1997 年度実績報告書

標的臓器の分子生物学的修飾と免疫寛容

研究課題

研究課題/領域番号	09470247
研究機関	名古屋大学
研究代表者	横山逸男名古屋大学, 医学部, 講師 (60240206)
研究分担者	デルカルピオカルロス豊橋技術科学工科大学, エコロジー工学系, 講師 (20231053) 小島泰樹名古屋大学, 医学部, 医員小林孝彰名古屋大学, 医学部, 医員林衆治名古屋大学, 医学部, 助手 (30218573) 高木弘名古屋大学, 医学部, 教授 (70154755)
キーワード	同種免疫 / アポトーシス / Fasリガンド / CTLA-4 / 可溶性ペプチド / 遺伝子導入 / 細胞毒性T細胞 / Fas抗原
研究概要	同種移植における免疫反応ダイナミックな変化を、標的細胞の傷害機構として最も重要と考えられるアポトーシスの面から研究を行った。膜表面のレセプターによるシグナル伝達を介した、Fas誘導型アポトーシスによる細胞死であるという認識から、invitroにおいてFasリガンドのホモロジータンパクを解析し、その効果を認識した。これによれば、Fas誘導型メカニズムとはいえFasおよびそのリガンドの存在のみではアポトーシスの誘導が必ずしも起きるわけではないことが確認された。すなわち標的細胞内のシグナル伝達の差が重要な点であることが示唆された。またFasリガンドのいくつかのペプチドのうちその生物学的活性の差も、標的細胞内のシグナル伝達に依存している可能性が高いと考えられた。一方、こうした可溶性ペプチドによる非免疫学的影響についても今後検討する必要がある。細胞傷害性T細胞のレセプターの反応に基づく、各免疫制御因子として、MHC-T細胞レセプターの他、B7-CD28による補助因子が重要であるため、小動物を用いたCTLA4の遺伝子導入実験を行った。その結果invitroおよびvivoの実験から、肝移植における免疫拒絶反応の制御の可能性もあるという結果が得られた。この免疫反応のメカニズムにおいてもカスパーゼを介したアポトーシスの関与を示唆する結果が得られた。これらの実験から同種移植の免疫反応について、当初の目的であった、宿主の基本的免疫防御機構を低下させることなく標的臓器の分子生物学的修飾による免疫寛容の樹立への道を開くものと期待し得た。実際小動物による肝移植モデルにおいて、標的臓器にCTLAを遺伝子導入することが出来、肝実質からの可溶性分子の放出によるB7-CD28の阻害が可能であったことは意義深いと考えられる。今後は他の分子(例えば可溶性MHCなど)の生物学的活性とその役割を認識し、その上で標的臓器の分子生物的修飾による免疫寛容の樹立に向かい研究を進める。

研究成果
(25件)

すべてその他

すべて文献書誌 (25件)

