Development of in vitro preservation of human islets to establish the global islets transplant network

• Project/Area Number: 19591481
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: Osaka University
• Principal Investigator: TANEMURA Masahiro Osaka University, 医学系研究科, 助教 (30379250)
• Co-Investigator(Kenkyū-buntansha): ITO Toshinori 大阪大学, 医学系研究科, 寄附講座教授 (20231152) ; NOMURA Masaya 大阪大学, 医学系研究科, 助教 (30403190)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2007: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 移植外科学 / 膵島移植 / I型糖尿病 / オートファージ / アポトーシス / 長期保存

Research Abstract

本研究ではオートファジー様細胞死と膵島保存・機能傷害との関連を解析した。1 ng/mlまたは10ng/mlのラパマイシン濃度でマウス膵島を処理した。その結果、オートファジー誘導のマーカーであるLC3-IIタンパクの膵島内蓄積を確認し、膵島viabilityも約50%抑制されることを確認した。また、膵島のインスリン分泌能はグルコース負荷テストにおいて、10ng/mlラパマイシン処理では分泌はほぼ完全に抑制された。一方、オートファジー阻害剤・3-methladenineで追加処理することによりLC3-IIタンパク膵島内蓄積、膵島viability、膵島インスリン分泌能を有意に改善させることができ、膵島におけるオートファジー誘導は移植用膵島の保存・品質管理に強く関与していることが示唆された。

