Clarification of immunoregulatory mechanisms by crosstalk of immune cells

• Project/Area Number: 17H04376
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Nagai Shigenori 東京医科歯科大学, 大学院医歯学総合研究科, 准教授 (50348801)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: 免疫麻痺 / 免疫学

Outline of Final Research Achievements

It is important to clarify the mechanisms about the immune suppression after sepsis for prevention of secondary infection. In this study, we investigated the role of PD-1/PD-L1 on this immune suppression. We found the number and ration of Gr1+CD11b+ myeloid cells were increased but T cell function was suppressed in zymosan-treated WT mice but not in zymosan-treated PD-1/PD-Li double knockout mice. These results suggest that PD-1/PD-L1 pathway negatively regulates immune suppression after sepsis.

Academic Significance and Societal Importance of the Research Achievements

敗血症では、初期に免疫細胞の活性化によるサイトカインストームが起こるが、その後多くの症例において重度の免疫抑制がもたらされる。これが感染症を続発させる原因になるが、その病態生理は未だ不明である。これを解明することができれば、院内感染の原因ともなっているこの微生物感染症を減らすことができ、その治療ターゲットの候補としてPD-1/PD-L1が見つけられたという点で、新たな治療法の開発が期待される。

Research Products

• [Journal Article] Orthotopic tongue squamous cell carcinoma (SCC) model exhibiting a different tumor-infiltrating T-cell status with margin-restricted CD8+ T cells and regulatory T cell-dominance, compared to skin SCC. (2020)
  • Author(s): Kashima Y, Nishii N, Tachinami H, Furusawa E, Nagai S, Harada H, Azuma M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 20 Issue: 1 Pages: 218-224
  • DOI: 10.1016/j.bbrc.2020.03.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tolerogenic properties of CD206+ macrophages appeared in the sublingual mucosa after repeated antigen-painting. (2020)
  • Author(s): Yang Y, Nagai S, Kang S, Xia Y, Kawano Y, Miyake K, Karasuyama H, Azuma M.
  • Journal Title: International Immunology Volume: - Issue: 8 Pages: 509-518
  • DOI: 10.1093/intimm/dxaa014
  • Peer Reviewed / Open Access
• [Journal Article] 6.Hypoxia-inducible factor 1α promotes interleukin 1β and tumour necrosis factor α expression in lipopolysaccharide-stimulated human dental pulp cells (2020)
  • Author(s): Fujii M, Kawashima N, Tazawa K, Hashimoto K, Nara K, Noda S, Nagai S, Okiji T
  • Journal Title: International Endodontic Journal. Volume: 53 Issue: 5 Pages: 636-646
  • DOI: 10.1111/iej.13264
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Fabrications of boron-containing apatite ceramics via ultrasonic spray-pyrolysis route and their responses to immunocytes. (2020)
  • Author(s): Nakagawa D, Nakamura M, Nagai S, *Aizawa M.
  • Journal Title: J Mater Sci Mater Med. Volume: 31 Issue: 2 Pages: 20-20
  • DOI: 10.1007/s10856-020-6358-z
  • Peer Reviewed
• [Journal Article] 5.HIF1α inhibits LPS-mediated induction of IL-6 synthesis via SOCS3-dependent CEBPβ suppression in human dental pulp cells (2020)
  • Author(s): Mayuko Fujii; Kento Tazawa; Kentaro Hashimoto; Keisuke Nara; Sonoko Noda; Masashi Kuramoto; Shion Orikasa; Shigenori Nagai; Takashi Okiji
  • Journal Title: Biochem Biophys Res Commun Volume: 522 Issue: 2 Pages: 308-314
  • DOI: 10.1016/j.bbrc.2019.11.032
