1996 Fiscal Year Annual Research Report

遺伝子制御による異種臓器移植臨床への総合的研究

Research Project

Project/Area Number	07307014
Research Institution	NAGOYA UNIVERSITY
Principal Investigator	高木弘名古屋大学, 医学部, 教授 (70154755)
Co-Investigator(Kenkyū-buntansha)	門田守人大阪大学, 医学部, 教授 (00127309) 土肥雪彦広島大学, 医学部, 教授 (90034024) 岡隆宏京都府立医科大学, 医学部, 教授 (60079837) 中川原儀三福井医科大学, 医学部, 教授 (10019549) 磯野可一千葉大学, 医学部, 教授 (70009489)
Keywords	異種移植 / トランスジェニック動物 / 補体不活化因子 / 異種抗原 / ガラクトシルトランスフェラーゼ / 免疫寛容
Research Abstract	移植医療におけるドナー不足問題を解決するため、異種臓器移植の実現が待ち望まれている。その臨床応用へ向けて必要な知見を得ることが本研究の目的である。(1)超急性拒絶反応(2)細胞性免疫反応、免疫寛容のメカニズムの解明により新たなる異種移植制御法を研究開発した。(1)ラットCrry遺伝子、モルモットのDAF遺伝子を用い、レシピエント補体制御膜因子を遺伝子工学的にドナーに導入して補体系を制御する動物実験モデルを確立した。腫瘍異種抗原であるブタ、マウスのαガラクトース(αGal)抗原の転移酵素であるα1,3Gal転移酵素(α1,3GT)遺伝子の構造解析を行い、ノックアウト動物を作成中である。また、ブタではエクソンの一部が欠落したα1,3GTのバリアントが数種存在することが明らかにされ、これらの機能的な差異について検討中である。α1,3GTの競合阻害となりうるα1,2フコース転移酵素(α1,2FT)遺伝子を血管内皮細胞に導入することにより、αGal抗原発現が抑制されることを明らかにした。現在、α1,2FT遺伝子を導入したトランスジェニックブタを作成中である。しかし、細胞表層のシアル酸の減少はチューブ形成能の著名な低下を引き起こし、機能性糖鎖発現の変化により細胞機能の異常を来す可能性が示唆された。モルモットからラットの心移植モデルにおいて、補体系抑制のみならず、凝固系抑制の重要性を明らかにした。(2)ラットからマウスの移植系ではドナーの抗原提示細胞上の接着分子の機能抑制より、免疫不応答が誘導されることが確認された。脾ランゲルハンス島のマイクロカプセル化皮下誘導大網下移植法の確立、移植臓器への遺伝子導入法として用いられるアデノウイルスベクターの至適条件の決定を行った。xenogeneic chimerismが移植臓器生着と密接に関連しており、骨髄細胞の同時移植やレトロウイルスベクターを用いたドナーMHC遺伝子の導入が免疫寛容誘導に有用であった。

Research Products
(30 results)

All Other

All Publications (30 results)

