Development of a new strategy for pancreatic islet transplantation by molecular targeting agents

• Project/Area Number: 23390309
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: Hokkaido University
• Principal Investigator: YAMASHITA Kenichiro 北海道大学, 医学(系)研究科(研究院), 特任教授 (00399940)
• Co-Investigator(Kenkyū-buntansha): TODO Satoru 聖マリア学院大学, 看護学研究科, 教授 (60136463) ; KAMACHI Hirofumi 北海道大学, 大学院・医学研究科, 特任講師 (60374237) ; MATSUSHITA Michiaki 天使病院 (20250425) ; FURUKAWA Hiroyuki 旭川医科大学, 医学部, 教授 (70292026) ; OZAKI Michitaka 北海道大学, 保健科学研究院, 教授 (80256510)
• Co-Investigator(Renkei-kenkyūsha): UMEZAWA Kazuo 愛知医科大学, 医学部, 教授 (70114402)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2013: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2012: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2011: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: 膵ラ氏島移植 / 分子標的治療 / NF-κB / CD40

Research Abstract

Pancreatic islet transplantation (PIT) is an ideal cell-based therapy for type I diabetes. However, transplanted islets are injured immediately after grafting, and islet graft function deteriorates progressively. In order to overcome these hurdles, we focused on NF-kB and CD40, and tried to establish a safe and effective strategy for PIT in the current studies. In murine and canine PIT models, we found that agents which inhibits NF-kB activation such as DHMEQ, PPAR-gamma agonist and proteasome inhibitor, efficiently blocks inflammatory responses and prevents islet graft loss shortly after PIT. Also, CD40-CD40L costimulatory blockade potently suppressed rejection and markedly prolonged islet allograft survival in both mouse and monkey PIT models. Our results demonstrated that treatments targeting NF-kB and CD40 are very effective for preventing graft loss following PIT, and that these strategies would be applicable for clinical PIT.

