心および心肺移植における患者管理と臓器機能維持に関する総合的研究

2000 Fiscal Year Annual Research Report

• Project/Area Number: 10307033
• Research Institution: University of Tokyo
• Principal Investigator: 高本 眞一 東京大学, 医学部・附属病院, 教授 (60137833)
• Co-Investigator(Kenkyū-buntansha): 許 俊鋭 埼玉医科大学, 教授 (30153232) ; 田林 晄一 東北大学, 医学部, 教授 (90142942) ; 北村 惣一郎 東京大学, 国立循環器病センター, 院長 (10028607) ; 磯部 光章 東京医科歯科大学, 医学部, 教授 (80176263) ; 松田 暉 大阪大学, 医学部, 教授 (00028614)
• Keywords: 心臓移植 / 肺移植 / 移植術後管理 / 移植臓器機能保存 / 拒絶反応 / 臨床応用 / 早期診断 / 遺伝子治療

Research Abstract

本研究は心および心肺移植における患者管理と臓器機能維持に関して総合的な検討を行うことにある。
臓器機能保存について:森山は移植心虚血再灌流障害時好中球エラスターゼ阻害剤(ONO-5046-Na)の基礎研究を行い、本剤が保存・移植心の機能保存に対する有効性を示した。安井はAscorbyl Radicalの虚血再灌流後の冠動静脈血中濃度差を検討した。この値と再灌流後の左室機能が相関し、保存心の機能評価への有用性を示した。近藤は肺移植後虚血再灌流傷害による肺水腫に関し、肺胞細胞内刺激伝達の培養細胞株から、低温保存後再加温によるIL-8分泌、NF-kBの核内移行、p65およびF-actin再重合を示した。
拒絶反応制御について:磯部は拒絶心を持つマウス由来の活性化T細胞を培養平滑筋細胞に加え、平滑筋細胞増殖を誘導させた。この増殖はEgr-1 antisense ODNによって抑制された。Egr-1遺伝子が慢性拒絶に関与することを示した。松田はSD ratを用い、冠動脈注入によるHVJ liposome法でのNF-kBの結合部位に対するcis-element"decoy",ODNを導入した心臓を保存・移植し、本法が心筋保護効果の有ることを示した。
移植術後管理について:高本はニホンザル同種異所心移植で急性拒絶早期に移植心血管周囲にHGF,VEGFが発現する事を示した。この発現は拒絶の進行に伴い減弱し、早期診断への応用が示唆された。田林は心臓移植後急性拒絶時の心臓超音波を解析し、移植心ではcyclic variation magnitude,Sound speed,attenuation constantの減少を示した。小柳は過小ドナー心の際、Ischemic preconditioningが術後右心機能改善に寄与する可能性を示唆した。
臨床における問題点について:許は補助人工心臓による循環補助治療の臨床研究を18例に行い、平均補助期間は150日であり、補助開始後2ヶ月で心臓移植可能な状態まで回復する事を示した。北村は、臓器移植法下に施行した心臓移植5例に関して報告した。全例DCM。4例はLVAS装着し待機した。免疫抑制法はCyA,Mycophenolate mofetil,steroidの3剤を使用した。いずれも術後経過良好であることを報告した。

Research Products

• [Publications] Kawauchi M,Suzuki J,Takamoto S,Isobe M. et.al.: "Gene therapy for attenuating cardiac allograft arteriopathy using ex vivo E2F decoy transfection by HVJ-AVE-liposome method in mice and nonhuman primates."Circulatory Research. 87. 1063-1068 (2000)
• [Publications] Kawauchi M.Nakajima J.Endoh M.Oka T.Takamoto S.: "Ontogeny of antipig xenoantibody and hyperacute 70(4):686-8,2000"Transplantation. 70(4). 686-688 (2000)
• [Publications] Endoh M.Kawauchi M.Isobe M.Suzuki J.Nakajima J.Takeda M.Takamoto S.: "Nonmuscle myosin heavy chain and metalloproteinase-2 expression in concordantpulmonary xenografts.32(5):1151-2,2000"Transplantation Proceedings.. 32(5). 1151-1152 (2000)
• [Publications] Sakaguchi T.Sawa Y.Kitakaze M.Suzuki K.Nishimura M.Kaneda Y.Matsuda H.: "Ecto-5'-nucleotidase plays a role in the cardioprotective effects of heat shock protein 72 in ischemia-reperfusion injury in rat hearts. Fukushima N.Shirakura R.Ohtake S.Sawa Y.Nishimura M.Kobayashi Y.Saito S.Matsuda H.Studies of the multiorgan procurement system from non-heart-beating donors. Transplantation Proceedings.32(2):281-4,2000"Cardiovascular Research. 47(1). 74-80 (2000)
• [Publications] Kitagawa-Sakakida S.Tori M.Li Z.Horiguchi K.Izutani H.Matsuda H.Shirakura R.: "Active cell migration in retransplanted rat cardiac allografts during the course of chronic rejection.."Journal of Heart & Lung Transplantation. 19(6). 584-590 (2000)
• [Publications] Fukushima N.Shirakura R.Ohtake S.Sawa Y.Nishimura M.Kobayashi Y.Saito S.Matsuda H.: "Studies of the multiorgan procurement system from non-heart-beating donors.32(2):281-4,2000"Transplantation Proceedings. 32(2). 281-284 (2000)
