Immunological tolerance induced by surviving but not dying cellsfollowing sublethal stress

• Project/Area Number: 22390248
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: Fukushima Medical University
• Principal Investigator: GOTOH Mitsukazu 福島県立医科大学, 医学部, 教授 (50162160)
• Co-Investigator(Kenkyū-buntansha): SAITO Takuro 福島県立医科大学, 医学部, 医監兼教授 (20305361) ; ANAZAWA Takayuki 福島県立医科大学, 医学部, 助教 (90566811)
• Co-Investigator(Renkei-kenkyūsha): KENJO Akira 福島県立医科大学, 医学部, 講師 (40305355) ; ISE Kazuya 福島県立医科大学, 医学部, 講師 (90363746) ; KIMURA Takashi 福島県立医科大学, 医学部, 助教 (00381369) ; SUZUKI Hiroyuki 福島県立医科大学, 医学部, 教授 (30322340)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000); Fiscal Year 2012: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2011: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2010: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: 膵島 / 亜致死刺激 / 免疫寛容 / 細胞周期停止 / Mitomycin C / HMGB1 / calreticulin / 細胞死 / 移植 / 酸化ストレス / 小胞体ストレス

Research Abstract

Islets treated with sublethal concentration of MMC at 10μg/ml for 30 min induced immunological unresponsiveness when these islets were cultured for more than 20 hrs and transplanted into renal subcapsular space of STZ-induced diabetic mice. MMC treatment effectively reduced central necrotic area which pooled calreticulin and HMGB1 both inducing cross priming together. Western blot analysis suggested that MMC treatment and subsequent culture for 8 or 20 h upregulated the active form of p53 as well as the downstream gene p21waf1. Meanwhile, the active form of caspase-3 was not significantly changed. This indicates that the activation of p53 was directed at cell cycle arrest, but not at apoptosis processes through the activation of caspase-3. These findings together with previous in vivo results would support that a concept of surviving but not dying cells through sublethal stress induce unresponsiveness to the treated cells.

