Analysis of inflammation and sensitization on epicutaneous antigen exposure

• Project/Area Number: 18K08417
• 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: Juntendo University
• Principal Investigator: Takai Toshiro 順天堂大学, 大学院医学研究科, 先任准教授 (70338375)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 経皮感作 / プロテアーゼアレルゲン / アレルギーマーチ / マウスモデル / 予防・治療戦略 / Th2 / Th17 / プロテアーゼ

Outline of Final Research Achievements

Using a model protease antigen, we reported that the antigen protease activity on inhalation is essential to airway inflammation in epicutaneously presensitized mice; that cyclooxygenase inhibition promotes epicutaneous sensitization and subsequent airway inflammation; that epicutaneous tratment with antigen with inactivated protease activity prophylactically blocks subsequent induction of airway inflammation, and a new mechanism for subcutaneous sensitization. We found other mechanisms and a further new epicutaneous sensitization model with other symptoms, for which investigations are on-going.

Academic Significance and Societal Importance of the Research Achievements

本研究において、ダニ・花粉などのアレルゲン原因生物が産生・含有するプロテアーゼ活性に着目し、プロテアーゼ抗原を用いた経皮感作およびその後の気道炎症（アトピーマーチ）に関するモデルを独自に開発し解析した。従来の実験モデルとは異なる機序・治療標的が示唆された。将来の経皮免疫療法における課題を見いだすと共に、その解決手段を考案した。得られた知見は、実際の皮膚アレルギーおよびアトピーマーチなどの理解を前進し応用にも関与するとともに、基礎免疫学的な理解の前進にも貢献している。