Research Products

• [Journal Article] The efficacy of DHMEQ, a NF- κ B inhibitor , in islet transplantation : I. HMGB1 suppression by DHMEQ prevents early islet graft damage (2013)
  • Author(s): Kuraya D, Watanabe M, Koshizuka Y, Ogura M, Y oshida T, Asahi Y, Kamachi H, Nakamura T, Harashima H, Ozaki M, Umezawa K, Matsushita M, Y amashita K, T odo S
  • Journal Title: Transplantation Volume: 96(5) Issue: 5 Pages: 445-53
  • DOI: 10.1097/tp.0b013e31829b0744
  • Peer Reviewed
• [Journal Article] The efficacy of DHMEQ, a NF- κ B inhibitor , in islet transplantation : II. Induction DHMEQ treatment ameliorates subsequent allo-immune responses, and permits a long-term islet allograft acceptance (2013)
  • Author(s): Watanabe M, Y amashita K, Kamachi H, Kuraya D, Koshizuka Y, Shibasaki S, Asahi Y, Ono H, Emoto S, Ogura M, Y oshida T, Ozaki M, Umezawa K, Matsushita M, T odo S
  • Journal Title: Transplantation Volume: 96(5) Issue: 5 Pages: 454-62
  • DOI: 10.1097/tp.0b013e31829b077f
  • Peer Reviewed
• [Journal Article] ASKP1240, a fully human anti-CD40 monoclonal antibody , prolongs pancreatic islet allograft survival in nonhuman primates (2013)
  • Author(s): Watanabe M, Y amashita K, Suzuki T, Kamachi H, Kuraya D, Koshizuka Y, Ogura M, Y oshida T, Aoyagi T, Fukumori D, Shimamura T, Okimura K, Maeta K, Miura T, Sakai F, T odo S
  • Journal Title: Am J Transplant Volume: 13(8) Issue: 8 Pages: 1976-88
  • DOI: 10.1111/ajt.12330
  • Peer Reviewed
• [Journal Article] The efficacy of DHMEQ, a NF-κB inhibitor, in islet transplantation: I. HMGB1 suppression by DHMEQ prevents early islet graft damage (2013)
  • Author(s): Daisuke Kuraya, et al.
  • Journal Title: Transplantation Volume: (in press)
  • Peer Reviewed
• [Journal Article] The efficacy of DHMEQ, a NF-κB inhibitor, in islet transplantation: II. Induction DHMEQ treatment ameliorates subsequent allo-immune responses, and permits a long-term islet allograft acceptance (2013)
  • Author(s): Masaaki Watanabe, et. al
  • Journal Title: Transplantation Volume: (in press)
  • Peer Reviewed
• [Journal Article] ASKP1240, a Fully Human Anti-CD40 Monoclonal Antibody, Prolongs Pancreatic Islet Allograft Survival in Nonhuman Primates (2013)
  • Author(s): Masaaki Watanabe, et. al
  • Journal Title: American Journal of Transplantation Volume: (in press)
  • Peer Reviewed
• [Journal Article] Induction of insulin-dependent diabetes mellitus by total pancreatectomy for pancreatic islet transplantation in cynomolgus monkeys (2012)
  • Author(s): Yoshida T, Suzuki T, Watanabe M, Yamashita K, Koshizuka Y, Kuraya D, Ogura H, Kamachi H, Matsushita M, Todo S
  • Journal Title: J Hepatobiliary Pancreat Sci Volume: 19(6) Issue: 6 Pages: 661-6
  • DOI: 10.1007/s00534-011-0485-3
  • NAID: 10031126982
  • Peer Reviewed
• [Presentation] Roles of CD40-CD40L costimulatory pathway in pancreatic islet transplantation (2013)
  • Author(s): Koshizuka Y , Watanabe M, Suzuki T , Kamachi H, Ogura M, Yoshida T , Kuraya D, Fukumori D, Shimamura T , Okimura K, Maeta K, Miura T , Sakai F , T'odo S, Yamashita K
  • Organizer: 3rd ESOT Basic Science Meeting & 13th TTS Basic Science Symposium
  • Place of Presentation: Paris, France
  • Year and Date: 2013-11-08
• [Presentation] Improvement of normoglycemic rate by Proliferater-activated receptor-gamma agonist, pioglitazone, in canine islet autotransplantation (2013)
  • Author(s): Asahi Y , Yamashita K, Watanabe M, Ogura M, Ono H, Emoto S, Nagatsu A, Yoshida T , Koshizuka Y , Taketomi A, Todo S
  • Organizer: 16th Congress of the European Society for Organ Transplantation
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2013-09-09
• [Presentation] Prevention of early graft loss by Proliferator-activated receptor-gamma agonist, pioglitazonoe, in canine islet autotransplantation (2013)
  • Author(s): Asahi Y , Y amashita K, Watanabe M, Ogura M, Ono H, Handly DE, Emoto S, Nagatsu A, Y oshida T , Koshizuka Y , Kamachi H, T aketomi A, T odo S
  • Organizer: American Transplant Congress
  • Place of Presentation: Seattle, U.S.A
  • Year and Date: 2013-05-20
• [Presentation] 膵島移植における分子標的治療薬を用いた免疫療法 -膵島移植成績の向上に向けて- (2012)
  • Author(s): 山下健一郎
  • Organizer: 第39回日本膵・膵島移植研究会
  • Place of Presentation: 旭川
• [Presentation] Prevention of early graft loss by Proliferator-activated receptor-gamma agonist, pioglitazonoe, in canine islet autotransplantation
  • Author(s): Asahi Y, Yamashita K,Watanabe M,Ogura M,Ono H,Handly DE, Emoto S, Nagatsu A, Yoshida T,Koshizuka Y, Kamachi H, Taketomi A, Todo S.
  • Organizer: American Transplant Congress
  • Place of Presentation: Washington State Convention & Trade Center (Seattle, U.S.A.)
• [Presentation] IMPROVEMENT OF NORMOGLYCEMIC RATE BY PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AGONIST, PIOGLITAZONOE, IN CANINE ISLET
  • Author(s): Asahi Y, Yamashita K,Watanabe M, Ogura M, Ono H, Emoto S, Nagatsu A, Yoshida T,Koshizuka Y,Taketomi A, Todo S.
  • Organizer: 16th Congress of the European Society for Organ Transplantation
  • Place of Presentation: Austria Center Vienna (Vienna, Austria)