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Endogenous IL-33 exerts CD8+ T cell antitumor responses overcoming pro-tumor effects by regulatory T cells in a colon carcinoma model. (2019)
  • Author(s): Xia Y, Ohno T, Nishii N, Bhingare A, Tachinami H, Kashima Y, Nagai S, Saito H, Nakae S, Azuma M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 2019 Issue: 2 Pages: 331-336
  • DOI: 10.1016/j.bbrc.2019.08.058
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Silencing of PD-L2/B7-DC by Topical Application of Small Interfering RNA Inhibits Elicitation of Contact Hypersensitivity (2019)
  • Author(s): Furusawa Emi、Ohno Tatsukuni、Nagai Shigenori、Noda Taisei、Komiyama Takuya、Kobayashi Katsunori、Hamomato Hidetoshi、Miyashin Michiyo、Yokozeki Hiroo、Azuma Miyuki
  • Journal Title: Journal of Investigative Dermatology Volume: - Issue: 10 Pages: 2164-2173
  • DOI: 10.1016/j.jid.2019.02.037
  • Peer Reviewed / Open Access
• [Journal Article] Responses of Immune Cells to Hydroxyapatite Ceramics Loaded with Immunostimulators. (2019)
  • Author(s): Kagami S, Kizukuri R, Nagai S, *Aizawa M.
  • Journal Title: J Soc Inorg Mater Jpn. Volume: 26 Pages: 74-81
  • NAID: 40021829116
  • Peer Reviewed
• [Journal Article] Differences of tumor-recruiting myeloid cells in murine squamous cell carcinoma influence the efficacy of immunotherapy combined with a TLR7 agonist and PD-L1 blockade (2019)
  • Author(s): Tachinami Hidetake、Nishii Naoto、Xia Yulong、Kashima Yoshihisa、Ohno Tatsukuni、Nagai Shigenori、Li Lixin、Lau Walter、Tomihara Kei、Noguchi Makoto、Azuma Miyuki
  • Journal Title: Oral Oncology Volume: 91 Pages: 21-28
  • DOI: 10.1016/j.oraloncology.2019.02.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Systemic administration of a TLR7 agonist attenuates regulatory T cells by dendritic cell modification and overcomes resistance to PD-L1 blockade therapy. (2018)
  • Author(s): Nishii N, Tachinami H, Kondo Y, Xia Y, Kashima Y, Ohno T, Nagai S, Li L, Lau W, Harada H, Azuma M.
  • Journal Title: Oncotarget Volume: 9 Issue: 17 Pages: 13301-13312
  • DOI: 10.18632/oncotarget.24327
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PI3K-Akt pathway enhances the differentiation of interleukin-27-induced type 1 regulatory T cells. (2017)
  • Author(s): Nadya NA, Tezuka H, Ohteki T, Matsuda S., Azuma M, and *Nagai S.
  • Journal Title: Immunology Volume: 152 Issue: 3 Pages: 507-516
  • DOI: 10.1111/imm.12789
  • Peer Reviewed
• [Presentation] Identification of a unique macrophage subset induced by repeated antigen painting in sublingual mucosa to regulate T cell tolerance. (2019)
  • Author(s): Yue Yang, Shigenori Nagai, Miyuki Azuma
  • Organizer: 第47回日本免疫学会総会・学術集会
• [Presentation] One of PD-1 ligand, PD-L2 induced on Langerhans cells augments cutaneous T cell-mediated immune responses. (2019)
  • Author(s): Emi Furusawa, Tatsukuni Ohno, Shigenori Nagai, Takuya Komiyama, Katsunori Kobayashi, Hidetoshi Hamamoto, Michiyo Miyashin, Hiroo Yokozeki, Miyuki Azuma.
  • Organizer: 第47回日本免疫学会総会・学術集会
• [Presentation] PI3K-Akt pathway enhances the differentiation of interleukin 27-induced type 1 regulatory T cells. (2019)
  • Author(s): Nagai S, Adiba-Nadya N, Tezuka H, Ohteki T, Matsuda S, Azuma M.