Research Products

• [Journal Article] アレルゲンのプロテアーゼ活性と免疫応答 (2022)
  • Author(s): 高井敏朗
  • Journal Title: 臨床免疫・アレルギー科 Volume: 77 Pages: 405-410
• [Journal Article] Inhibition of both cyclooxygenase-1 and -2 promotes epicutaneous Th2 and Th17 sensitization and allergic airway inflammation on subsequent airway exposure to protease allergen in mice (2021)
  • Author(s): Suchiva, P., Takai, T., Kamijo, S., Maruyama, N., Yokomizo, T., Sugimoto, Y., Okumura, K., Ikeda, S., Ogawa, H.
  • Journal Title: International Archives of Allergy and Immunology Volume: - Issue: 9 Pages: 788-799
  • DOI: 10.1159/000514975
  • Peer Reviewed / Open Access
• [Journal Article] Epicutaneous challenge with protease allergen requires its protease activity to recall TH2 and TH17/TH22 responses in mice pre-sensitized via distant skin (2021)
  • Author(s): Ogasawara A, Yuki T, Takai T, Yokozeki K, Katagiri A, Takahashi Y, Yokozeki H, Basketter D, Sakaguchi H
  • Journal Title: J Immunotoxicol Volume: 18 Issue: 1 Pages: 118-126
  • DOI: 10.1080/1547691x.2021.1968548
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ALLERGEN BASICS: FROM COMPONENTS TO IMMUNOLOGY (2021)
  • Author(s): 高井敏朗
  • Journal Title: Japanese Journal of Allergology Volume: 70 Issue: 4 Pages: 255-262
  • DOI: 10.15036/arerugi.70.255
  • NAID: 130008052595
  • ISSN: 0021-4884, 1347-7935
  • Peer Reviewed
• [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] パパインの皮下感作におけるIL-17AによるIL-33非依存性好酸球炎症とIgE反応の増強 (2021)
  • Author(s): 上條清嗣, 原むつ子, 鈴木麻友, 中江進, 小川秀興, 奧村康, 高井敏朗
  • Journal Title: 臨床免疫・アレルギー科 Volume: 75 Pages: 299-306
• [Journal Article] Innate IL-17A enhances IL-33-independent skin eosinophilia and IgE response on subcutaneous papain sensitization (2020)
  • Author(s): Kamijo S, Hara M, Suzuki M, Nakae S, Ogawa H, Okumura K, Takai T
  • Journal Title: Journal of Investigative Dermatology Volume: in-press
  • NAID: 40022504096
  • Peer Reviewed
• [Journal Article] アレルゲンと自然免疫 (2020)
  • Author(s): 高井敏朗, 上條清嗣
  • Journal Title: 臨床免疫アレルギー科 Volume: 73 Pages: 160-167
• [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] アレルゲンのアジュバント作用 (2019)
  • Author(s): 高井敏朗
  • Journal Title: 日本職業・環境アレルギー学会雑誌 Volume: 26 Pages: 1-8
  • NAID: 40021984974
  • Peer Reviewed
• [Journal Article] 2 病態の新しい考え方 7) ダニの関与 (2019)
  • Author(s): 高井敏朗
  • Journal Title: 皮膚科の臨床 (増刊 変わりつつあるアトピー性皮膚炎の常識-最新の知識と治療の極意-) Volume: 61 Pages: 759-764
• [Journal Article] Cyclooxygenase inhibition in mice hightens adaptive-and innate-type responses against inhaled protease allergen and IL-33 (2019)
  • Author(s): Maruyama N, Takai T, Kamijo S, Suchiva P, Takeshige T, Suzuki M, Hara M, Matsuno K, Harada S, Narada N, Nakae S, Sudo K, Okuno T, Yokomizo T, Ogawa H, Okumura K, Ikeda S.
  • Journal Title: Allergy Volume: 印刷中
  • Peer Reviewed
• [Journal Article] ダニの関与 (2019)
  • Author(s): 高井敏朗
  • Journal Title: 皮膚科の臨床 臨時増刊「変わりつつあるアトピー性皮膚炎の常識-最新の知識と治療の極意-」 Volume: 60
• [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
• [Presentation] An enhancing role of innate IL-17A on IL-33-independent skin eosinophilia and IgE response in a subcutaneous papain sensitization model (2021)
  • Author(s): Seiji Kamijo, Susumu Nakae, Ko Okumura, Toshiro Takai.
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] New epicutaneous sensitization model to protease antigen: itch-associated skin inflammation, a variety of Th subsets and IgE (2021)
  • Author(s): Tomoko Yoshimura, Toshiro Takai, Seiji Kamijo,Toru Kimitsu, Yurie Masutani,Takasuke Ogawa, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda
  • Organizer: 第46回日本研究皮膚科学会年次学術大会
• [Presentation] Detergent-induced skin inflammation and itch in a mast cell-independent and antihistamine-resistant manner in C57BL/6 mice (2021)
  • Author(s): Yurie Masutani, Toshiro Takai, Seiji Kamijo,Toru Kimitsu, Tomoko Yoshimura, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda
  • Organizer: 第46回日本研究皮膚科学会年次学術大会
• [Presentation] プロテアーゼ抗原経皮投与による気道炎症予防：抗原修飾によるTh17誘導能消去 (2021)
  • Author(s): 木蜜徹, 上條清嗣, 国峯真也, 舛谷友里恵, 吉村智子, 小川秀興, 池田志斈, 奧村康, 高井敏朗
  • Organizer: 第70回日本アレルギー学会学術大会
• [Presentation] Innate IL-17A Enhances IL-33-Independent Skin Eosinophilia and IgE Response on Subcutaneous Papain Sensitization (2021)