Research Products

• [Journal Article] Mitomycin-C treatment significantly reduces central damage of islets in culture (2012)
  • Author(s): Saito T, Saito T, Sato Y, Ise K, Anazawa T, Oshibe I, Haga J, Yamamoto M, Waguri S, Gotoh M.
  • Journal Title: Pancreas Volume: 41(2) Pages: 245-252
  • DOI: 10.1097/mpa.0b013e31822461c7
  • Peer Reviewed
• [Journal Article] Preservation of pancreatic islets in cold UW solution Preservation of pancreatic islets in cold UW solution (2012)
  • Author(s): Ishii S, Saito T, Ise K, Yamashita M, Sato Y, Saito T, Tsukada M, Oshibe I, Kenjo A, Kimura T, Anazawa T, Suzuki S, Gotoh M
  • Journal Title: Islets Volume: 4(1) Pages: 32-39
  • DOI: 10.4161/isl.18607
  • Peer Reviewed
• [Journal Article] Adenine nucleotide levels in a closed enzymatic digestion system for porcine islet isolation (2012)
  • Author(s): Oshibe I, Saito T, Sato Y, Saito T, Tsukada M, Ise K, Kenjo A, Kimura T, Anazawa T, Suzuki S, Hashimoto Y, Gotoh M
  • Journal Title: Cell Transplantation Volume: 21(2-3) Pages: 483-491
  • DOI: 10.3727/096368911x605394
  • Peer Reviewed
• [Journal Article] A model to evaluate toxic factors influencing islets during collagenase digestion: the role of serine protease inhibitor in the protection of islets. (2012)
  • Author(s): Tsukada M, Saito T, Ise K, Kenjo A, Kimura T, Satoh Y, Sai to T, Anazawa T, Oshibe I, Suzuki S, Hashimoto Y, Gotoh M
  • Journal Title: Cell Transplantation Volume: 21(2-3) Pages: 473-482
  • DOI: 10.3727/096368911x605385
  • Peer Reviewed
• [Journal Article] Mizoribine as Sole Immunosuppressive Agent in Islet Xenotransplantation Models: A Candidate Immunosuppressant Causing no Adverse Effects on Islets. (2012)
  • Author(s): Yamashita M, Saito T, Ise K, Ishii S, Satoh Y, Saito T, Oshibe I, Shimizu H, Kenjo A, Kimura T, Gotoh M.
  • Journal Title: Cell Transplantation Volume: 21(2-3) Pages: 535-545
  • DOI: 10.3727/096368911x605457
  • Peer Reviewed
• [Journal Article] Improved islet yield and function by use of a chloride channel blocker during collagenase digestion. (2011)
  • Author(s): Anazawa T, Sato Y, Saito T, Tsuchiya T, Kenjo A, Kimura T, Haga J, Miyake M, Waguri S, Hazama A, Gotoh M.
  • Journal Title: Transplantation Volume: 92(8) Pages: 871-877
  • DOI: 10.1097/tp.0b013e31822e6eb4
  • Peer Reviewed
• [Journal Article] Reversal of diabetes by the creation of neo-islet tissues into a subcutaneous site using islet cell sheets. (2011)
  • Author(s): Saito T, Ohashi K, Utoh R, Shimizu H, Ise K, Suzuki H, Yamato M, Okano T, Gotoh M
  • Journal Title: Transplantation Volume: 92(11) Pages: 1231-1236
  • DOI: 10.1097/tp.0b013e3182375835
  • Peer Reviewed
• [Journal Article] Actions of the Japanese Pancreas and Islet Transplantation Association Regarding Transplanted Human Islets Isolated Using Liberase HI (2010)
  • Author(s): Saito T, Anazawa T, Gotoh M, Uemoto S, Kenmochi T, Kuroda Y, Satomi S, Itoh T, Yasunami Y, Kitamoto T, Mohri S, Teraoka S
  • Journal Title: Transplantation Proceedings. Volume: 42(10) Pages: 4213-4216
  • DOI: 10.1016/j.transproceed.2010.09.142
  • Peer Reviewed
• [Journal Article] Islet transplantation using donors after cardiac death: report of the Japan Islet Transplantation Registry (2010)
  • Author(s): Saito T, Gotoh M, Satomi S, Uemoto S, Kenmochi T, Itoh T, Kuroda Y, Yasunami Y, Matsumoto S, Teraoka S.
  • Journal Title: Transplantation. Volume: 90(7) Pages: 740-747
  • DOI: 10.1097/tp.0b013e3181ecb044
  • Peer Reviewed
• [Journal Article] Actions of the Japanese Pancreas and Islet Transplantation Association Regarding Transplanted Human Islets Isolated Using Liberase HI. (2010)
  • Author(s): Saito T
  • Journal Title: Transplantation Proceedings Volume: 42(10) Pages: 4213-4216
  • Peer Reviewed
• [Journal Article] Islet transplantation using donors after cardiac death : report of the Japan Islet Transplantation Registry. (2010)
  • Author(s): Saito T
  • Journal Title: Transplantation Volume: 90(7) Pages: 740-747
  • Peer Reviewed
• [Presentation] 重症低血糖発作を伴うインスリン依存性糖尿病に対する心停止ドナーからの膵島移植:日本膵・膵島移植研究会事務局報告 (2011)
  • Author(s): 穴澤貴行,土屋貴男,見城 明,芳賀淳一郎,佐藤 哲,三宅将生,狹間章博,後藤満一
  • Organizer: 第47回日本移植学会総会
  • Place of Presentation: 仙台
• [Presentation] Inhibition of chloride ion influx into islet cells protects islets during pancreatic islet isolation. (2011)
  • Author(s): Anazawa T, Tsuchiya T, Kenjo A, Haga J, Sato T, Sato N, Saito T, Sat o Y, Miyake M, Hazama A, Gotoh M
  • Organizer: The 13th World congress of International pancreas and islet transplantation association
  • Place of Presentation: Prague, Czech Republic.
• [Presentation] Functional Islet Tissue Engineering in Subcutaneous Site Using Fabricated Islet Cell Sheets. (2011)
  • Author(s): Shimizu H, Ohashi K, Saito T, Utoh R, Ise K, Yamat o M, Okano T, Gotoh M.
  • Organizer: The 13th World congress of International pancreas and islet transplantation association.
  • Place of Presentation: Prague, Czech Republic
• [Presentation] Inhibition of chloride ion influx into islet cells protects islets during pancreatic islet isolation (2011)
  • Author(s): Anazawa T, Tsuchiya T, Kenjo A, Haga J, Sato T, Sato N, Saito T, Sato Y, Miyake M, Hazama A, Gotoh M
  • Organizer: The 13th World congress of International pancreas and islet transplantation association
  • Place of Presentation: Prague, Czech Republic
• [Presentation] Mitomycin-C treatment protects islets from the progression of central damage during culture (2011)
  • Author(s): Haga J, Saito T, Anazawa T, Tsuchiya T, Kenjo A, Sato S, Sato N, Saito T, Ise K, Yamamoto M, Waguri S, Gotoh M
  • Organizer: The 13th World congress of International pancreas and islet transplantation association
  • Place of Presentation: Prague, Czech Republic
• [Presentation] Functional Islet Tissue Engineering in Subcutaneous Site Using Fabricated Islet Cell Sheets (2011)
  • Author(s): Shimizu H, Ohashi K, Saito T, Utoh R, Ise K, Yamato M, Okano T, Gotoh M
  • Organizer: The 13th World congress of International pancreas and islet transplantation association
  • Place of Presentation: Prague, Czech Republic
• [Presentation] Cl^-チャネル阻害による細胞保護効果の膵島分離への応用-臨床膵島移植確立への細胞生理学的アプローチ- (2011)
  • Author(s): 穴澤貴行, 土屋貴男, 見城明, 芳賀淳一郎, 佐藤哲, 三宅将生, 狭間章博, 後藤満一
  • Organizer: 第111回日本外科学会定期学術集会
  • Place of Presentation: 東京(誌上開催)
• [Presentation] Mitomycin-C treatment significantly reduces central necrotic damage of islets in culture (2010)
  • Author(s): Saito T, Saito T, Sato Y, Ise K, Oshibe I, Waguri S, Gotoh M.
  • Organizer: The 23th International Congress of the Transplantation Society.
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2010-08-16
• [Presentation] Mitomycin-C treatment significantly reduces central necrotic damage of islets in culture. (2010)
  • Author(s): Saito T
  • Organizer: The 23th International Congress of The Transplantation Society
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2010-08-16