• [Publications] Sawa Y.Fukushima N.Nishimura M.Sakaguchi T.Ohtake S.Matsuda H.: "Development of new techniques using genetic and tissue engineering for the treatment of severe heart failure."Transplantation Proceedings. 32(2). 242-244 (2000)
• [Publications] 1) Suzuki S.Sugita M.Ono S.Song C.Kondo T.Fujimura S.: "Difference in the effects of low temperatures on the tension of human pulmonary artery and vein ring segments."Respiration. 67(2). 189-193 (2000)
• [Publications] Suzuki S,Inoue K,Sugita M,Tsubochi H,Kondo T,Fujimura S.: "Effects of EP4 solution and LPD solution versus Euro-Collins solution on Na/K-ATPase activity in rat alveolar type II cells and human alveolar epithelial cell line A549 cells..19 : 887-893,2000"The Journal of Heart and Lung Transplantation. 19. 887-893 (2000)
• [Publications] 島田和佳,松村輔二,近藤丘 他: "東日本における肺移植適応患者の実態についての検討。"日本呼吸器学会雑誌. 38. 762-769 (2000)
• [Publications] Kono T.Koide N.Hama Y.Kitahara H.Nakano H.Suzuki J.Isobe M.Amano J.: "Expression of vascular endothelial growth factor and angiogenesis in cardiac myxoma : a study of fifteen patients."Journal of Thoracic & Cardiovascular Surgery. 119(1). 101-107 (2000)
• [Publications] Suzuki J.Isobe M.Kawauchi M.Endoh M.Amano J.Takamoto S.: "Altered expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in acutely rejected myocardium and coronary arteriosclerosisin cardiac allografts of nonhuman primates."Transplant International. 13(2). 106-113 (2000)
• [Publications] 1) Yamagami S.Isobe M.Tsuru T.: "Characterization of cytokine profiles in corneal allograft with anti-adhesion therapy."Transplantation.. 69(8). 1655-1659 (2000)
• [Publications] Suzuki J.Isobe M.Morishita R.Nishikawa T.Amano J.Kaneda Y.: "Antisense Bcl-x oligonucleotide induces apoptosis and prevents arterial neointimal formation in murine cardiac allografts."Cardiovascular Research. 45(3). 783-787 (2000)
• [Publications] Cioca DP.Watanabe N.Isobe M.: "Apoptosis of peripheral blood lymphocytes is induced by catecholamines."Japanese Heart Journal.41(3):385-98,2000. 41(3). 385-398 (2000)
• [Publications] Kitabayashi H.Isobe M.Watanabe N.Suzuki J.Yazaki Y.Sekiguchi M.: "FTY720 prevents development of experimental autoimmune myocarditis through reduction of circulating lymphocytes."Journal of Cardiovascular Pharmacology. 35(3). 410-416 (2000)
• [Publications] Isobe M,Suzuki J,Morishita R,Kaneda Y,Amano J :: "Gene therapy for heart transplantation-associated coronary arteriosclerosis. Ann Ny Acad Sci, Atherosclerosis :"The fifth Saratoga International Conference. 902. 77-83 (2000)
• [Publications] Suzuki J.Isobe M.Morishita R.Nishikawa T.Amano J.Kaneda Y.: "Prevention of cardiac allograft arteriosclerosis using antisense proliferating-cell nuclear antigen oligonucleotide."Transplantation. 70(2). 398-400 (2000)
• [Publications] Wada Y.Suzuki J.Tsukioka K.Zhang T.Takayama K.Endoh M.Watanabe N.Kurabayashi M.Kawauchi M.Nagai R.Takamoto S.Isobe M.Amano J.: "Expression of the transcriptional factor egr-1/BTEB2 in cardiac xenograft vascular remodeling."Transplantation Proceedings. 32(5). 1089-1091 (2000)
• [Publications] Tsukioka K.Suzuki J.Kawauchi M.Wada Y.Zhang T.Endoh M.Takayama K.Takamoto S.Isobe M.Amano J.: "Altered expression of matrix metalloproteinases in pig-to-primate xenotransplanted hearts."Transplantation Proceedings. 32(5). 996-998 (2000)
