Development of tolerance induction method using clone pigs remodeled for expressing human ABO blood group antigen

• Project/Area Number: 21380168
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied animal science
• Research Institution: Obihiro University of Agriculture and Veterinary Medicine
• Principal Investigator: OGAWA Haruko 帯広畜産大学, 動物・食品衛生研究センター, 准教授 (10400079)
• Co-Investigator(Kenkyū-buntansha): OHNISHI Akira 独立行政法人農業生物資源研究所, 医用モデルブタ研究開発ユニット, 上級研究員 (30414890) ; KOBAYASHI Takaaki 名古屋大学, 大学院・医学系研究科, 寄附講座教授 (70314010)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥15,080,000 (Direct Cost: ¥11,600,000、Indirect Cost: ¥3,480,000); Fiscal Year 2011: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2009: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
• Keywords: クローン家畜 / 核移植 / 移植 / 拒絶反応 / 免疫寛容 / ABO式血液型抗原 / 移植・再生医療 / 免疫学 / 糖鎖 / バイオテクノロジー / 血液型抗原 / クローン動物 / リンパ球 / ABO

Research Abstract

This study aims to generate transgenic pigs expressing human ABO blood group antigens by using nuclear transfer method, and utilize the pigs to develop a novel tolerance induction method to control the rejection in ABO-incompatible transplantation. First, transgenic pig carrying one of the two glycosyltransferase genes to be transferred was produced, and then the second glycosyltransferase gene was transferred to the somatic cells of the transgenic pig. Using the genetically-engineered cells as a donor cell for nuclear transfer, purposed transgenic pig was produced. There has been seen some problems in the growth after birth and the expression of the purposed antigen, therefore additional studies are ongoing to solve the problems.

