Analysis of the mechanisms of immunotolerance induced by anti-CD80/86 antibodies

• Project/Area Number: 18K16265
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Teikyo University
• Principal Investigator: Uchiyama Masateru 帝京大学, 医学部, 助教 (60713295)
• 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: ¥1,430,000 (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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 移植免疫学 / CD80/86 / 制御性T細胞 / 養子移植 / ドナー特異的抗体 / アナジー細胞 / 免疫寛容 / マウス心臓移植 / マウス / 心臓移植 / 抗体関連拒絶反応

Outline of Final Research Achievements

①　The CD80/86 antibodies could control allo-proliferation through a specific cell population other than Treg.
②　The CD80/86 antibodies could induce the downregulation of a donor-specific antibody through B cell suppression.
③　CD80/86-induced CD4+ anergy T cells show the suppression of allo-proliferation and a donor-specific antibody.

Academic Significance and Societal Importance of the Research Achievements

臓器移植術という究極的な治療において、最も重要なことは如何に移植臓器と折り合いをつけ、長期にわたり機能不全を起こさないようにするかである。現在も、それを達成するために、基本的な拒絶反応治療薬であるステロイドを始めとする非特異的な免疫抑制剤が使用されるが、副作用や新規悪性腫瘍などの多くの問題を抱えている。当検討において判明したCD80/86抗体による免疫寛容維持の機序の解明は、ドナー特異的な拒絶反応に対する治療、つまりオーダーメイド治療に繋がると考えられる。もちろん、この抗体のみですべての臓器移植に関する治療が完結するわけではないが、免疫抑制剤の減量に繋がる重要な知見を含む検討であると思われる。

