Roles of intestinal mast cells in tolerance induction to food allergens

• Project/Area Number: 18K08416
• 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: Nakano Nobuhiro 順天堂大学, 医学(系)研究科(研究院), 助教 (30420839)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); 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: 食物アレルギー / 経口免疫療法 / マスト細胞 / Notchシグナル / 骨髄由来免疫抑制細胞 / 腸管マスト細胞 / アレルギー / 免疫寛容

Outline of Final Research Achievements

The purpose of this study was to elucidate the immunological mechanisms by which tolerance is induced to food allergens. We have shown that Notch receptor-mediated signaling contributes to the establishment of sustained unresponsiveness to food allergens induced by oral immunotherapy through systemic and local expansion of immunosuppressive cells, such as IL-10-producing helper T cells and myeloid-derived suppresser cells by using a mouse model of oral immunotherapy. These findings provide insights into how patients with food allergies can achieve tolerance by oral immunotherapy.

Academic Significance and Societal Importance of the Research Achievements

食物アレルギー患者は年々増加しており、食物アレルギーを根治できる治療法の開発が切実に求められている。経口免疫療法は原因食物に対して一時的に耐性を誘導するが、一部の症例では持続的な耐性も獲得される。しかしながら、持続的な耐性獲得のメカニズムの多くは不明である。本研究では、マウスモデルを使用することにより持続的な耐性獲得に関与する細胞群及び分子を明らかにした。得られた知見を基に、より有効な経口免疫療法を開発できるのではないかと考えている。

