Challenge to develop a novel immunosuppressant that defies the conventional wisdom

• Project/Area Number: 20K21624
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Tohoku University
• Principal Investigator: Goto Masafumi 東北大学, 医学系研究科, 教授 (50400453)
• Co-Investigator(Kenkyū-buntansha): 稲垣 明子 東北大学, 医学系研究科, 助教 (20360224)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2022: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2021: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 免疫抑制剤 / 膵島移植 / KRP-203 / FTY720 / 新生血管 / 耐糖能障害 / 耐糖能

Outline of Research at the Start

現在の移植医療で必須とされている免疫抑制剤は、患者のみならず移植グラフトにも糖尿病や血管障害などの悪影響を及ぼす事が明らかとなり社会問題と化している。申請者らは新たな作用機序を有するKRP-203に着目し、この新規物質が糖尿病を引き起こさない、血管障害を生じない、拒絶反応を効果的に制御できる事を本研究にて実証し、体に優しい理想的免疫抑制剤として確立する事を目指す。また本研究においては、KRP-203が元来強力な抗炎症作用も保持している事を鑑み、拒絶反応が起こらない同種同系モデルにおいてもグラフト生着を促進するという大胆な仮説を検証する事により、移植医療における免疫抑制剤の立ち位置転換に挑む。

Outline of Final Research Achievements

In the present study, we focused on KRP-203 to establish a new immunosuppressive protocol that does not depend on calcineurin inhibitors, which are the current standard immunosuppressants. As a result, unlike calcineurin inhibitors, it was proved that KRP-203 does not induce glucose intolerance or inhibition of neovascularization in transplanted cell grafts. It was also found to be a safe and effective immunosuppressive agent that can effectively control allogeneic immune rejection when combined with rapamycin.

Academic Significance and Societal Importance of the Research Achievements

本研究により、副作用が社会的課題となっている現行の標準法であるカルシニューリン阻害剤に依存しない、患者の体や移植グラフトに優しい新たな免疫抑制療法を樹立することができた。本研究の恩恵を最も直接的に享受するのは糖尿病治療を目的とする膵島移植であるが、耐糖能障害がないという観点では膵臓移植も対象となるし、新生血管構築阻害がないという観点では肝細胞移植など多くの細胞移植医療に恩恵をもたらすことが期待される。

