A novel strategy to minimize mTOR-induced autophagy to pancreatic islet beta cells

• Project/Area Number: 20591524
• 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: ITO Toshinori Osaka University, 医学系研究科, 寄附講座教授 (20231152)
• Co-Investigator(Kenkyū-buntansha): TANEMURA Masahiro 大阪大学, 医学系研究科, 助教 (30379250)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2008: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 膵島移植 / 1型糖尿病 / オートファジー / 長期成績 / mTOR阻害剤 / 3-MA / I型糖尿病 / オートファージ / mTOR inhibitor r / mTOR inhibitor

Research Abstract

Mammalian target of rapamycin (mTOR) inhibitor has extensively used in clinical islet transplantation to prevent the graft rejection. Recently, mTOR inhibitor has also reported to induce autophagy to various kinds of cell lines. Autophagy is an essential, homeostatic process by which cells break down their own components. However, its role on pancreatic islets has not been thoroughly understood. In this study we demonstrated that both in vitro and in vivo, rapamycin treatment induced autophagy to islets. Furthermore, addition of autophagy inhibitor resulted in better graft outcome. These results suggest that rapamycin with autophagy inhibitor would be an ideal combination to prevent graft rejection without autophagy induction.

Research Products

• [Journal Article] Successful pregnancy after simultaneous pancreas-kidney transplantation from a brain-dead donor: the first case report in Japan. (2011)
  • Author(s): Koyama S, Tomimatsu T, Kanagawa T, Daimon E, Kimura T, Kuroda A, Tanemura M, Doki Y, Ito T.
  • Journal Title: J Obstetrics Gynaecol Res. in press
• [Journal Article] Combined Transplantation of Pancreatic Islets and Adipose Tissue-Derived Stem Cells Enhances the Survival and Insulin Function of Islet Grafts in Diabetic Mice. (2010)
  • Author(s): Ohmura Y, Tanemura M, Kawaguchi N, Machida T, Tanida T, Deguchi T, Wada H, Kobayashi S, Marubashi S, Eguchi H, Takeda Y, Matsuura N, Ito T, Nagano H, Doki Y, Mori M.
  • Journal Title: Transplantation. 90(12) Pages: 1366-73
• [Journal Article] Increased immunogenicity of tumor-associated antigen, MUC1, engineered to express α-gal epitopes : A novel approach to immunotherapy in pancreatic cancer. (2010)
  • Author(s): Deguchi T, Tanemura M, Miyoshi E, Nagano H, Machida T, Ohmura Y, Kobayashi S, Marubashi S, Eguchi H, Takeda Y, Ito T, Mori M, Doki Y, Sawa Y.
  • Journal Title: Cancer Research. 70(13) Pages: 5259-69
• [Journal Article] Combined Transplantation of Pancreatic Islets and Adipose Tissue-Derived Stem Cells Enhances the Survival and Insulin Function oflslet Grafts in Diabetic Mice (2010)
  • Author(s): Ohmura Y, Tanemura M, Kawaguchi N, Machida T, Tanida T, Deguchi T, Wada H, Kobayashi S, Marubashi S, Eguchi H, Takeda Y, Matsuura N, Ito T, Nagano H, Doki Y, Mori M.
  • Journal Title: Transplantation Volume: 27;90(12) Pages: 1366-73
  • Peer Reviewed
• [Journal Article] Increased immunogenicity of tumor-associated antigen, MUC1, engineered to express α-gal epitopes : A novel approach to immunotherapy in pancreatic cancer. (2010)
  • Author(s): Deguchi T, Tanemura M, Miyoshi E, Nagano H, Machida T, Ohmura Y, Kobayashi S, Marubashi S, Eguchi H, Takeda Y, Ito T, Mori M, Doki Y, Sawa Y.
  • Journal Title: Cancer Research Volume: 70(13) Pages: 5259-69
  • Peer Reviewed
• [Journal Article] Effects of preceding interferon therapy on outcome after surgery for hepatitis C virus-related hepatocellular carcinoma. (2010)
  • Author(s): Tomimaru Y, Nagano H, Eguchi H, Kobayashi S, Marubashi S, Wada H, Tanemura M, Umeshita K, Hiramatsu N, Takehara T, Doki Y, Mori M
  • Journal Title: J of Surg Oncol Volume: 15;102(4) Pages: 308-14
