroid-resistant asthma model (2023)
  • Author(s): Kouyama S, Ohtomo-Abe A, Kawasaki Y, Nakamura Y, Hamada Y, Kamide Y, Sekiya K, Fukutomi Y, Ohtomo T, Kaminuma O, Mori A
  • Organizer: Asia Pacific Society of Respirology 2023 International Congress
  • Int'l Joint Research
• [Presentation] Pharmacological characterization of T cell-induced bronchoconstriction (2023)
  • Author(s): Kouyama S, Ohtomo-Abe A, Kawasai Y, Iwata M, Nakamura Y, Kamide Y, Sekiya K, Fukutomi Y, Ohtomo T, Kaminuma, O, Mori A
  • Organizer: World Allergy Congress 2023
  • Int'l Joint Research
• [Presentation] T cell-dependent steroid-resistant asthma is mediated by tyrosine kinases of costimulatory signal (2022)
  • Author(s): Mori, A., Kouyama, S., Ohtomo-Abe, A., Iwamoto, K., Yano, K., Fujita, N., Iwata, M., Nagayama, K., Nakamura, Y., Hamada, Y., Watai, K., Kamide, Y., Sekiya, K., Fukutomi, Y., Ohtomo, T., Kaminuma, O
  • Organizer: European Academy of Allergy and Clinical Immunology Hybrid Congress 2022
  • Int'l Joint Research
• [Presentation] Control of T cell-dependent steroid-resistant asthma model by several kinase inhibitors (2022)
  • Author(s): Mori, A., Kouyama, S., Yamaguchi, M., Ohtomo-Abe, A., Iwamoto, K., Yano, K., Fujita, N., Iwata, M., Nagayama K., Ryu, K., Nakamura, Y., Hamada, Y., Watai, K., Kamide, Y., Sekiya, K., Fukutomi, Y., Ohtomo, T., Kaminuma, O.
  • Organizer: European Respiratory Society International Congress 2022
  • Int'l Joint Research
• [Presentation] Pharmacological characterization of T cell-dependent steroid-resistant asthma model using several kinase inhibitors (2022)
  • Author(s): Mori, A., Kouyama, S., Ohtomo-Abe, A., Kawasaki, Y., Iwata, M., Nakamura, Y., Hamada, Y., Kamide, Y., Sekiya, K., Fukutomi, Y., Ohtomo, T., Kaminuma, O.
  • Organizer: The 26th Congress of the Asian Pacific Society of Respirology
  • Int'l Joint Research
• [Presentation] 重症喘息のステロイド抵抗性とその制御 (2022)
  • Author(s): 森晶夫、神山智、大友暁美、山口美也子、組谷千恵美、岩本圭右、矢野光一、藤田教寛、岩田真紀、永山貴紗子、劉楷、中村祐人、濱田祐斗、渡井健太郎、上出庸介、福冨友馬、関谷潔史、松元幸一郎、谷口安、小林信之、大友隆之、神沼修
  • Organizer: 第95回日本薬理学会年会
• [Presentation] Molecular characterization of bronchoconstriction induced by activated T cells (2021)
  • Author(s): Kouyama, S., Yamaguchi, M., Kumitani, C., Ohtomo-Abe, A., Kawasaki, Y., Iwamoto, K., Yano, K., Iwata, M., Nagayama, K., Ryu, K., Nakamura, Y., Hamada, Y., Watai, K., Kamide, Y., Sekiya, K., Fukutomi Y, Ohtomo, T., Kaminuma, O, and Mori, A.
  • Organizer: European Respiratory Society 2021 International Congress (London, on line)
  • Int'l Joint Research
• [Presentation] Possible mechanisms of T cell-induced bronchoconstriction (2021)
  • Author(s): Mori, A., Kouyama, S., Ohtomo-Abe, A., Ryu, K., Nakamura, Y., Hamada, Y., Watai, K., Kamide, Y., Sekiya, K., Ohtomo, T., Kaminuma, O.
  • Organizer: Asia Pacific Association of Allergy, Asthma and Clinical Immunology International Conference 2021 (Taipei, on line)
  • Int'l Joint Research
• [Presentation] Pharmacological characterization of T cell-induced bronchoconstriction in vivo and in vitro (2021)
  • Author(s): Mori, A., Kouyama, S., Yamaguchi, Y., Kumitani, C., Ohtomo-Abe, A., Kawasaki, Y., Iwamoto, K., Yano, K., Iwata, M., Nagayama, K., Ryu, K., Nakamura, Y., Hamada, Y., Watai, K., Kamide, Y., Sekiya, K., Fukutomi, Y., Ohtomo, T., and Kaminuma, O
  • Organizer: European Academy of Allergy and Clinical Immunology Hybrid Congress 2021 (Madrid 8211; Krakow, on line)
  • Int'l Joint Research
• [Presentation] Pharmacological analysis of helper T cell-dependent, steroid-resistant asthma (2020)
  • Author(s): Mori A, Kouyama S
  • Organizer: european academy of allergy and clinical immunology 2020
  • Int'l Joint Research
• [Presentation] Pharmacological analysis of T cell-dependent, steroid-resistant asthma. (2020)
  • Author(s): Mori A, Kouyama S
  • Organizer: european respiratory society international congress 2020
  • Int'l Joint Research