Research Products

• [Journal Article] Comparative study on signal transduction in endothelial cells after anti-A/B and HLA antibody reaction : implication of accommodation (2012)
  • Author(s): Iwasaki K, Miwa Y, Ogawa H, Iwamoto M, Furusawa T, Onishi A, Kuzuya T, Haneda M, Watarai Y, Uchida K, Kobayashi T.
  • Journal Title: Transplantation Volume: 93 Issue: 4 Pages: 390-397
  • DOI: 10.1097/tp.0b013e3182424df3
  • Peer Reviewed
• [Journal Article] Production of cloned pigs expressing human thrombomodulin in endothelial cells (2012)
  • Author(s): Yazaki S, Iwamoto M, Onishi A, Miwa Y, Hashimoto M, Oishi T, Suzuki S, Fuchimoto D, Sembon S, Furusawa T, Liu D, Nagasaka T, Kuzuya T, Ogawa H, Yamamoto K, Iwasaki K, Haneda M, Maruyama S, Kobayashi T.
  • Journal Title: Xenotransplantation Volume: 19 Issue: 2 Pages: 82-91
  • DOI: 10.1111/j.1399-3089.2012.00696.x
  • Peer Reviewed
• [Journal Article] Potent immunosuppression for ABO-incompatible renal transplantation may not be a risk factor for malignancy (2012)
  • Author(s): Yamamoto T, Kawaguchi T, Watarai Y, Tujita M, Hiramitsu T, Nanmoku K, Goto N, Katayama A, Kobayashi T, Uchida K.
  • Journal Title: Transplant Proc. Volume: 44 Issue: 1 Pages: 210-213
  • DOI: 10.1016/j.transproceed.2011.11.048
  • Peer Reviewed
• [Journal Article] Comparative study on signal transduction in endothelial cells after anti-A/B and human leukocyte antigen antibody reaction : implication of accommodation (2012)
  • Author(s): Iwasaki K., Miwa Y., Ogawa H., et al.
  • Journal Title: Transplantation Volume: 93 Pages: 390-397
  • Peer Reviewed
• [Journal Article] Potent immunosuppression for ABO-incompatible renal transplantation may not be a risk factor for malignancy (2012)
  • Author(s): Yamamoto T., Kawaguchi T., Watarai Y., wt al.
  • Journal Title: Transplant Proc Volume: 44 Pages: 210-213
  • Peer Reviewed
• [Journal Article] ABO血液型糖鎖抗原の切断 (2011)
  • Author(s): 小林孝彰
  • Journal Title: Organ Biology Volume: 18 Pages: 116-120
  • NAID: 130004709993
  • URL: http://mol.medicalonline.jp/archive/select?jo=ca3organ
  • Peer Reviewed
• [Journal Article] Surveillance of avian influenza virus in migratory water birds in eastern Hokkaido, Japan. (2011)
  • Author(s): Bui VN
  • Journal Title: Journal of Veterinary Medical Science Volume: 73 Pages: 209-215
• [Journal Article] Potential value of human thrombomodulin and DAF expression for coagulation control in pig-to-human xenotransplantation (2010)
  • Author(s): Miwa Y, Yamamoto K, Onishi A, Iwamoto M, Yazaki S, Haneda M, Iwasaki K, Liu D, Ogawa H, Nagasaka T, Uchida K, Nakao A, Kadomatsu K, Kobayashi T.
  • Journal Title: Xenotransplantation Volume: 17 Issue: 1 Pages: 26-37
  • DOI: 10.1111/j.1399-3089.2009.00555.x
  • Peer Reviewed
• [Journal Article] Potential value of human thrombomodulin and DAF expression for coagulation control in pig-to-human xenotransplantation. (2010)
  • Author(s): Miwa Y
  • Journal Title: Xenotransplantation. 17 Pages: 26-37
  • Peer Reviewed
• [Journal Article] Successful cross-breeding of cloned pigs expressing endo-galactosidase C and hDAF (2009)
  • Author(s): Yazaki S, Iwamoto M, Onishi A, Miwa Y, Suzuki S, Fuchimoto D, Sembon S, Furusawa T, Hashimoto M, Oishi T, Liu D, Nagasaka T, Kuzuya T, Maruyama S, Ogawa H, Kadomatsu K, Uchida K, Nakao A, Kobayashi T.
  • Journal Title: Xenotransplantation Volume: 16 Issue: 6 Pages: 511-521
  • DOI: 10.1111/j.1399-3089.2009.00549.x
  • Peer Reviewed
• [Journal Article] Removal of blood group A/B antigen in organs by ex vivo and in vivo administration of endo-galactosidase (ABase) for ABO-incompatible transplantation (2009)
  • Author(s): Kobayashi T, Liu D, Ogawa H, Miwa Y, Nagasaka T, Maruyama S, Li Y-T, Onishi A, Iwamoto M, Kuzuya T, Kadomatsu K, Uchida K, Nakao A.
  • Journal Title: Transpl. Immunol Volume: 20 Pages: 132-138
  • URL: http://dx.doi.org/10.1016/j.trim.2008.09.007
  • Peer Reviewed
• [Journal Article] Successful cross-breeding of clonal pigs expressing endo-b-galactosisdase C(EndoGalC)and human decay accelerating factor(hDAF). (2009)
  • Author(s): Yazaki S
  • Journal Title: Xenotransplantation. 16 Pages: 511-521
  • Peer Reviewed
• [Presentation] Successful production and breeding of cloned pigs expressing human thrombomodulin in endothelial cells (2011)
  • Author(s): Iwamoto M, Yazaki S, Onishi A, Miwa Y, Hashimoto M, Oishi T, Suzuki S, Fuchimoto D, Sembon S, Nagasaka T, Liu D, Iwasaki K, Haneda M, Yamamoto K, Maruyama S, Kobayashi T.
  • Organizer: CTS-IXA 2011 Joint Congress
  • Place of Presentation: Miami (USA)