• [Publications] Zhang T.Suzuki J.Kawauchi M.Nakano H.Kuroda H.Koide N.Kitahara H.Ohta K.Wada Y.Tsukioka K.Takayama K.Endoh M.Takamoto S.Isobe M.Amano J.: "Expression of monocyte chemoattractant protein 1 in pig-to-primate cardiac xenografts."Transplantation Proceedings. 32(5). 984-986 (2000)
• [Publications] 2) Takayama K.Suzuki J.Kawauchi M.Tsukioka K.Wada Y.Zhang T.Endoh M.Takamoto S.Amano J.Isobe M.: "Hepatocyte growth factor and vascular endothelial growth factor expression in pig-to-primate xenotransplanted hearts."Transplantation Proceedings.. 32(5). 987-989 (2000)
• [Publications] Hayashi S,Watanabe N.Nakazawa K.Suzuki J,Tsushima K.Tamatani T.Sakamoto S.Isobe M.: "Roles of P-Selectin in inflammation, neointimal formation, and vascular remodeling in balloon injured rat carotid arteries."Circulation. 102. 1710-1717 (2000)
• [Publications] Takahashi W,Suzuki J,Izawa A,Takayama K,Yamazaki S,Isobe M.: "Inducible nitric oxide- mediated myocardial apoptosis contributes to graft failure during acute cardiac allograft rejection in mice."Jpn Heart J.41. 41. 493-506 (2000)
• [Publications] 3) Suzuki J,Morishita R,Amanot J,Kaneda Y,Isobe M.: "Decoy against nuclear factor-kappa B attenuates myocardial cell infiltration and arterial neointimal formation in murine cardiac allografts."Gene Therapy. 7. 1847-1852 (2000)
• [Publications] Tsukioka K.Suzuki J.Kawauchi M.Wada Y.Zhang T.Endoh M.Takayama K.Takamoto S.Isobe M.Amano J.: "Altered expression of matrix metalloproteinases in pig-to-primate xenotransplanted hearts."Transplantation Proceedings.32(5):996-8,2000. 32(5). 996-998 (2000)
• [Publications] 1)松崎益徳,許俊鋭 他。: "慢性心不全治療ガイドライン"Jpn Circ J. 64(suppl IV). 1023-1079 (2000)
• [Publications] 竹越襄,松田暉,許俊鋭 t他。: "急性重症心不全治療ガイドライン。"Jpn Circ Journal. 64(suppl IV). 1129-1165 (2000)
• [Publications] Kyo S,Tanabe H,Asano H,Ouchi H,Nogaki H,Ishikawa M,Yokote T,Noda H,Omoto R.: "Clinical effects of ventricular assist system in end-stage cardiac failure."Jpn J Thorac Cardiovasc Surg. 48. 440-446 (2000)
• [Publications] 許俊鋭: "心不全の外科治療-特に体内設置型補助人工心臓TCI-LVASの経験。"進歩する心臓研究. 20(1). 35-44 (2000)
• [Publications] 許俊鋭: "人工心臓と補助循環。"Heart View. 4. 437-441 (2000)
• [Publications] 2)許俊鋭: "心不全の外科治療-左室縮小術"今日の治療. 8. 60-65 (2000)
• [Publications] Kawauchi M,Suzuki J,Morishita R,Wada Y,Izawa A,Tomita N,Amano J,Kaneda Y,Ogihara T,Takamoto S,Isobe M.: "Gene therapy for attenuating cardiac allograft arteriopathy using ex vivo E2F decoy transfection by HVJ-AVE-liposome method in mice and nonhuman primates."Circulatory Research. 87. 1063-1068 (2000)
• [Publications] Kawauchi M.Nakajima J.Endoh M.Oka T.Takamoto S.: "Ontogeny of antipig xenoantibody and hyperacute"Transplantation. 70(4). 686-688 (2000)
• [Publications] Endoh M.Kawauchi M.Isobe M.Suzuki J.Nakajima J.Takeda M.Takamoto S.: "Nonmuscle myosin heavy chain and metalloproteinase-2 expression in concordantpulmonary xenografts."Transplantation Proceedings.. 32(5). 1151-1152 (2000)
• [Publications] Murakawa T,Nakajima J,Ono,Murakami A,Suematsu Y,Takamoto S: "Allogenicity of cryopreserved human fibroblasts : Cryopreservation does not downregulate the allogenicity of fibroblasts making up the matrices of allografts."Journal of Thoracic & Cardiovascular Surgery. 120. 712-719 (2000)