Research Products

• [Journal Article] Rapamycin induces autophagy in islets : Relevance for islets transplantation (2009)
  • Author(s): Tanemura M, Saga A, Kawamoto K, Machida T, Deguchi T, Nishida T, Sawa Y, Doki Y, Mori M, Ito T
  • Journal Title: Transplant Proc 41(1) Pages: 334-338
  • Peer Reviewed
• [Journal Article] Adenovirus-mediated gene expression of human c-FLIP_L protects pig islets against human CD8^+ CTL-mediated cytotoxicity (2009)
  • Author(s): Tanemura M, Saga A, Kawamoto K, Machida T, Deguchi T, Nishida T, Sawa Y, Doki Y, Mori M, Ito T
  • Journal Title: Transplant Proc 41(1) Pages: 319-322
  • Peer Reviewed
• [Journal Article] Intra-and extracellular remodeling effectively prevent human CD8^+ CTL-mediated xenocytotoxicity by coexpression of membrane-bound human FasL and pig c-FLIP_L in pig endothelial cells (2009)
  • Author(s): Tanemura M, Saga A, Kawamoto K, Machida T, Deguchi T, Nishida T, Sawa Y, Doki Y, Mori M, Ito T
  • Journal Title: Transplant Proc 41(1) Pages: 391-395
  • Peer Reviewed
• [Journal Article] Rapamycin induces autophagy in islets : Relevance for islets transplantation. (2009)
  • Author(s): Tanemura M, Saga A, Kawamoto K, Machida T, Deguchi T, Nishida T, Sawa Y, Doki Y, Mori M, Ito T.
  • Journal Title: Transplantation Proceedings (In press)
  • Peer Reviewed
• [Journal Article] Adenovirus-mediated gene expression of human c-FLIP_L protects pigislets against human CD8^+ CTL-mediated cytotoxicity (2009)
  • Author(s): Tanemura M, Saga A, Kawamoto K, Machida T, Deguchi T, Nishida T, Sawa Y, Doki Y, Mori M, Ito T.
  • Journal Title: Transplantation Proceedings (In press)
  • Peer Reviewed
• [Journal Article] Intra- and extracellular remodeling effectively prevent human CD8^+ CTL-mediated xenocytotoxicity by coexpression of membrane-bound human FasL and pig c-FLIP_L in pig endothelial cells. (2009)
  • Author(s): Tanemura M, Saga A, Kawamoto K, Machida T, Deguchi T, Nishida T, Sawa Y, Doki Y, Mori M, Ito T.
  • Journal Title: Transplantation Proceedings (In press)
  • Peer Reviewed
• [Journal Article] Adenoviral-mediated overexpression of either membrane-bound human FasL or human decoy Fas can prolong pig islet xenograft survival in rat transplant model (2008)
  • Author(s): Kawamoto K, Tanemura M, Saga A, Komoda H, Fumimoto Y, Deguchi T, Machida T, Sawa Y, Nishida T, Ito T
  • Journal Title: Transplant Proc 40(2) Pages: 477-9
  • Peer Reviewed
• [Journal Article] Pig cellular FLICE-like Inhibitory Protein (c-FLIP) overexpression in pig xenograft cells induces resistance to human CD8^+ CTL-mediated xenocytotoxicity (2008)
  • Author(s): Tanemura M, Saga A, Kawamoto K, Manabe N, Machida T, Deguchi T, Sawa Y, Nishida T, Ito T
  • Journal Title: Transplant Proc 40(2) Pages: 559-63
  • Peer Reviewed
• [Journal Article] Prolonged survival of pig islets xenograft by adenovirus- mediated expression of either membrane-bound human FasL orhuman decoy Fas antigen gene (2008)
  • Author(s): Kawamoto K, Tanemura M, Doki Y, Mori M, Sawa Y. et.al.(9人中2番目, Corresponding author)
  • Journal Title: Xenotransplantation 15(5) Pages: 333-343
  • Peer Reviewed
• [Journal Article] In vitro and in vivo prevention of human CD8^+ CTL-mediated xenocytotoxicity by pig c-FLIP expression in porcine endothelial cells (2008)
  • Author(s): Tanemura M, Saga A, Kawamoto K et.al.(8人中1番目)
  • Journal Title: Am J Transplant 8(2) Pages: 288-297
  • Peer Reviewed
• [Journal Article] Prolonged survival of pig islets xenograft by adenovirus-mediated expression of either membrane-bound human FasL orhuman decoy Fasantigen gene. (2008)
  • Author(s): Kawamoto K, Tanemura M, Ito T, Deguchi T, Machida T, Nishida T, Doki Y, Mori M, Sawa Y.
  • Journal Title: Xenotransplantation 15(5), 2008 Pages: 333-343
  • Peer Reviewed
• [Journal Article] In vitro and in vivo prevention of human CD8^+ CTL-mediatedxenocytotoxicity by pig c-FLIP expression in porcine endothelial cells. (2008)
  • Author(s): Tanemura M, Saga A, Kawamoto K, Deguchi T, Machida T, Nishida T, Sawa Y, Ito T.
  • Journal Title: Am J Transplant. 8(2) Pages: 288-297
  • Peer Reviewed