Research Products

• [Journal Article] Development of a novel method for measuring tissue oxygen pressure to improve the hypoxic condition in subcutaneous islet transplantation (2022)
  • Author(s): Mitsugashira Hiroaki、Imura Takehiro、Inagaki Akiko、Endo Yukiko、Katano Takumi、Saito Ryusuke、Miyagi Shigehito、Watanabe Kimiko、Kamei Takashi、Unno Michiaki、Goto Masafumi
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 14731-14731
  • DOI: 10.1038/s41598-022-19189-2
  • Peer Reviewed / Open Access
• [Journal Article] Use of perfluorohexyloctane for preservation of rat liver after circulatory death and a prolonged cold preservation model for hepatocyte transplantation (2022)
  • Author(s): Matsumura M, Imura T, Inagaki A, Ogasawara H, Miyagi S, Ohashi K, Unno M, Kamei T, Goto M
  • Journal Title: Transplant International Volume: 35 Pages: 10659-10659
  • DOI: 10.3389/ti.2022.10659
  • Peer Reviewed
• [Journal Article] Acceptance of Murine Islet Allografts Without Immunosuppression in Inguinal Subcutaneous White Adipose Tissue Pretreated With bFGF (2022)
  • Author(s): Nakafusa Yuki、Nitta Naoyoshi、Ishii Kazunari、Shirasu Naoto、Iwamoto Takahiro、Nemoto Takayuki、Nakamura Masafumi、Goto Masafumi、Iwata Hiroo、Taniguchi Masaru、Yasunami Yohichi
  • Journal Title: Diabetes Volume: 71 Issue: 8 Pages: 1721-1734
  • DOI: 10.2337/db21-0684
  • Peer Reviewed / Open Access
• [Journal Article] Cotransplantation with adipose tissue-derived stem cells improves engraftment of transplanted hepatocytes (2022)
  • Author(s): Yamana H, Inagaki A, Imura T, Nakamura Y, Nishimaki H, Katano T, Ohashi K, Miyagi S, Kamei T, Unno M, Goto M
  • Journal Title: Transplantation Volume: 106 Issue: 10 Pages: 1963-1973
  • DOI: 10.1097/tp.0000000000004130
  • Peer Reviewed / Open Access
• [Journal Article] Mesenchymal stem cells secretions enhanced ATP generation on isolated islets during transplantation (2022)
  • Author(s): Teratani T, Kasahara N, Fujimoto Y, Sakuma Y, Miki A, Goto M, Sata N, Kitayama J
  • Journal Title: Islets Volume: 14 Issue: 1 Pages: 69-81
  • DOI: 10.1080/19382014.2021.2022423
  • Peer Reviewed / Open Access
• [Journal Article] Distribution of amniotic epithelial cells after intraportal infusion in a rat model (2022)
  • Author(s): Tanaka M, Tokodai K, Sato M, Yamada S, Okita H, Ito T, Saito M, Hoshiai T, Miyagi S, Miki T, Unno M, Kamei T, Goto M
  • Journal Title: Transplantation Proceedings Volume: - Issue: 2 Pages: 513-515
  • DOI: 10.1016/j.transproceed.2021.09.077
  • Peer Reviewed / Open Access
• [Journal Article] Short-term inhalation of isoflurane improves the outcomes of intraportal hepatocyte transplantation (2022)
  • Author(s): Nishimaki H, Saitoh Y, Inagaki A, Nakamura Y, Imura T, Fathi I, Yamana H, Ohashi K, Miyagi S, Kamei T, Unno M, Goto M
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 4241-4241
  • DOI: 10.1038/s41598-022-08237-6
  • Peer Reviewed / Open Access
• [Journal Article] KRP-203 is a Desirable Immunomodulator for Islet Allotransplantation (2021)
  • Author(s): Fathi I, Nishimura R, Imura T, Inagaki A, Kanai N, Ushiyama A, Kikuchi M, Maekawa M, Yamaguchi H, Goto M
  • Journal Title: Transplantation Volume: - Issue: 5 Pages: 963-972
  • DOI: 10.1097/tp.0000000000003870
  • Peer Reviewed / Open Access
• [Journal Article] Optimization of dye solutions for detecting damaged pancreatic tissues during islet isolation procedures (2021)
  • Author(s): Imura T, Inagaki A, Igarashi Y, Goto M
  • Journal Title: PLOS ONE Volume: 16 Issue: 8 Pages: e0255733-e0255733
  • DOI: 10.1371/journal.pone.0255733
  • Peer Reviewed / Open Access
• [Journal Article] Preferable transplant site for hepatocyte transplantation in a rat model (2021)
  • Author(s): Ogasawara H, Inagaki A, Fathi I, Imura T, Yamana H, Saitoh Y, Matsumura M, Fukuoka K, Miyagi S, Nakamura Y, Ohashi K, Unno M, Kamei T, Goto M
  • Journal Title: Cell Transplantation Volume: Jan-Dec 30
  • DOI: 10.1177/09636897211040012
  • Peer Reviewed / Open Access
• [Journal Article] Decellularized whole-organ pre-vascularization: A novel approach for organogenesis (2021)
  • Author(s): Fathi I, Imura T, Inagaki A, Nakamura Y, Nabawi A, Goto M