• [Publications] Sawa Y.Fukushima N. Nishimura M.Sakaguchi T.Ohtake S.Matsuda H.: "Development of new techniques using genetic and tissue engineering for the treatment of severe heart failure."Transplantation Proceedings. 32(2). 242-244 (2000)
• [Publications] 1) Suzuki S.Sugita M.Ono S.Song C.Kondo T.Fujimura S.: "Difference in the effects of low temperatures on the tension of human pulmonary artery and vein ring segments."Respiration. 67(2). 189-193 (2000)
• [Publications] Suzuki S,Inoue K,Sugita M,Tsubochi H,Kondo T,Fujimura S.: "Effects of EP4 solution and LPD solution versus Euro-Collins solution on Na/K-ATPase activity in rat alveolar type II cells and human alveolar epithelial cell line A549 cells..19:887-893,2000"The Journal of Heart and Lung Transplantation. 19. 887-893 (2000)
• [Publications] 島田和佳,松村輔二,近藤丘 他: "東日本における肺移植適応患者の実態についての検討。"日本呼吸器学会雑誌. 38. 762-769 (2000)
• [Publications] Kono T.Koide N.Hama Y.Kitahara H.Nakano H.Suzuki J.Isobe M.Amano J.: "Expression of vascular endothelial growth factor and angiogenesis in cardiac myxoma : a study of fifteen patients."Journal of Thoracic & Cardiovascular Surgery. 119(1). 101-107 (2000)
• [Publications] Suzuki J.Isobe M.Kawauchi M.Endoh M.Amano J.Takamoto S.: "Altered expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in acutely rejected myocardium and coronary arteriosclerosisin cardiac allografts of nonhuman primates."Transplant International. 13(2). 106-113 (2000)
• [Publications] 1) Yamagami S.Isobe M.Tsuru T.: "Characterization of cytokine profiles in corneal allograft with anti-adhesion therapy."Transplantation.. 69(8). 1655-1659 (2000)
• [Publications] Suzuki J.Isobe M.Morishita R.Nishikawa T.Amano J.Kaneda Y.: "Antisense Bcl-x oligonucleotide induces apoptosis and prevents arterial neointimal formation in murine cardiac allografts."Cardiovascular Research. 45(3). 783-787 (2000)
• [Publications] Cioca DP.Watanabe N.Isobe M.: "Apoptosis of peripheral blood lymphocytes is induced by catecholamines."Japanese Heart Journal.41(3):385-98,2000. 41(3). 385-398 (2000)
• [Publications] Kitabayashi H.Isobe M.Watanabe N.Suzuki J.Yazaki Y.Sekiguchi M.: "FTY720 prevents development of experimental autoimmune myocarditis through reduction of circulating lymphocytes."Journal of Cardiovascular Pharmacology. 35(3). 410-416 (2000)
• [Publications] Isobe M,Suzuki J,Morishita R,Kaneda Y,Amano J :: "Gene therapy for heart transplantation-associated coronary arteriosclerosis. Ann Ny Acad Sci, Atherosclerosis :"The fifth Saratog a International Conference. 902. 77-83 (2000)
• [Publications] Suzuki J.Isobe M.Morishita R.Nishikawa T.Amano J.Kaneda Y.: "Prevention of cardiac allograft arteriosclerosis using antisense proliferating-cell nuclear antigen oligonucleotide."Transplantation. 70(2). 398-400 (2000)
• [Publications] Wada Y.Suzuki J.Tsukioka K.Zhang T.Takayama K.Endoh M.Watanabe N.Kurabayashi M.Kawauchi M.Nagai R.Takamoto S.Isobe M.Amano J.: "Expression of the transcriptional factor egr-1/BTEB2 in cardiac xenograft vascular remodeling."Transplantation Proceedings. 32(5). 1089-1091 (2000)
• [Publications] Tsukioka K.Suzuki J.Kawauchi M.Wada Y.Zhang T.Endoh M.Takayama K.Takamoto S.Isobe M.Amano J.: "Altered expression of matrix metalloproteinases in pig-to-primate xenotransplanted hearts."Transplantation Proceedings. 32(5). 996-998 (2000)