  • Author(s): Seiji Kamijo, Mutsuko Hara, Mayu Suzuki, Susumu Nakae, Hideoki Ogawa, Ko Okumura, Toshiro Takai
  • Organizer: 第70回日本アレルギー学会学術大会
• [Presentation] アレルゲンの基礎~抗原から免疫学まで~ (2021)
  • Author(s): 高井敏朗
  • Organizer: 第７回 総合アレルギー講習会(日本アレルギー学会主催）
• [Presentation] Epicutaneous vaccination with protease allergen prevents airway inflammation induced by protease allergen inhalation in mice (2020)
  • Author(s): Kunimine S, Takai T, Kamijo S, Maruyama N, Kimitsu T, Masutani, Y, Yoshimura T, Suchiva P, Shimizu S, Okumura K, Ogawa H, Ikeda S
  • Organizer: 日本研究皮膚科学会
• [Presentation] Epicutaneous vaccination with ovalbumin prevents airway IL-33-dependent antigen-specific Th2 differentiation in mice (2020)
  • Author(s): Kimitsu K, Takai T, Kunimine S, Kamijo S, Maruyama N, Masutani Y, Yoshimura T, Suchiva P, Shimizu S, Okumura, Ogawa H, Ikeda S
  • Organizer: 日本研究皮膚科学会
• [Presentation] Inhibition of both COX-1 and -2 promotes epicutaneous sensitization to protease allergen and subsequent airway inflammation in mice (2020)
  • Author(s): Masutani Y, Suchiva P, Takai T, Kamijo S, Maruyama N, Kimitsu T, Yoshimura T, Kunimine S, Shimizu S, Yokomizo T, Sugimoto Y, Okumura K, Ikeda S, Ogawa H
  • Organizer: 日本研究皮膚科学会
• [Presentation] Epicutaneous sensitization to protease allergen via detergent-treated skin promotes IgE production and skin inflammation (2020)
  • Author(s): Yoshimura T, Takai T, Ogawa T, Maruyama N, Yamanashi H, Kamijo S, Kimitsu T, Masutani Y, Okumura K, Ogawa H, Ikeda S
  • Organizer: 日本研究皮膚科学会
• [Presentation] Cyclooxygenase inhibition in mice heightens adaptive- and innate-type responses against inhaled protease allergen and IL-33 (2020)
  • Author(s): Kamijo S, Matsuno K, Harada N, Nakae S, Yokomizo T, Ogawa H, Ikeda S, Okumura K, Takai T
  • Organizer: JSA/WAO Joint Congress 2020
  • Int'l Joint Research
• [Presentation] Cyclooxygenase inhibitor promotes epicutaneous sensitization to protease allergen and subsequent airway Inflammation (2019)
  • Author(s): Suchiva P, Takai T, Maruyama N, Kamijo S, Okumura K, Ikeda S, Ogawa H
  • Organizer: 日本研究皮膚科学会
• [Presentation] Epicutaneous allergen vaccination prevents protease- and IL-33-mediated airway allergen sensitization (2019)
  • Author(s): Kunimine S, Takai T, Kamijo S, Maruyama N, Suchiva P, Ogawa H, Okumura K, Ikeda S
  • Organizer: 日本研究皮膚科学会
• [Presentation] Cyclooxygenase inhibition in mice heightens adaptive- and innate-type responses against inhaled protease allergen and IL-33 (2019)
  • Author(s): Kamijo S, Takai T, Matsuno K, Harada N, Nakae S, Yokomizo T, Ogawa H, Okumura K, Ikeda S
  • Organizer: 日本免疫学会
• [Presentation] NSAID promotes epicutaneous sensitization to protease allergen and subsequent airway eosinophilia (2019)
  • Author(s): Suchiva P, Takai T, Maruyama N, Kamijo S, Ikeda S, Okumura K, Ogawa H
  • Organizer: 日本アレルギー学会
• [Presentation] アレルゲンの基礎：抗原から免疫まで (2019)
  • Author(s): 高井敏朗
  • Organizer: 総合アレルギー講習会（日本アレルギー学会主催）
  • Invited
• [Presentation] Allergens as adjuvants: Epicutaneous sensitization to protease allergen and subsequent airway inflammation in murine models (2019)
  • Author(s): Takai T
  • Organizer: Chinese Pediatric Society
  • Invited
• [Presentation] アレルゲンはなぜアレルゲンになるのか (2018)
  • Author(s): 高井敏朗
  • Organizer: 第49回 日本職業・環境アレルギー学会総会・学術大会
  • Invited
• [Presentation] 皮膚の界面活性剤処理はテープストリッピングと異なる様式でプロテアーゼ抗原に対する経皮感作を促進する (2018)
  • Author(s): 高井敏朗、越智啓乃、清村咲子、丸山奈津子、西岡いずみ、上條清嗣、飯田秀雄、中江進、小川秀興、池田志斈、奧村康
  • Organizer: 第67回日本アレルギー学会学術集会
• [Presentation] Airway inflammation after epicutaneous sensitization requires protease activity of low-dose allergen inhalation (2018)
  • Author(s): Kamijo S, Suchiva P, Ogawa H, Ikeda S, Okumura K, Takai T
  • Organizer: 第46回日本免疫学会学術集会
• [Remarks]
  • URL: https://research-center.juntendo.ac.jp/atopy_center/research/
• [Remarks]
  • URL: https://research-center.juntendo.ac.jp/atopy_center/research/g2/
• [Remarks] 研究内容 アトピー疾患研究センター
  • URL: https://research-center.juntendo.ac.jp/atopy_center/research/
• [Remarks] 環境因子とアレルギー疾患（バリア・免疫。神経）
  • URL: https://research-center.juntendo.ac.jp/atopy_center/research/g2/