  • Journal Title: Frontiers in Bioengineering and Biotechnology Volume: 9 Pages: 756755-756755
  • DOI: 10.3389/fbioe.2021.756755
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The liver surface is an attractive transplantation site for pancreatic islet transplantation (2021)
  • Author(s): Inagaki A, Imura T, Nakamura Y, Ohashi K, Goto M
  • Journal Title: Journal of Clinical Medicine Volume: 10(4) Issue: 4 Pages: 724-724
  • DOI: 10.3390/jcm10040724
  • Peer Reviewed / Open Access
• [Journal Article] Improvement of hepatocyte engraftment by co-transplantation with pancreatic islets in hepatocyte transplantation (2021)
  • Author(s): Saitoh Y, Inagaki A, Fathi I, Imura T, Nishimaki H, Ogasawara H, Matsumura M, Miyagi S, Yasunami Y, Unno M, Kamei T, Goto M
  • Journal Title: J Tissue Eng Regen Med Volume: Jan 23 Issue: 4 Pages: 1-14
  • DOI: 10.1002/term.3170
  • Peer Reviewed / Open Access
• [Journal Article] Effects of Short-Term Normothermic and Subnormothermic Perfusion After Cold Preservation on Liver Transplantation From Donors After Cardiac Death (2020)
  • Author(s): Yamada S, Miyagi S, Hara Y, Kakizaki Y, Sasajima H, Mitsui K, Fujimori K, Unno M, Kamei T, Goto M
  • Journal Title: Transplantation Proc Volume: 52(6) Issue: 6 Pages: 1639-1642
  • DOI: 10.1016/j.transproceed.2020.01.147
  • Peer Reviewed
• [Journal Article] Cytoprotective Effects of Mesenchymal Stem Cells During Liver Transplantation From Donors After Cardiac Death in Swine (2020)
  • Author(s): Sasajima H, Miyagi S, Yamada S, Kakizaki Y, Kamei T, Unno M, Goto M
  • Journal Title: Transplantation Proc Volume: 52(6) Issue: 6 Pages: 1891-1900
  • DOI: 10.1016/j.transproceed.2020.01.165
  • Peer Reviewed
• [Journal Article] Effects of re-augmenting maintenance immunosuppression on post-transplant donor-specific HLA antibodies in liver transplantation (2020)
  • Author(s): Tokodai K, Miyagi S, Nakanishi W, Fujio A, Kashiwadate T, Goto M, Unno M, Kamei T
  • Journal Title: Transpl Immunology Volume: Sep 9 Pages: 101334-101334
  • DOI: 10.1016/j.trim.2020.101334
  • Peer Reviewed / Open Access
• [Presentation] 不織布構造ゼラチン基材の前留置期間が皮下膵島移植のグラフト生着へ及ぼす影響に関する検討 (2023)
  • Author(s): 齊藤竜助
  • Organizer: 第50回日本膵・膵島移植学会
• [Presentation] 皮下における膵島生着環境の創出 (2023)
  • Author(s): 稲垣明子
  • Organizer: 第22回日本再生医療学会
• [Presentation] 膵島移植 (2022)
  • Author(s): 後藤昌史
  • Organizer: 日本消化器病学会第3回再生医療セミナー
  • Invited
• [Presentation] A Gelatin Hydrogel Nonwoven Fabric Improves Outcomes of Subcutaneous Islet Transplantation (2022)
  • Author(s): 金井哲史
  • Organizer: 29th International Congress of The Transplantation Society
  • Int'l Joint Research
• [Presentation] 皮下膵島移植における不織布構造ゼラチン基材の前留置期間が移植結果へ及ぼす影響 (2022)
  • Author(s): 齊藤竜助
  • Organizer: 第58回日本移植学会
• [Presentation] ラット皮下膵島移植における不織布構造ゼラチン基材の前留置が移植結果へ及ぼす影響 (2022)
  • Author(s): 齊藤竜助
  • Organizer: 第48回日本臓器保存生物医学会
• [Presentation] 膵島移植 (2021)
  • Author(s): 後藤昌史
  • Organizer: 日本消化器病学会第2回再生医療セミナー
  • Invited
• [Presentation] 幹細胞移植や異種移植などの膵島移植代用治療を促進する細胞デバイスの開発 (2021)
  • Author(s): 後藤昌史
  • Organizer: 第49回日本膵・膵島移植学会
• [Presentation] KRP-203 is a Desirable Immunomodulator for Islet Allotransplantation (2021)
  • Author(s): Fathi Ibrahim
  • Organizer: 第49回日本膵・膵島移植学会
• [Presentation] 膵島移植と再生医療のクロストーク (2021)
  • Author(s): 後藤昌史
  • Organizer: 第21回日本再生医療学会
  • Invited
• [Presentation] 不織布構造ゼラチン基材の導入による経門脈移植を凌駕する革新的皮下膵島移植法の確立 (2021)
  • Author(s): 金井 哲史,稲垣 明子,中村 保宏,猪村 武弘,Ibrahim Fathi,三頭 啓明,斎藤 竜助,宮城 重人,亀井 尚,海野 倫明,田畑 泰彦,後藤 昌史
  • Organizer: 第48回日本膵膵島移植研究会
• [Presentation] 皮下膵島移植における低酸素環境改善に役立つ新規組織内酸素濃度測定方法の確立 (2021)
  • Author(s): 三頭啓明、猪村武弘、稲垣明子、Fathi Ibrahim、宮城重人、亀井 尚、海野倫明、後藤昌史
  • Organizer: 第48回日本膵膵島移植研究会
• [Presentation] A Preliminary Study of Decellularized Whole-Organ Pre-vascularization: A Novel Approach for Organogenesis (2021)
  • Author(s): Fathi Ibrahim、猪村武弘、稲垣明子、後藤昌史
  • Organizer: The second Congress of Asian Pancreas and Islet Transplant Association (APITA 2021)
  • Int'l Joint Research
• [Presentation] 安全な再生医療実現へ向けた革新的細胞デバイスの構築 (2021)
  • Author(s): 後藤昌史、稲垣明子 、渡邉君子
  • Organizer: 第20回日本再生医療学会（招待講演）
  • Invited
• [Presentation] 移植医療と再生医療の融合がもたらす糖尿病医療の今後の展開 (2020)
  • Author(s): 後藤昌史
  • Organizer: 第56回日本移植学会（招待講演）
  • Invited