Research Products

• [Journal Article] Development of LT-HSC-Reconstituted Non-Irradiated NBSGW Mice for the Study of Human Hematopoiesis In Vivo (2021)
  • Author(s): Adigbli George、Hua Peng、Uchiyama Masateru、Roberts Irene、Hester Joanna、Watt Suzanne M.、Issa Fadi
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 642198-642198
  • DOI: 10.3389/fimmu.2021.642198
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analysis of therapeutic potential of monocytic myeloid-derived suppressor cells in cardiac allotransplantation (2021)
  • Author(s): Keiichi Fujimoto, Koichiro Uchida, EnzhiYin, Jun Zhu, Yuko Kojima, Masateru Uchiyama, Yasuto Yamamoto, Hisashi Bashuda, Ryu Matsumoto, Koji Tokushige, Masaki Harada, Takenori Inomata, Jiro Kitaura, Akira Murakami, Ko Okumura, Kazuyoshi Takeda.
  • Journal Title: Transplant Immunology Volume: 67 Pages: 101405-101405
  • DOI: 10.1016/j.trim.2021.101405
  • URL: https://pure.teikyo.jp/en/publications/b688fd25-c4da-4be1-8b65-c586b81e5ee3
  • Peer Reviewed / Open Access
• [Journal Article] Systemic silencing of Phd2 causes reversible immune regulatory dysfunction (2019)
  • Author(s): Atsushi Yamamoto, Joanna Hester, Philip S. Macklin, Kento Kawai, Masateru Uchiyama, et al.
  • Journal Title: J Clin Invest Volume: 129 Issue: 9 Pages: 3640
  • DOI: 10.1172/jci124099
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A successful case of percutaneous left ventricular assist device “Impella” to postmyocardial infarction ventricular septal perforation in Japan (2019)
  • Author(s): Mitsuru Iida, Masateru Uchiyama, Tomoki Shimokawa.
  • Journal Title: Artificial Organs Volume: 43 Issue: 8 Pages: 806
  • DOI: 10.1111/aor.13434
  • Peer Reviewed
• [Journal Article] The Early Outcome of Aortic Valve Replacement Surgery for Dialysis Patients. (2019)
  • Author(s): Mitsuru Iida, Kenji Nishimura, Kaori Kono, Ken Chen, Tsukasa Ikeda, Hiroo Ota, Masateru Uchiyama, Naomi Ozawa, Tomohiro Imazuru, Tomoki Shimokawa
  • Journal Title: Journal of Cardiol Ther Volume: 6 Pages: 793-7
  • Peer Reviewed
• [Journal Article] Graft Protective Effect of HMG-CoA Reductase Inhibitor Pravastatin in Murine Cardiac Allograft Transplantation (2018)
  • Author(s): Enzhi Yin, Masanori Hara, Masateru Uchiyama, Masanori Niimi
  • Journal Title: Transplantation Proceedings Volume: 50 Issue: 9 Pages: 2804
  • DOI: 10.1016/j.transproceed.2018.05.029
  • Peer Reviewed
• [Journal Article] Graft protective effect and induction of CD4⁺Foxp3⁺ cell by Thrombomodulin on allograft arteriosclerosis in mice (2018)
  • Author(s): Enzhi Yin, Shigefumi Matsuyama, Masateru Uchiyama, Kento Kawai, and Masanori Niimi
  • Journal Title: Journal of Cardiothoracic Surgery Volume: 13 Issue: 1
  • DOI: 10.1186/s13019-018-0731-8
  • Peer Reviewed / Open Access
• [Journal Article] Regulatory T cells for tolerance (2018)
  • Author(s): Kento Kawai, Masateru Uchiyama, Joanna Hester, Kathryn Wood, Fadi Issa
  • Journal Title: Human Immunology Volume: 79 Issue: 5 Pages: 294
  • DOI: 10.1016/j.humimm.2017.12.013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Anti-CD80/86 Antibody (RM80/GL-1) Suppressed Donor Specific Antibody (2021)
  • Author(s): Yasuto Yamamoto, Koichiro Uchida, Masanori Niimi, Masateru Uchiyama
  • Organizer: アジア移植学会
  • Int'l Joint Research
• [Presentation] Agonistic anti-CD272 antibody (6B2) suppressed donor specific antibody through inducible regulatory T cells. (2020)
  • Author(s): Yasuto Yamamoto, Masateru Uchiyama, Koichiro Uchida, Hideo Yagita, Masanori Niimi.
  • Organizer: American Transplant Congress
  • Int'l Joint Research
• [Presentation] マウストレッドミル運動モデルを用いた芍薬甘草湯による筋肥大抑制効果とCD8陽性細胞の機能抑制効果 (2020)
  • Author(s): 山本 康人、内山 雅照、新見正則
  • Organizer: 日本獣医学会
• [Presentation] Anti-CD272 Antibody (6B2) Induced Indefinite Survival of Fully MHC-Mismatched Murine Cardiac Allograft. (2019)
  • Author(s): Yasuto Yamamoto, Masateru Uchiyama, Enzhi Yin, and Masanori Niimi.
  • Organizer: アメリカ移植学会
  • Int'l Joint Research
• [Presentation] 抗BTLA抗体によるマウス移植心の生着延長効果について (2019)
  • Author(s): 山本康人、内山雅照、八木田秀雄、新見正則
  • Organizer: 第162回 日本獣医学会
• [Presentation] Effects of Shinrin-yoku to alloimmune responses in murine model. (2019)
  • Author(s): Yasuto Yamamoto, Hiroko Ochiai, Masateru Uchiyama and Masanori Niimi.
  • Organizer: 第16回 アジア移植学会
  • Int'l Joint Research
• [Remarks] Reseachmap
  • URL: https://researchmap.jp/mautiya
• [Remarks] research map
  • URL: https://researchmap.jp/mautiya
• [Remarks] 帝京大学医学部 外科学・心臓血管外科学講座 移植免疫・腫瘍免疫研究室
  • URL: https://teikyo-trig.amebaownd.com/
• [Remarks] research map
  • URL: https://researchmap.jp/mautiya/