• [Journal Article] In vitro and in vivo prevention of human CD8^+ CTL-mediated xenocytotoxicity by pig c-FLIP expression in porcine endothelial cells (2008)
  • Author(s): Tauemura M, Saga A, Kawamoto K, et. al.(8人中1番目)
  • Journal Title: Am J Transplant. 8(2) Pages: 288-297
  • Peer Reviewed
• [Journal Article] Pig cellular FLICE-like Inhibitory Protein (c-FLIP) overexpression in pig xenogra ft cells induces resistance to human CD8^+ CTL-mediated xenocytotoxicity. (2008)
  • Author(s): Tanemura M, Saga A, Kawamoto K, et. al.(8人中1番目)
  • Journal Title: Tansplant Proc. (In press)
  • Peer Reviewed
• [Journal Article] Adenoviral-mediated overexpression of either membrane-bound human FasLor humandecoy Fas can prolong pig islet xenograft survival in rat transplant model. (2008)
  • Author(s): Kawamoto K, Tanemura M, Saga A, et. al.(8人中2番目)
  • Journal Title: Tansplant Proc. (In press)
  • Peer Reviewed
• [Presentation] 移植膵島でのオートファジー誘導の臨床的意義-膵島移植後免疫抑制療法としてラパマイシンは妥当か? (2008)
  • Author(s): 種村匡弘
  • Organizer: 日本移植学会総会(44)
  • Place of Presentation: 大阪
• [Presentation] Intra-and extracellular remodeling effectively prevent human CD8^+ CTL-mediated xenocytotoxicity by coexpression of human membrane-bound FasL and pig c-FLIP_L in pig endothelial cells (2008)
  • Author(s): Tanemura M. et. al.
  • Organizer: International congress of the transplantation society (22)
  • Place of Presentation: Sydney
• [Presentation] Adenovirus-mediated gene expression of human c-FLIPL protects pig islets against human CD8+ CTL-mediated cytotoxicity (2008)
  • Author(s): Tanemura M. et. al.
  • Place of Presentation: Sydney
• [Presentation] Rapamycin induces autophagy in islets : Relevance for islets transplantation (2008)
  • Author(s): Tanemura M. et. al.
  • Place of Presentation: Sydney
• [Presentation] Intra- and extracellular remodeling effectively prevent human CD8+ CTL-mediated xenocytotoxicity by coexpression of human membrane-bound FasL and pig c-FLIPL in pig endothelial cells (2008)
  • Author(s): Tanemura M, Saga A, Kawamoto K, Machida T, Deguchi T, Nishida T, Sawa Y, Doki Y, Mori M, Ito T.
  • Organizer: International congress of the transplantation society (22)
  • Place of Presentation: Sydney
• [Presentation] Adenovirus-mediated gene expression of human c-FLIPL protects pig islets against human CD8+ CTL-mediated cytotoxicity (2008)
  • Author(s): Tanemura M, Saga A, Kawamoto K, Machida T, Deguchi T, Nishida T, Sawa Y, Doki Y, Mori M, Ito T.
  • Organizer: International congress of the transplantation society (22)
  • Place of Presentation: Sydney
• [Presentation] Rapamycin induces autophagy in islets : Relevance for isletstransplantation. (2008)
  • Author(s): Tanemura M, Saga A, Kawamoto K, Machida T, Deguchi T, Nishida T, Sawa Y, Doki Y, Mori M, Ito T.
  • Organizer: International congress of the transplantation society (22)
  • Place of Presentation: Sydney
• [Presentation] 移植膵島でのオートファジー誘導の臨床的意義膵島移植後免疫抑制療法としてラパマイシンは妥当か? (2008)
  • Author(s): 種村匡弘, 嵯峨礼美, 川本弘一, 出口貴司, 町田智彦, 西田俊朗, 澤芳樹, 森正樹, 土岐祐一郎, 伊藤壽記
  • Organizer: 日本移植学会総会(44)
  • Place of Presentation: 大阪
• [Presentation] ブタcellular FLICE inhibitory protein(c-FLIP)過剰発現による細胞内シグナル伝達リモデリングを応用したヒトCD8^+ CTL細胞傷害性の制御 (2007)
  • Author(s): 嵯峨礼美, 種村匡弘, 川本弘一, 菰田弘, 文元雄一, 出口貴司, 町田智彦, 西田俊朗, 澤芳樹, 伊藤壽記
  • Organizer: 第43回日本移植学会総会、シンポジウム
  • Place of Presentation: 仙台
  • Year and Date: 2007-11-23
• [Presentation] I型糖尿病に対する異種膵島移植療法の確立-レシピエント細胞性拒絶回避の免疫学的戦略- (2007)
  • Author(s): 種村匡弘、川本弘一、嵯峨礼美、菰田弘、大森健、文元雄一、島田和典、出口貴司、澤芳樹、西田俊朗、伊藤壽記
  • Organizer: 第107回日本外科学会定期学術集会、ワークショップ
  • Place of Presentation: 大阪
  • Year and Date: 2007-04-13
• [Presentation] Pig cellular FLICE-like Inhibitory Protein (c-FLIP) overexpression in pig xenograft cells induces resistance to human CD8^+ CTL-mediated xenocytotoxicity (2007)
  • Author(s): Tanemura M. et. al.
  • Organizer: Joint Conference of IPITA, CTS and IXA
  • Place of Presentation: Minneapolis, Minnesota, USA
• [Book] シュプリンガージャパン刊「膵臓移植-糖尿病根治をめざして-」12章術後管理II合併症(i)外科的合併症 (2009)
  • Author(s): 伊藤壽記(編集)、種村匡弘
• [Book] 膵臓移植 -糖尿病根治をめざして- (2009)
  • Author(s): 種村匡弘, 伊藤壽記
  • Publisher: シュプリンガー・ジャパン(印刷中)
• [Book] 膵臓移植 -糖尿病根治を目指して- (2008)
  • Author(s): 種村匡弘
  • Publisher: シュプリンがー・ジャパン株式会社(In press)