Research Products

• [Journal Article] A possible association between a novel NLRP1 mutation and an autoinflammatory disease involving liver cirrhosis (2021)
  • Author(s): Yasudo Hiroki、Ando Taiki、Maehara Akie、Ando Tomoaki、Izawa Kumi、Tanabe Atsushi、Kaitani Ayako、Nomura Shigeru、Seki Masafumi、Yoshida Kenichi、Oda Hirotsugu、Okamoto Yoko、Wang Hexing、Kamei Anna、Kojima Mayuki、Kimura Meiko、Uchida Koichiro、Nakano Nobuhiro、Kaneko Junichi、et al.
  • Journal Title: Hepatology Volume: - Issue: 4 Pages: 2296-2299
  • DOI: 10.1002/hep.31818
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Notch signaling contributes to the establishment of sustained unresponsiveness to food allergens by oral immunotherapy (2021)
  • Author(s): Yoneyama Toshiyuki、Nakano Nobuhiro、Hara Mutsuko、Yamada Hiromichi、Izawa Kumi、Uchida Koichiro、Kaitani Ayako、Ando Tomoaki、Kitaura Jiro、Ohtsuka Yoshikazu、Ogawa Hideoki、Okumura Ko、Shimizu Toshiaki
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 147 Issue: 3 Pages: 1063-1076
  • DOI: 10.1016/j.jaci.2020.07.011
  • Peer Reviewed
• [Journal Article] Differential Lipid Recognition by Mouse versus Human CD300f, Inhibiting Passive Cutaneous Anaphylaxis, Depends on a Single Amino Acid Substitution in its Immunoglobulin-Like Domain (2020)
  • Author(s): Izawa K、Kaitani A、Ando Tomoaki、Maehara A、Nagamine M、Yamada H、Ando T、Ide T、Matsuzawa M、Okamoto Y、Yin E、Fukase S、Wang H、Kamei A、Uchida S、Maeda K、Nakano N、Uchida K、Tamura N、Ikeda K、Ebihara N、Shimizu T、Voehringer D、Roers A、Ogawa H、Okumura K、Kitaura J
  • Journal Title: Journal of Investigative Dermatology Volume: 140 Issue: 3 Pages: 710-713
  • DOI: 10.1016/j.jid.2019.08.439
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD300f is a potential therapeutic target for the treatment of food allergy (2019)
  • Author(s): Uchida Shino、Izawa Kumi、Ando Tomoaki、Yamada Hiromichi、Uchida Koichiro、Negishi Naoko、Kaitani Ayako、Maehara Akie、Nagamine Masakazu、Kamei Anna、Takamori Ayako、Maeda Keiko、Nakano Nobuhiro、Shimizu Toshiaki、Ogawa Hideoki、Okumura Ko、Nagahara Akihito、Watanabe Sumio、Kitaura Jiro
  • Journal Title: Allergy Volume: 75 Issue: 2 Pages: 471-474
  • DOI: 10.1111/all.14034
  • NAID: 40022209298
  • Peer Reviewed / Open Access
• [Journal Article] Identification of inhibitory mechanisms in pseudo-allergy involving Mrgprb2/MRGPRX2-mediated mast cell activation (2019)
  • Author(s): Takamori A, Ozawa K, Kaitani A, Ando T, Okamoto Y, Maehara A, Tanabe A, Nagamine M, Yamada H, Uchida S, Uchida K, Isobe M, Hatayama T, Watanabe D, Ando T, Ide T, Matsuzawa M, Maeda K, Nakano N, Tamura N, Ikeda K, Ebihara N, Shimizu T, Ogawa H, Okumura K, Kitaura J
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 143 Issue: 3 Pages: 1231-1235
  • DOI: 10.1016/j.jaci.2018.10.034
  • Peer Reviewed / Open Access
• [Journal Article] Leukocyte mono-immunoglobulin-like receptor 8 (LMIR8)/CLM-6 is an FcRγ-coupled receptor selectively expressed in mouse tissue plasmacytoid dendritic cells (2018)
  • Author(s): Kaitani A, Izawa K, Maehara A, Isobe M, Takamori A, Matsukawa T, Takahashi M, Yamanishi Y, Oki T, Yamada H, Nagamine M, Uchida S, Uchida K, Ando T, Maeda K, Nakano N, Shimizu T, Takai T, Ogawa H, Okumura K, Kitamura T, Kitaura J
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 8259-8259
  • DOI: 10.1038/s41598-018-25646-8
  • Peer Reviewed / Open Access
• [Presentation] 粘膜型マスト細胞の分化機構の解明 (2020)
  • Author(s): 中野信浩、才田一樹、北浦次郎、八代拓也、西山千春、奥村 康、小川秀興
  • Organizer: 日本農芸化学会2020年度大会
• [Presentation] Establishment of sustained unresponsiveness to food allergens by oral immunotherapy is prevented by inhibition of Notch signaling (2020)
  • Author(s): Nobuhiro Nakano, Toshiyuki Yoneyama, Mutsuko Hara, Hiromichi Yamada, Kumi Izawa, Koichiro Uchida, Ayako Kaitani, Tomoaki Ando, Jiro Kitaura, Yoshikazu Ohtsuka, Toshiaki Shimizu, Hideoki Ogawa, Ko Okumura
  • Organizer: JSA/WAO Joint Congress 2020
  • Int'l Joint Research
• [Presentation] Transcription factor EHF contributes to differentiation of Langerhans cells and development of allergic contact dermatitis (2020)
  • Author(s): Nobuhiro Nakano, Jiro Kitaura, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda
  • Organizer: 日本研究皮膚科学会 第45回年次学術大会・総会
• [Presentation] 転写調節因子EHF がランゲルハンス細胞において果たす役割の解析 (2019)
  • Author(s): 中野信浩、矢野堅士、八代拓也、西山千春、北浦次郎、奥村 康、小川秀興
  • Organizer: 日本農芸化学会2019年度大会
• [Presentation] Contribution of Notch signaling to the sustained unresponsiveness to food allergens achieved by oral immunotherapy (2019)
  • Author(s): Nobuhiro Nakano, Toshiyuki Yoneyama, Jiro Kitaura, Toshiaki Shimizu, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda
  • Organizer: 日本研究皮膚科学会 第44回年次学術大会・総会
• [Presentation] Differentiation of mucosal mast cells is induced by the coordinated actions of Notch signaling and TGF-β/Smad signaling (2019)
  • Author(s): Nobuhiro Nakano, Kazuki Saida, Chiharu Nishiyama, Hideo Yagita, Jiro Kitaura, Ko Okumura, Hideoki Ogawa
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Notchシグナルは経口免疫療法による食物抗原に対する持続的な不応答性の確立に寄与する (2019)
  • Author(s): 米山俊之，中野信浩，山田啓迪，原むつ子，北浦次郎，大塚宜一，奥村 康，清水俊明
  • Organizer: 第68回日本アレルギー学会学術大会
• [Presentation] Role of the transcription factor EHF in mouse Langerhans cells. (2018)
  • Author(s): Nobuhiro Nakano, Kento Yano, Chiharu Nishiyama, Jiro Kitaura, Ko Okumura, Hideoki Ogawa.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Cross-talk between Notch signaling and TGF-β signaling regulates mucosal mast cell differentiation. (2018)
  • Author(s): Kazuki Saida, Takuya Yashiro, Kazumi Kasakura, Mutsuko Hara, Chiharu Nishiyama, Ko Okumura, Nobuhiro Nakano.
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Notchシグナルの阻害が食物アレルギーマウスモデルにおける経口免疫寛容の誘導に与える影響 (2018)
  • Author(s): 米山俊之，中野信浩，山田啓迪，原むつ子，北浦次郎，大塚宜一，奥村 康，清水俊明
  • Organizer: 第55回日本小児アレルギー学会学術大会
• [Presentation] 食物アレルギーマウスモデルにおけるNotchシグナルの阻害が減感作の誘導に与える影響 (2018)
  • Author(s): 米山俊之，中野信浩，山田啓迪，原むつ子，北浦次郎，大塚宜一，奥村 康，清水俊明
  • Organizer: 第67回日本アレルギー学会学術大会
• [Remarks] 順天堂大学大学院医学研究科アトピー疾患研究センターのホームページ
  • URL: https://research-center.juntendo.ac.jp/atopy_center/
• [Remarks] プレスリリース：経口免疫療法により食物アレルギー症状の発生が抑えられるメカニズムを解明
  • URL: https://www.juntendo.ac.jp/news/20200827-01.html
• [Remarks] 順天堂大学大学院医学研究科アトピー疾患研究センターのホームページ
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/atopy_center/
• [Remarks] 順天堂大学大学院医学研究科アトピー疾患研究センターのホームページ
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/atopy_center/