  • Peer Reviewed
• [Journal Article] MicroRNA-21 induces resistance to the anti-tumour effect of interferon-α/5-fluorouracil in hepatocellular carcinoma cells. (2010)
  • Author(s): Tomimaru Y, Eguchi H, Nagano H, Wada H, Tomokuni A, Kobayashi S, Marubashi S, Takeda Y, Tanemura M, Umeshita K, Doki Y, Mori M.
  • Journal Title: Br J Cancer Volume: 9;103(10) Pages: 1617-26
  • Peer Reviewed
• [Journal Article] GBP2 mRNA in peripheral blood leukocytes of liver transplant recipients as a marker for acute cellular rejection. (2009)
  • Author(s): Kobayashi S, Marubashi S, Hama N, Asaoka T, Eguchi H, Takeda Y, Tanemura M, Doki Y, Mori M.
  • Journal Title: Transplant int. 23(4) Pages: 390-6
• [Journal Article] Intra- and extracellular remodeling effectively prevent human CD8+ CTL-mediated xenocytotoxicity by coexpression of membrane-bound human FasL and pig c-FLIPL 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: 391-394
• [Journal Article] Adenovirus-mediated gene expression of human c-FLIPL 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
• [Journal Article] Rapamycin induces autophagy in islets : Relevance for islet 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: 334-38
• [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 Proceedings 41(1) Pages: 334-338
  • Peer Reviewed
• [Journal Article] Adenovirus-mediated gene expression of human c-FLIPL 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 Proceedings 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-FLIPL 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 Proceedings 41(1) Pages: 391-394
  • Peer Reviewed
• [Journal Article] Rapamycin induces autophagy in islets : Relevance for isletstransplantation. (2009)
  • Author(s): Tanemura M, Saga A, KawamotoK, Machida T, Deguchi T, Nishida T, Sawa Y, Doki Y, MoriM, 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, KawamotoK, Machida T, Deguchi T, Nishida T, Sawa Y, Doki Y, MoriM, Ito T.
  • Journal Title: Transplantation Proceedings (In press)
  • Peer Reviewed
• [Journal Article] Prolonged survival of pig islets xenograft by adenovirus-mediated expression of either membrane-bound human FasL or human decoy Fas antigen 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) Pages: 333-43
• [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, Deguchi T, Machida T, Nishida T, Sawa Y, Ito T.
  • Journal Title: Am J Transplant. 8(2) Pages: 288-297
• [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
• [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
• [Journal Article] Development of beta-Cells in the Native Pancreas After Pancreas Allo-Transplantation in the Spontaneously Diabetic Torii Rat. (2008)
  • Author(s): Shimada K, Ito T, Tanemura M, Komoda H, Fumimoto Y, Kawamoto K, Nishida T, Kaneto H, Sawa Y.
  • Journal Title: J Surg Res. 145(2) Pages: 229-37
• [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, KawamotoK, Deguchi T, Machida T, Nishida T, Sawa Y, Ito T.
  • Journal Title: Am J Transplant. 8(2) Pages: 288-297
  • Peer Reviewed
• [Presentation] Hybrid islet transplantation with marginal islet mass and adipose tissue-derived stem cells can elicit long-term islet graft survival and support normoglycemia in diabetic mice. (2010)
  • Author(s): Y.Ohmura, M.Tanemura, T.Machida, T.Deguchi, H.Wada, S.Kobayashi, S.Marubashi, H.Eguchi, Y.Takeda, N.Kawaguchi, N.Matsuura, T.Ito, H.Nagano, Y.Doki, M.Mori
  • Organizer: XXIII International Congress of The Transplantation Society
  • Place of Presentation: Vancouver, CANADA
  • Year and Date: 2010-08-16