[Publications] H.Takagi: "How can human DAF and HRF20 prevent HAR in transgenic mice?" Transplantation Proceedings. 28. 599-600 (1996)
[Publications] H.Takagi: "Introduction of α(1,2)-fucosyltransferase and its effect on α-Gal epitopes in transgenic pig." Xenotransplantation. 3. 81-86 (1996)
[Publications] H.Takagi: "Inhibitation of human complement-dependent cell lysis by bovine aortic endothelial cells transfected" European Surgical Research. 28. 440-446 (1996)
[Publications] H.Takagi: "Tissue distributio of Galα(1,3)Gal epitope in heart,kidney,and liver of pig and mouse" Transplantation Proceedings. 28. 216- (1996)
[Publications] H.Takagi: "Genetic engineering targeted to donor organs using adenoviral vector" Transplantation Proceedings. 28. 215- (1996)
[Publications] H.Takagi: "Inhibitory effect of double transfection to xenoendothelial cells" Journal of Surgical Research. 61. 165-169 (1996)
[Publications] 高木弘: "異種移植" 医学のあゆみ. 177. 258-259 (1996)
[Publications] 高木弘: "異種臓器移植におけるトランスジェニックブタ作製の重要性" 細胞工学. 15. 81-89 (1996)
[Publications] 高木弘: "異種移植への展望" 臨床透析. 12. 269-270 (1996)
[Publications] 高木弘: "遺伝子制御による異種移植の研究" 日本消化器外科学会雑誌. 29. 907-910 (1996)
[Publications] 高木弘: "異種移植" 日本外科学会雑誌. 97. 1010-1017 (1996)
[Publications] T.Oka: "Prolongation of xenograft survival by soluble complement receptor type 1 and antithrombin-III combination therapy" Transplantation Proceedings. 28. 685-686 (1996)
[Publications] H.Takagi: "Converting α-Gal epitope of pig into II antigen" Transplantation Proceedings. 28. 553- (1996)
[Publications] H.Takagi: "Xenotransplantation research in Japan" Xeno. 4. 62-63 (1996)
[Publications] H.Takagi: "Establishment of a human DAF/HRF20 double transgenic mouse line is not sufficient to suppress hyperacute rejection" Sargery Today. 26. 993-998 (1996)
[Publications] H.Takagi: "Tetrahydropyranyladriamycin with FK506 combination therapy for hamster-to-rat concordant xenotransplantation" Transplantation Proceedings. 28. 709-710 (1996)
[Publications] H.Takagi: "Effect of antisense ribozyme to pig α(1,3)Galactosyl transferase gene on the expression of Galα(1,3)Gal epitope" Transplantation Proceedings. 28. 628- (1996)
[Publications] M.Monden: "Participation of donor adhesion molecules in islet xenograft rejection." Transplantation Proceedings. 27. 256-257 (1996)
[Publications] M.Monden: "Role of adhesion molecules in islet allo- and xenograft rejection." Transplantation Proceedings. 28. 617- (1996)
[Publications] H.Okada: "IgM natural antibody against an asialo-oligosaccharide,gangliotetraose (Gg4),sensitizes HIV-I infected cells for cytolysis" International Immunology. 8. 153-158 (1996)
[Publications] H.Okada: "Human pregnancy serum suppresses the proliferative response of lymphocytes to autologous PHA-activated T lymphoblasts" American Journal of Reproductive Immunology. 35. 63-69 (1996)
[Publications] H.Okada: "Local inflammation caused by a monoclonal antibody that blocks the function of the rat membrane inhibitor of C3 convertase" The Journal of Immunology. 156. 1182-1188 (1996)
[Publications] H.Okada: "Molecular cloning of murine decay accelerating factor by immunoscreening" International Immunology. 8. 379-385 (1996)
[Publications] H.Okada: "Quantification of the CD55 and CD59,membrane inhibitors of complement on HIV-1 particles as a function" Microbiol.Immunol.40. 561-567 (1996)
[Publications] H.Okada: "Complement plyaa an essential role in shock following intestinal is chaemia in rats" Clinical and Experimental Immunology. 106. 156-159 (1996)
[Publications] H.Okada: "Antisense homology boxes in C5a receptor and C5a anaphylatoxin" The Journal of Immunology. 157. 4591-4601 (1996)
[Publications] H.Okada: "Molecular cloning of guinea pig membrane cofactor protein" The Journal of Immunology. 157. 4946-4952 (1996)
[Publications] R.Kannagi: "Suppression of sialyl lew is X expression and E-selectin mediated cell adhesion in cultured human lymphoid cells" The Journal of Biological Chemistry. 271. 31556-31561 (1996)
[Publications] 神奈木玲児: "異種移植と糖鎖" 医学のあゆみ. 180. 112-113 (1997)
[Publications] T.Muramatsu: "A transgenic mouse line with α-1,3/4-fucosyl-transferase cDNA : production and characteristics" Glycoconjugate Journal. 12. 795-801 (1995)

1996 Fiscal Year Annual Research Report

遺伝子制御による異種臓器移植臨床への総合的研究

Principal Investigator

高木 弘 名古屋大学, 医学部, 教授 (70154755)

Research Products

[Publications] H.Takagi: "How can human DAF and HRF20 prevent HAR in transgenic mice?" Transplantation Proceedings. 28. 599-600 (1996)

[Publications] H.Takagi: "Introduction of α(1,2)-fucosyltransferase and its effect on α-Gal epitopes in transgenic pig." Xenotransplantation. 3. 81-86 (1996)

[Publications] H.Takagi: "Inhibitation of human complement-dependent cell lysis by bovine aortic endothelial cells transfected" European Surgical Research. 28. 440-446 (1996)

[Publications] H.Takagi: "Tissue distributio of Galα(1,3)Gal epitope in heart,kidney,and liver of pig and mouse" Transplantation Proceedings. 28. 216- (1996)