  • Organizer: 17th International Congress of Immunology.
  • Int'l Joint Research
• [Presentation] Repeated antigen painting induces tolerogenic cells in sublingual mucosa. (2019)
  • Author(s): Yang Y, Nagai S, Azuma M.
  • Organizer: 17th International Congress of Immunology.
  • Int'l Joint Research
• [Presentation] Differences of tumor-recruiting myeloid cells in murine squamous cell carcinoma influence the efficacy of immunotherapy combined with a TLR7 agonist and PD-L1 blockade. (2019)
  • Author(s): Azuma M, Tachinami H, Nishii N, Xia Y, Kashima Y, Nagai S, Li L, Tomihara K, Noguchi M.
  • Organizer: 17th International Congress of Immunology.
  • Int'l Joint Research
• [Presentation] Silencing of PD-L2 by topical application of small interfering RNA inhibits elicitation of contact hypersensitivity. (2019)
  • Author(s): Azuma M, Furusawa E, Nagai S, Yokozeki H.
  • Organizer: 17th International Congress of Immunology.
  • Int'l Joint Research
• [Presentation] Fabrication of boron-containing apatite ceramics by reaction sintering process and their cellular responses to immunocytes. (2019)
  • Author(s): Daiki Nakagawa, Sanae Kagami, Shigenori Nagai, and Mamoru Aizawa.
  • Organizer: The 19th Asian BioCeramics Symposium (ABC2019).
  • Int'l Joint Research
• [Presentation] 反応焼結法により作製したホウ素含有アパタイトセラミックスと免疫細胞との相互作用． (2019)
  • Author(s): 中川 大輝，加々見 早苗，永井 重徳，相澤 守．
  • Organizer: 第41回日本バイオマテリアル学会大会．
• [Presentation] Fabrication of boron-containing apatite ceramics with well-controlled chemical composition by reaction sintering method and their cellular response to immunocytes. (2019)
  • Author(s): Daiki Nakagawa, Sanae Kagami, Shigenori Nagai, and Mamoru Aizawa.
  • Organizer: The 13th Pacific Rim Conference of Ceramic Societies (PACRIM13).
  • Int'l Joint Research
• [Presentation] Immunosuppressive status of CD206hi cells appeared in sublingual mucosa. (2018)
  • Author(s): Yang Yue, 永井 重徳，東 みゆき
  • Organizer: 第60回歯科基礎医学会学術大会
• [Presentation] イノシトールリン酸を表面修飾した水酸アパタイトセラミックスの作製とその免疫細胞応答． (2018)
  • Author(s): 上野 太郎，木造 理萌子，山田 清貴，永井 重徳，相澤 守．
  • Organizer: 第22回生体関連セラミックス討論会．
• [Presentation] Fabrication of boron-containing apatite ceramics by reaction sintering method and their cellular responses of immunocytes. (2018)
  • Author(s): D. Nakagawa, R. Kizukuri, S. Kagami, S. Nagai and M. Aizawa.
  • Organizer: The 18th Asian Bioceramics Symposium.
  • Int'l Joint Research
• [Presentation] 免疫賦活担持水酸アパタイトセラミックスの作製と免疫細胞応答性． (2018)
  • Author(s): 加々見 早苗，木造 理萌子，永井 重徳，相澤 守．
  • Organizer: 第40回日本バイオマテリアル学会大会．
• [Presentation] 反応焼結法によるホウ素含有アパタイトセラミックスの作製とその免疫細胞応答性. (2018)
  • Author(s): 中川 大輝，木造 理萌子，加々見 早苗，永井 重徳，相澤 守．
  • Organizer: 第27回無機リン化学討論会.
• [Presentation] Responses of Immune Cells to Hydroxyapatite Ceramics Loaded with Immunostimulators. (2018)
  • Author(s): S. Kagami, R. Kizukuri, S. Nagai, and M. Aizawa.
  • Organizer: 30th Symposium and Annual Meeting of the International Society for Ceramics in Medicine.
  • Int'l Joint Research
• [Presentation] ２つのマウス扁平上皮癌モデルの癌微小環境におけるミエロイド系細胞の相違とTLR7アゴニストの投与効果． (2018)
  • Author(s): 立浪 秀剛，西井 直人，永井 重徳，加島 義久，冨原 圭，野口 誠，東 みゆき
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 抗腫瘍応答における内因性および腫瘍内投与IL-33の機能評価． (2018)