• [Presentation] Hybrid islet transplantation with marginal islet mass and adipose tissue-derived stem cells can elicit long-term islet graft survival and support normoglycemia in diabetic mice. (2010)
  • Author(s): Y.Ohmura, M.Tanemura, T.Machida, T.Deguchi, H.Wada, S.Kobayashi, S.Marubashi, H.Eguchi, Y.Takeda, N.Kawaguchi, N.Matsuura, T.Ito, H.Nagano, Y.Doki, M.Mori
  • Organizer: XXIII International Congress of The Transplantation Society
  • Place of Presentation: バンクーバー(カナダ)
  • Year and Date: 2010-08-16
• [Presentation] MUC1, remodeled to express α-gal epitopes immune-based therapy can elicit both significant prolonged survival and effective antibody production against multiple tumor-associated antigens. (2010)
  • Author(s): Tanemura M, Deguchi T, Miyoshi E, Nagano H, Ohmura Y, Machida T, Wada H, Kobayashi S, Marubash S, Eguchi H, Takeda Y, Ito T, Mori M, Doki Y
  • Organizer: AACR 101nd Annual Meeting
  • Place of Presentation: Washington, USA
• [Presentation] MUC1, remodeled to express α-gal epitopes immune-based therapy can elicit both significant prolonged survival and effective antibody production against multiple tumor-associated antigens (2010)
  • Author(s): Tanemura M, Deguchi T, Miyoshi E, Nagano H, Ohmura Y, Machida T, Wada H, Kobayashi S, Marubash S, Eguchi H, Takeda Y, Ito T, Mori M, Doki Y
  • Organizer: AACR 101nd Annual Meeting
  • Place of Presentation: ワシントン(アメリカ)
• [Presentation] ラパマイシン毒性としての移植膵島におけるオートファジー誘導の意義 (2009)
  • Author(s): 種村匡弘、出口貴司、町田智彦、永野浩昭、出口貴司、丸橋繁、江口英利、武田裕、塚本里加子、伊藤壽記、森正樹、土岐祐一郎
  • Organizer: 第45回日本移植学会総会
  • Place of Presentation: 東京
• [Presentation] 異種膵島移植療法の臨床応用に向けた先端研究 (2009)
  • Author(s): 種村匡弘、伊藤壽記、永野浩昭、出口貴司、町田智彦、小林省吾、丸橋繁、武田裕、北川透、堂野恵三、門田守人、森正樹、土岐祐一郎
  • Organizer: 第21回日本肝胆膵外科学会・学術集会
  • Place of Presentation: 名古屋
• [Presentation] Rapamycin Induces Autophagy in Islets and Impairs Islet Function. (2009)
  • Author(s): Tanemura M., Ito T., Machida T., Deguchi T., Kobayashi S., Marubashi S., Takeda Y., Nagano H., Sawa Y., Mori M., Doki Y.
  • Organizer: American Transplantation Congress.
  • Place of Presentation: Boston
• [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: 第44回日本移植学会総会
  • 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-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: 22th International congress of the transplantation society.
  • 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: 22th International congress of the transplantation society.
  • Place of Presentation: Sydney
• [Presentation] Rapamycin induces autophagy in islets : Relevance for islets transplantation. (2008)
  • Author(s): Tanemura M, Saga A, Kawamoto K, Machida T, Deguchi T, Nishida T, Sawa Y, Doki Y, Mori M, Ito T.
  • Organizer: 22th International congress of the transplantation society.
  • Place of Presentation: Sydney
• [Book] 膵臓移植-糖尿病根治を目指して- (2009)
  • Author(s): 寺岡慧、伊藤壽記編集
  • Total Pages: 474
  • Publisher: シュプリンガージャパン出版
• [Book] 膵臓移植-糖尿病根治を目指して (2009)
  • Author(s): 寺岡慧, 伊藤壽記 編集
  • Total Pages: 474
  • Publisher: シュプリンガー・ジャパン
• [Book] 膵臓移植-糖尿病根治を目指して- (2009)
  • Author(s): 伊藤壽記
  • Publisher: シュプリンガー・ジャパン株式会社(印刷中)
• [Patent(Industrial Property Rights)] 膵島移植時の膵島生着率を高める膵島移植の生着改善剤、膵島移植 用生物製剤、及び膵島移植用キット (2010)
  • Inventor(s): 種村匡弘
  • Industrial Property Rights Holder: 大阪大学
  • Filing Date: 2010-08-06
• [Patent(Industrial Property Rights)] 膵島の分離方法および膵島組織を保護するための保護液 (2010)
  • Inventor(s): 種村匡弘
  • Industrial Property Rights Holder: 大阪大学
  • Filing Date: 2010-07-13
• [Patent(Industrial Property Rights)] 膵島移植時の膵島生着率を高める膵島移植の生着改善剤、膵島移植用生物製剤、及び膵島移植用キット (2010)
  • Inventor(s): 種村匡弘
  • Industrial Property Rights Holder: 大阪大学
  • Industrial Property Number: 2010-177993
  • Filing Date: 2010-08-06