• [Publications] Zhang T.Suzuki J.Kawauchi M.Nakano H.Kuroda H.Koide N.Kitahara H.Ohta K.Wada Y.Tsukioka K.Takayama K.Endoh M.Takamoto S.Isobe M.Amano J.: "Expression of monocyte chemoattractant protein 1 in pig-to-primate cardiac xenografts."Transplantation Proceedings.. 32(5). 984-986 (2000)
• [Publications] 2) Takayama K.Suzuki J.Kawauchi M.Tsukioka K.Wada Y.Zhang T.Endoh M.Takamoto S.Amano J.Isobe M.: "Hepatocyte growth factor and vascular endothelial growth factor expression in pig-to-primate xenotransplanted hearts."Transplantation Proceedings.. 32(5). 987-989 (2000)
• [Publications] Hayashi S,Watanabe N,Nakazawa K,Suzuki J,Tsushima K,Tamatani T,Sakamoto S,Isobe M.: "Roles of P-Selectin in inflammation, neointimal formation, and vascular remodeling in balloon injured rat carotid arteries."Circulation. 102. 1710-1717 (2000)
• [Publications] Takahashi W,Suzuki J,Izawa A,Takayama K,Yamazaki S,Isobe M.: "Inducible nitric oxide- mediated myocardial apoptosis contributes to graft failure during acute cardiac allograft rejection in mice."Jpn Heart J.41. 41. 493-506 (2000)
• [Publications] 3) Suzuki J,Morishita R,Amanot J,Kaneda Y,Isobe M.: "Decoy against nuclear factor-kappa B attenuates myocardial cell infiltration and arterial neointimal formation in murine cardiac allografts."Gene Therapy. 7. 1847-1852 (2000)
• [Publications] Tsukioka K.Suzuki J.Kawauchi M.Wada Y.Zhang T.Endoh M.Takayama K.Takamoto S.Isobe M.Amano J.: "Altered expression of matrix metalloproteinases in pig-to-primate xenotransplanted hearts."Transplantation Proceedings.32(5):996-8,2000. 32(5). 996-998 (2000)
• [Publications] 1)松崎益徳,許俊鋭 他。: "慢性心不全治療ガイドライン。"Jpn Circ J. 64(suppl IV). 1023-1079 (2000)
• [Publications] 竹越襄,松田暉,許俊鋭 t他。: "急性重症心不全治療ガイドライン。"Jpn Circ Journal. 64(suppl IV). 129-165 (2000)
• [Publications] Kyo S,Tanabe H,Asano H,Ouchi H,Nogaki H,Ishikawa M,Yokote Y,Koyanagi T,Noda H,Omoto R.: "Clinical effects of ventricular assist system in end-stage cardiac failure."Jpn J Thorac Cardiovasc Surg. 48. 440-446 (2000)
• [Publications] 許俊鋭: "心不全の外科治療-特に体内設置型補助人工心臓TCI-LVASの経験。"進歩する心臓研究. 20(1). 35-44 (2000)
• [Publications] 許俊鋭: "人工心臓と補助循環。"Heart View. 4. 437-441 (2000)
• [Publications] 2)許俊鋭: "心不全の外科治療-左室縮小術"今日の治療. 8. 60-65 (2000)
• [Publications] Kawauchi M,Suzuki J,Morishita R,Wada Y,Izawa A,Tomita N,Amano J,Kaneda Y,Ogihara T,Takamoto S,Isobe M.: "Gene therapy for attenuating cardiac allograft arteriopathy using ex vivo E2F decoy transfection by HVJ-AVE-liposome method in mice and nonhuman primates."Circulatory Research. 87. 1063-1068 (2000)
• [Publications] Kawauchi M.Nakajima J.Endoh M.Oka T.Takamoto S.: "Ontogeny of antipig xenoantibody and hyperacute"Transplantation. 70(4). 686-688 (2000)
• [Publications] Endoh M.Kawauchi M.Isobe M.Suzuki J.Nakajima J.Takeda M.Takamoto S.: "Nonmuscle myosin heavy chain and metalloproteinase-2 expression in concordantpulmonary xenografts."Transplantation Proceedings.. 32(5). 1151-1152 (2000)
• [Publications] Murakawa T,Nakajima J,Ono,Murakami A,Suematsu Y,Takamoto S: "Allogenicity of cryopreserved human fibroblasts : Cryopreservation does not downregulate the allogenicity of fibroblasts making up the matrices of allografts."Journal of Thoracic & Cardiovascular Surgery. 120. 712-719 (2000)