  • Author(s): 夏 玉龍，西井 直人，永井 重徳，東 みゆき，大野 建州
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Involvement of CD206+ cells in oral mucosal tolerance. (2018)
  • Author(s): Yue Yang, Shigenori Nagai, Miyuki Azuma.
  • Organizer: 第47回日本免疫学会総会・学術集会．
• [Presentation] Site-specific regulation of oral mucosa-recruiting CD8+ T cells -Comparison of contact allergy between skin and oral mucosa-. (2017)
  • Author(s): Worawalun HIRUNWIDCHAYARAT, Emi FURUSAWA, Tatsukuni OHNO, Shigenori NAGAI, Miyuki AZUMA.
  • Organizer: 第46回日本免疫学会総会・学術集会
• [Presentation] PI3K-Akt pathway enhances type 1 regulatory T cell differentiation induced by IL-27. (2017)
  • Author(s): １．Shigenori Nagai, Niken Adiba Nadya, Hiroyuki Tezuka, Toshiaki Ohteki, Satoshi Matsuda, Miyuki Azuma.
  • Organizer: 第46回日本免疫学会総会・学術集会
• [Presentation] PI3K-Akt pathway enhances Tr1 differentiation induced by IL-27. (2017)
  • Author(s): Shigenori Nagai, Niken Adiba Nadya, Hiroyuki Tezuka, Toshiaki Ohteki, Satoshi Matsuda, Miyuki Azuma.
  • Organizer: The 5th Annual Meeting of the International Cytokine and Interferon Society (Cytokines 2017)
  • Int'l Joint Research
• [Presentation] Effect of surface roughness on immune cells of hydroxyapatite ceramics modified with inositol phosphate. (2017)
  • Author(s): Taro Ueno, Rihoko Kizukuri, Kiyotaka Yamada, Shigenori Nagai, and Mamoru Aizawa.
  • Organizer: 17th Asian BioCeramics Symposium 2017.
• [Presentation] Development of Immunoceramics in the CaO-P2O5-SiO2-B2O3 System and their Cellular Responses. (2017)
  • Author(s): Rihoko Kizukuri, Kiyotaka Yamada, Michiyo Honda, Shigenori Nagai and Mamoru Aizawa.
  • Organizer: 29th Symposium and Annual Meeting of the International Society for Ceramics in Medicine.
  • Int'l Joint Research
• [Presentation] reparation of Hydroxyapatite Ceramics Loaded with Various Immunostimulators and Their Responses to Immune Cells. (2017)
  • Author(s): Sanae Kagami, Rihoko Kizukuri, Shigenori Nagai, and Mamoru Aizawa.
  • Organizer: The 15th International Conference on Advanced Materials.
  • Int'l Joint Research
• [Presentation] イノシトールリン酸を表面修飾した水酸アパタイトセラミックスの免疫細胞応答性． (2017)
  • Author(s): 上野 太郎，木造 理萌子，山田 清貴，永井 重徳，相澤 守．
  • Organizer: 第26回無機リン化学討論会．
• [Presentation] 上皮系細胞におけるB7-H1発現に関わるシグナル探索． (2017)
  • Author(s): 金 キン，永井 重徳，東 みゆき．
  • Organizer: 第59回歯科基礎医学会学術大会
• [Presentation] PI3K-Akt経路はIL-27誘導Tr1細胞分化を増強する．第59回歯科基礎医学会学術大会， (2017)
  • Author(s): Nadya Niken Adiba，東 みゆき，永井 重徳．
  • Organizer: 第59回歯科基礎医学会学術大会
• [Presentation] 口腔接触アレルギーにおける粘膜局所でのCD8+ T細胞の不活化． (2017)
  • Author(s): Hirunwidchayarat Worawalun，古澤 慧美，Kang Siwen，大野 建州，永井 重徳, 東 みゆき．
  • Organizer: 第59回歯科基礎医学会学術大会
• [Book] Co-signal Molecules in T cell Activation (2019)
  • Author(s): Nagai S, Azuma M
  • Total Pages: 326
  • Publisher: Springer
  • ISBN: 9789813297166
• [Remarks] 東京医科歯科大学分子免疫学分野ホームページ
  • URL: http://www.tmd.ac.jp/mim/
• [Remarks] プレスリリース「舌下粘膜に現れるCD206陽性マクロファージは、舌下免疫療法の免疫抑制に関わる」
  • URL: http://www.tmd.ac.jp/archive-tmdu/kouhou/20200402_1.pdf
• [Remarks] 東京医科歯科大学 分子免疫学分野
  • URL: http://www.tmd.ac.jp/mim/
• [Remarks] 東京医科歯科大学 医歯学総合研究科 分子免疫学分野
  • URL: http://www.tmd.ac.jp/mim/index.html