• [Presentation] Difference in signal transduction between anti-A/B and anti-HLA antibody binding to endothelial cells (2011)
  • Author(s): Iwasaki K, Miwa Y, Haneda M, Kobayashi T.
  • Organizer: CTS-IXA 2011 Joint Congress
  • Place of Presentation: Miami (USA)
• [Presentation] Complement and thrombin block endothelial cell accommodation (2011)
  • Author(s): Iwasaki K, Miwa Y, Haneda M, Kobayashi T.
  • Organizer: CTS-IXA 2011 Joint Congress
  • Place of Presentation: Miami (USA)
• [Presentation] 異種移植における凝固系制御の試み:ヒトトロンボモジュリン遺伝子導入クローンブタの作出 (2011)
  • Author(s): 岩元正樹,矢崎智子,三輪祐子,丸山彰一,鈴木俊一,橋本径子,大石貴嗣,劉大革,長坂隆治,小林孝彰,大西彰
  • Organizer: 第47回日本移植学会総会
  • Place of Presentation: 仙台
• [Presentation] ERK活性化細胞外因子はAccommodation誘導を阻害する (2011)
  • Author(s): 岩崎研太,三輪祐子,羽根田正隆,矢崎智子,岩元正樹,大西彰,小川晴子,小林孝彰
  • Organizer: 第47回日本移植学会総会
  • Place of Presentation: 仙台
• [Presentation] human thrombomodulin高発現体細胞クローンブタおよびその後代の作出 (2011)
  • Author(s): 岩元正樹,矢崎智子,三輪祐子,山本晃士,丸山彰一,鈴木俊一,淵本大一郎,千本正一郎,鈴木美佐枝,橋本径子,大石貴嗣,羽根田正隆,岩崎研太,中尾昭公,小林孝彰,大西彰
  • Organizer: 第16回日本病態プロテアーゼ学会
  • Place of Presentation: 大阪
• [Presentation] Successful production and breeding of cloned pigs expressing human thrombomodulin in endothelial cells (2011)
  • Author(s): Iwamoto M., Yazaki S., Onishi A., et al.
  • Organizer: CTS-IXA 2011 Joint Congress (oral)
  • Place of Presentation: Miami (USA)
• [Presentation] Difference in signal transduction between anti-A/B and anti-HLA antibody binding to endothelial cells (2011)
  • Author(s): Iwasaki K., Miwa Y., Haneda M., et al.
  • Organizer: CTS-IXA 2011 Joint Congress (oral)
  • Place of Presentation: Miami (USA)
• [Presentation] Complement and thrombin block endothelial cell accommodation (2011)
  • Author(s): Iwasaki K., Miwa Y., Haneda M., et al.
  • Organizer: CTS-IXA 2011 Joint Congress (oral)
  • Place of Presentation: Miami (USA)
• [Presentation] Functional difference between membrane-bound and soluble human thrombomodulin (2011)
  • Author(s): Miwa Y., Yazaki S., Iwamoto M., et al.
  • Organizer: CTS-IXA 2011 Joint Congress (oral)
  • Place of Presentation: Miami (USA)
• [Presentation] 異種移植におけるhuman thrombomodulinの有用性 (2011)
  • Author(s): 三輪祐子, 矢崎智子, 岩元正樹, 他
  • Organizer: 第16回日本病態プロテアーゼ学会
  • Place of Presentation: 大阪
• [Presentation] 異種移植における可溶性および膜型ヒトトロンボモジュリンの比較検討 (2011)
  • Author(s): 三輪祐子, 矢崎智子, 岩元正樹, 他
  • Organizer: 第47回日本移植学会総会
  • Place of Presentation: 仙台
• [Presentation] ABO不適合移植における抗体接着が誘導する細胞保護に関する研究 (2010)
  • Author(s): 岩崎研太,三輪祐子,羽根田正隆,矢崎智子,岩本正樹,大西彰,小川晴子,小林孝彰
  • Organizer: 第46回日本移植学会総会
  • Place of Presentation: 京都
• [Presentation] The reduction of RAF/MEK/ERK pathway by anti-ABO association may be the identity of accommodation in ABO-incompatible transplantation (2010)
  • Author(s): Iwasaki K, Miwa Y, Haneda M, Ogawa H, Uchida K, Takeda A, Nakao A, Kobayashi T.
  • Organizer: 23rd International Congress of The Transplantation Society
  • Place of Presentation: Vancouver (Canada)
• [Presentation] Effective suppression of direct prothrombinase activity in porcine endothelial cells by human thrombomodulin (hTM) gene transfer or its soluble form (2010)
  • Author(s): Miwa Y, Yazaki S, Iwamoto M, Onishi A, Yamamoto K, Iwasaki K, Haneda M, Maruyama S, Kadomatsu K, Uchida K, Kobayashi T.
  • Organizer: American Transplant Congress 2010
  • Place of Presentation: San Diego (USA)
• [Presentation] ABO式血液型抗原に対する免疫寛容の誘導に関する研究 (2009)
  • Author(s): 小川晴子
  • Organizer: 第45回日本移植学会総会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2009-09-17
• [Presentation] Human thrombomodulin plays an important role in coagulaiton control : engine braking is essential for physiological regulation (2009)
  • Author(s): Miwa Y, Iwasaki K, Yamamoto K, Maruyama S, Onishi A, Iwamoto M, Yazaki S, Liu DG, Nagasaka T, Haneda M, Kadomatsu K, Kobayashi T.
  • Organizer: IPITA-IXA 2009
  • Place of Presentation: Venice (Italy)
• [Presentation] ABO式血液型抗原に対する免疫寛容の誘導に関する研究 (2009)
  • Author(s): 小川晴子,大西彰,岩元正樹,羽根田正隆,岩崎研太,三輪祐子,小林孝彰
  • Organizer: (口演)第45回日本移植学会総会
  • Place of Presentation: 東京
• [Presentation] Potential impacts of human DAF and thrombomodulin on thrombin regulation (2009)
  • Author(s): Miwa Y, Yamamoto K, Onishi A, Iwamoto M, Maruyama S, Nakao A, Kadomatsu K, Kobayashi T.
  • Organizer: American transplant congress 2009
  • Place of Presentation: Boston (USA)
• [Book] 異種移植研究から臨床へ:遺伝子組換えブタに対する期待と日本の役割 (2010)
  • Author(s): 小林孝彰
  • Publisher: Techno Innovation
• [Book] 腎移植における免疫モニタリングの試み.今日の移植 (2009)
  • Author(s): 小林孝彰
• [Book] ABO血液型抗体の測定腎移植のすべて (2009)
  • Author(s): 小林孝彰
  • Publisher: メジカルレビュー社