[Publications] H.Takagi: "Genetic engineering targeted to donor organs using adenoviral vector" Transplantation Proceedings. 28. 215- (1996)

[Publications] H.Takagi: "Inhibitory effect of double transfection to xenoendothelial cells" Journal of Surgical Research. 61. 165-169 (1996)

[Publications] 高木弘: "異種移植" 医学のあゆみ. 177. 258-259 (1996)

[Publications] 高木弘: "異種臓器移植におけるトランスジェニックブタ作製の重要性" 細胞工学. 15. 81-89 (1996)

[Publications] 高木弘: "異種移植への展望" 臨床透析. 12. 269-270 (1996)

[Publications] 高木弘: "遺伝子制御による異種移植の研究" 日本消化器外科学会雑誌. 29. 907-910 (1996)

[Publications] 高木弘: "異種移植" 日本外科学会雑誌. 97. 1010-1017 (1996)

[Publications] T.Oka: "Prolongation of xenograft survival by soluble complement receptor type 1 and antithrombin-III combination therapy" Transplantation Proceedings. 28. 685-686 (1996)

[Publications] H.Takagi: "Converting α-Gal epitope of pig into II antigen" Transplantation Proceedings. 28. 553- (1996)

[Publications] H.Takagi: "Xenotransplantation research in Japan" Xeno. 4. 62-63 (1996)

[Publications] H.Takagi: "Establishment of a human DAF/HRF20 double transgenic mouse line is not sufficient to suppress hyperacute rejection" Sargery Today. 26. 993-998 (1996)

[Publications] H.Takagi: "Tetrahydropyranyladriamycin with FK506 combination therapy for hamster-to-rat concordant xenotransplantation" Transplantation Proceedings. 28. 709-710 (1996)

[Publications] H.Takagi: "Effect of antisense ribozyme to pig α(1,3)Galactosyl transferase gene on the expression of Galα(1,3)Gal epitope" Transplantation Proceedings. 28. 628- (1996)

[Publications] M.Monden: "Participation of donor adhesion molecules in islet xenograft rejection." Transplantation Proceedings. 27. 256-257 (1996)

[Publications] M.Monden: "Role of adhesion molecules in islet allo- and xenograft rejection." Transplantation Proceedings. 28. 617- (1996)

[Publications] H.Okada: "IgM natural antibody against an asialo-oligosaccharide,gangliotetraose (Gg4),sensitizes HIV-I infected cells for cytolysis" International Immunology. 8. 153-158 (1996)

[Publications] H.Okada: "Human pregnancy serum suppresses the proliferative response of lymphocytes to autologous PHA-activated T lymphoblasts" American Journal of Reproductive Immunology. 35. 63-69 (1996)

[Publications] H.Okada: "Local inflammation caused by a monoclonal antibody that blocks the function of the rat membrane inhibitor of C3 convertase" The Journal of Immunology. 156. 1182-1188 (1996)

[Publications] H.Okada: "Molecular cloning of murine decay accelerating factor by immunoscreening" International Immunology. 8. 379-385 (1996)

[Publications] H.Okada: "Quantification of the CD55 and CD59,membrane inhibitors of complement on HIV-1 particles as a function" Microbiol.Immunol.40. 561-567 (1996)

[Publications] H.Okada: "Complement plyaa an essential role in shock following intestinal is chaemia in rats" Clinical and Experimental Immunology. 106. 156-159 (1996)

[Publications] H.Okada: "Antisense homology boxes in C5a receptor and C5a anaphylatoxin" The Journal of Immunology. 157. 4591-4601 (1996)

[Publications] H.Okada: "Molecular cloning of guinea pig membrane cofactor protein" The Journal of Immunology. 157. 4946-4952 (1996)

[Publications] R.Kannagi: "Suppression of sialyl lew is X expression and E-selectin mediated cell adhesion in cultured human lymphoid cells" The Journal of Biological Chemistry. 271. 31556-31561 (1996)

[Publications] 神奈木玲児: "異種移植と糖鎖" 医学のあゆみ. 180. 112-113 (1997)

[Publications] T.Muramatsu: "A transgenic mouse line with α-1,3/4-fucosyl-transferase cDNA : production and characteristics" Glycoconjugate Journal. 12. 795-801 (1995)

高木弘名古屋大学, 医学部, 教授 (70154755)