Identification of novel therapeutic targets by elucidating the pathogenesis of murine allergic march models

• Project/Area Number: 17K10007
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Juntendo University
• Principal Investigator: Kamijo Seiji 順天堂大学, 医学(系)研究科(研究院), 助教 (00445470)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: アレルギーマーチ / プロテアーゼアレルゲン / 経皮免疫寛容 / 経皮アレルゲン感作 / マウスモデル / アレルギー / アレルゲン免疫療法 / アレルゲン / アレルギー性皮膚炎症 / アレルギー性気道炎症 / アレルギー学

Outline of Final Research Achievements

"Allergic march" refers to the natural history of allergic diseases, in which sensitization develops to more and more allergens, and the symptoms develops to more and more organs. In the present study, we used a papaya-derived allergen, papain, as a model allergen to induce murine models of the allergic march. Analyzing the murine allergic march models, we found that oral administration of cyclooxygenase inhibitor aggravates the allergic airway inflammation in the papain-induced allergic march model mice. We also found that papain-exposed skin tissue produces larger amount of sST2 (a soluble decoy receptor of IL-33) than papain-exposed lung tissue. Our results suggested that while allergy-inducing function of IL-33 is suppressed by the large amount of sST2, innate immune cell-derived IL-17A contributes to the allergen sensitization in the papain-exposed skin tissue.

Academic Significance and Societal Importance of the Research Achievements

「アレルギーマーチ」とは、時間の経過とともに次第に複数の器官にアレルギー症状が現れ、複数のアレルゲンにアレルギー応答を示すようになってゆくことを表す語である。「アレルギーマーチ」における最初のアレルゲン感作には皮膚のアレルゲン曝露が重要であることが提唱されている。本研究の成果は経皮アレルゲン感作の予防に皮膚バリアの維持が重要であることを示すとともに、アレルゲン曝露を受けた皮膚でのサイトカイン応答の詳細を明らかにした。また本研究の成果により、シクロオキシゲナーゼ阻害剤が気道のアレルギーを悪化させる事や、プロテアーゼ阻害剤処理アレルゲンを用いた経皮免疫寛容の誘導がより安全性が高いことが示された。

Research Products

• [Journal Article] Epicutaneous vaccination with protease inhibitor-treated papain prevents papain-induced Th2-mediated airway inflammation without inducing Th17 in mice (2021)
  • Author(s): Kunimine S, Takai T, Kamijo S, Maruyama N, Kimitsu T, Masutani Y, Yoshimura T, Suchiva P, Shimizu S, Ogawa H, Okumura K, Ikeda S
  • Journal Title: Biochem Biophys Res Commun Volume: 546 Pages: 192-199
  • DOI: 10.1016/j.bbrc.2020.12.090
  • Peer Reviewed
• [Journal Article] Innate IL-17A enhances IL-33-independent skin eosinophilia and IgE response on subcutaneouspapain sensitization (2021)
  • Author(s): Kamijo S, Hara M, Suzuki M, Nakae S, Ogawa H, Okumura K, Takai T
  • Journal Title: J Invest Dermatol Volume: 141 Issue: 1 Pages: 105-113.e14
  • DOI: 10.1016/j.jid.2020.05.088
  • Peer Reviewed
• [Journal Article] Cyclooxygenase inhibition in mice heightens adaptive‐ and innate‐type responses against inhaled protease allergen and IL ‐33 (2019)
  • Author(s): Maruyama Natsuko、Takai Toshiro、Kamijo Seiji、Suchiva Punyada、Ohba Mai、Takeshige Tomohito、Suzuki Mayu、Hara Mutsuko、Matsuno Kei、Harada Sonoko、Harada Norihiro、Nakae Susumu、Sudo Katsuko、Okuno Toshiaki、Yokomizo Takehiko、Ogawa Hideoki、Okumura Ko、Ikeda Shigaku
  • Journal Title: Allergy Volume: 印刷中 Issue: 11 Pages: 2237-2240
  • DOI: 10.1111/all.13831
  • Peer Reviewed / Open Access
• [Journal Article] Airway inflammation after epicutaneous sensitization of mice requires protease activity of low-dose allergen inhalation. (2018)
  • Author(s): Nishioka I, Takai T, Maruyama N, Kamijo S, Suchiva P, Suzuki M, Kunimine S, Ochi H, Shimura S, Sudo K, Ogawa H, Okumura K, Ikeda S.
  • Journal Title: J Allergy Clin Immunol Volume: 印刷中 Issue: 6 Pages: 2271-2273
  • DOI: 10.1016/j.jaci.2017.11.035
  • Peer Reviewed
• [Journal Article] Skin treatment with detergent promotes protease allergen-dependent epicutaneous sensitization in a manner different from tape stripping in mice (2017)
  • Author(s): Ochi H, Takai T, Shimura S, Maruyama N, Nishioka I, Kamijo S, Iida H, Nakae S, Ogawa H, Okumura K, Ikeda S
  • Journal Title: J Invest Dermatol Volume: 掲載確定 Issue: 7 Pages: 1578-1582
  • DOI: 10.1016/j.jid.2017.02.970
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Cyclooxygenase inhibition in mice heightens adaptive- and innate-type responses against inhaled protease allergen and IL-33 (2020)
  • Author(s): Seiji Kamijo, Kei Matsuno, Norihiro Harada, Susumu Nakae, Takehiko Yokomizo, Hideoki Ogawa, Shigaku Ikeda, Ko Okumura, Toshiro Takai
  • Organizer: 第６９回日本アレルギー学会学術集会
  • Int'l Joint Research
• [Presentation] 経皮アレルギー感作とアレルギーマーチにおける抗原プロテアーゼ活性 (2019)
  • Author(s): 上條清嗣、高井敏朗
  • Organizer: 第24回 日本病態プロテアーゼ学会学術集会
  • Invited
• [Presentation] Cyclooxygenase inhibition in mice heightens adaptive- and innate-type responses against inhaled protease allergen and IL-33 (2019)
  • Author(s): Seiji Kamijo, Punyada Suchiva, Kei Matsuno, Norihiro Harada, Susumu Nakae, Takehiko Yokomizo, Hideoki Ogawa, Shigaku Ikeda, Ko Okumura, Toshiro Takai
  • Organizer: 第48回 日本免疫学会学術集会
• [Presentation] Airway inflammation after epicutaneous sensitization requires protease activity of low-dose allergen inhalation (2018)
  • Author(s): Seiji Kamijo, Natsuko Maruyama, Punyada Suchiva, Katsuko Sudo, Hideoki Ogawa, Shigaku Ikeda, Ko Okumura, Toshiro Takai
  • Organizer: 日本免疫学会総会・学術集会
• [Presentation] Protease allergen-induced local IL-17A production in skin tissue and accumulation of IL-17A+ γδ T cells in skin draining lymph nodes; possible contribution to enhancement of skin eosinophilia and serum IgE response. (2017)
  • Author(s): KAMIJO Seiji et al.
  • Organizer: 日本免疫学会総会・学術集会