[文献書誌] Yokoyama T, Takagi H: "Apoptosis in pig endothelial cells after reperfusion and its prevention by genetic induction of human Cu, Zn-SOD cDNA." Transplantation Proceeding. 29. 1364-1364 (1997)
[文献書誌] Morozumi K, Yokoyama I: "Electron-mictoscopic peritubular capillary lesion in a specific and uself diagnostic indicator for chronic rejection of renal allografts showing less specific morphologic lesion in the cyclosporine" Transplantation Proceeding. 29. 89-92 (1997)
[文献書誌] Takeda A, Yokoyama I, Takagi H: "Sevare cyclosporine arteriolopathy with focal segmental glomerulosclerosis is not a fatal finding in chronic renal allograt failure after year 5 of transplantaition using cyclosporine" Transplantation Proceeding. 29. 96-99 (1997)
[文献書誌] Hayashi S, Yokoyama I, Takagi H: "Effect of antisense ribozyme to alpha(1,3)galactosyl transferase gene on the expression of GAl alpha(1,3)GAL epitope" Transplantation Proceeding. 29. 893-893 (1997)
[文献書誌] Koike C, Yokoyama I, Takagi H: "Reduction of α-gal epitopes in transgenic pig by. introduction of human α1-2 fucosyltransferase." Transplantation Proceeding. 294. 894-894 (1997)
[文献書誌] Negita M, Yokoyama I, Takagi H: "Protective effect of human suoeroxide dismutase cDNA transfection in the prevention of cold preservation injury." Transplantation Proceeding. 29. 1363-1363 (1997)
[文献書誌] T Nagasaka, I Yokoyama, H Takagi: "α-Galactosyl oligosaccharides conjugated with polyethylene glycol as potential inhibitors of hyperacute rejection upon xenotransplantation" BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMUNICATIONS. 232. 731-736 (1997)
[文献書誌] S Hayashi, I Yokoyama, HTakagi: "Adenovirus-mediated gene transfer to the xenogeneic liver in liver xenotransplantation : The transduction of complement regulatory factor genes(DAF and HRF20)" Transplantation Proceeding. 29. 2211-2211 (1997)
[文献書誌] S Hayashi, I Yokoyama, H Takagi: "Effect of CTLA4-Ig gene transfer using adenoviral vector in organ and cell transplantation" Transplantation Proceeding. 29. 2212-2212 (1997)
[文献書誌] S Hayashi, I Yokoyama, H Takagi: "Adenovirus-mediated gene transfer of antisense ribozyme for α(1,3)garactosyl transferase gene and (1,2)fucosyltransferase gene in xenotranplantation" Transplantation Proceeding. 29. 2213-2213 (1997)
[文献書誌] Y Namii, I Yokoyama, H Takagi: "Evidence that the adenoviral vector containing the CTLA-Ig gene improves transgene expression and graft survival" Transplantation Proceeding. 29. 1738-1739 (1997)
[文献書誌] H Asano, I Yokoyama, H Takagi: "Significance of tumor necrosis factor microsatellite polymorphism in renal transplantation" Tissue Antigens. 50. 484-488 (1997)
[文献書誌] Negita M, Yokoyama I, Takagi H: "Protective Effect of Human Superoxide Dismutase cDNA Transfection in the Prevention of Cold Preservation Injury" Transplantation Proceeding. 29. 1363-1363 (1997)
[文献書誌] Yokoyama I Takagi H: "Apoptosis in Pig Endothelial Cells After Reperfusion and Its Prevention by Induction of Human Cu, Zn-SOD cDNA" Transplantation Proceeding. 29. 1364-1364 (1997)
[文献書誌] Hayashi S, Yokoyama I, Takagi H: "Effect of CTL4-Ig Gene Transfer Using Adenovial Vector in Organ and Cell transplantation" Transplantation Proceedings. 29. 2212-2212 (1997)
[文献書誌] Katayama A, Yokoyama I, Takagi H: "Studies of α-Gal Dependent Hyperacute Xenotransplant Reiection Using DOuble Knockout Embryonic Stem Cells" Transplantation Proceedings. 29. 2262-2262 (1997)
[文献書誌] C Koike, I Yokoyama, H Takagi: "Direct gene replacement of the mouse α(1,3)-galactsyltransgferase gene with human α(1,2)-fucosyltransgferase gene : Converting α galactsyl epitopes into H antigens" Xenotransplantation. 4. 147-153 (1997)
[文献書誌] H Asano, I Yokoyama, H Takagi: "Significance of tumor necrosis factor microsatellite polymorphism in renal transplantation" TISSUE ANTIGENS. 50. 484-488 (1997)
[文献書誌] S Hayashi, I Yokoyama, H Takagi: "Inhibition of establishment of Hepatic metastasis in mice by combination gene therapy using both herpes simplex virusthymidine kinase and granulocyte macrophage-colony stimulating factor gene in mune colon cancer" Cancer Genen Therapy. 4-6. 339-344 (1997)
[文献書誌] T Kojima, I Yokoyama,: "Inhibition of completment-mediated immune hemolysis by the constant domain of immunoglobuin" Peptido Chemistry. (in press).
[文献書誌] Yokoyama I, Takagi H: "Transplant Portal venous flow velocity measured by the implantable miniature Doppler probe in pig liver transplantation." Interntional. (in press).
[文献書誌] Yokoyama I, Takagi H: "Fas antigen expression and its modification by immunosuppressants" Dig Dis Sci. (in press).
[文献書誌] Yokoyama I, Takagi H: "Prevention of endothelial cell apoptosis with genetic induction of human Cu, Zn-SOD cDNA." Transplantation. (in press).
[文献書誌] Yokoyama I, Takagi H: "Portal venous flow velocity measured by the implantable miniature Doppler probe in pig liver transplantation" International. (in press).
[文献書誌] Yokoyama I, Takagi H: "Fas antigen expression and its modification by immunosuppressants." Dig Dis Sci. (in press).

1997 年度 実績報告書

標的臓器の分子生物学的修飾と免疫寛容

研究代表者

横山 逸男 名古屋大学, 医学部, 講師 (60240206)

研究成果

[文献書誌] Yokoyama T, Takagi H: "Apoptosis in pig endothelial cells after reperfusion and its prevention by genetic induction of human Cu, Zn-SOD cDNA." Transplantation Proceeding. 29. 1364-1364 (1997)

[文献書誌] Morozumi K, Yokoyama I: "Electron-mictoscopic peritubular capillary lesion in a specific and uself diagnostic indicator for chronic rejection of renal allografts showing less specific morphologic lesion in the cyclosporine" Transplantation Proceeding. 29. 89-92 (1997)

[文献書誌] Takeda A, Yokoyama I, Takagi H: "Sevare cyclosporine arteriolopathy with focal segmental glomerulosclerosis is not a fatal finding in chronic renal allograt failure after year 5 of transplantaition using cyclosporine" Transplantation Proceeding. 29. 96-99 (1997)

[文献書誌] Hayashi S, Yokoyama I, Takagi H: "Effect of antisense ribozyme to alpha(1,3)galactosyl transferase gene on the expression of GAl alpha(1,3)GAL epitope" Transplantation Proceeding. 29. 893-893 (1997)

[文献書誌] Koike C, Yokoyama I, Takagi H: "Reduction of α-gal epitopes in transgenic pig by. introduction of human α1-2 fucosyltransferase." Transplantation Proceeding. 294. 894-894 (1997)

[文献書誌] Negita M, Yokoyama I, Takagi H: "Protective effect of human suoeroxide dismutase cDNA transfection in the prevention of cold preservation injury." Transplantation Proceeding. 29. 1363-1363 (1997)

[文献書誌] T Nagasaka, I Yokoyama, H Takagi: "α-Galactosyl oligosaccharides conjugated with polyethylene glycol as potential inhibitors of hyperacute rejection upon xenotransplantation" BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMUNICATIONS. 232. 731-736 (1997)

[文献書誌] S Hayashi, I Yokoyama, HTakagi: "Adenovirus-mediated gene transfer to the xenogeneic liver in liver xenotransplantation : The transduction of complement regulatory factor genes(DAF and HRF20)" Transplantation Proceeding. 29. 2211-2211 (1997)

[文献書誌] S Hayashi, I Yokoyama, H Takagi: "Effect of CTLA4-Ig gene transfer using adenoviral vector in organ and cell transplantation" Transplantation Proceeding. 29. 2212-2212 (1997)

[文献書誌] S Hayashi, I Yokoyama, H Takagi: "Adenovirus-mediated gene transfer of antisense ribozyme for α(1,3)garactosyl transferase gene and (1,2)fucosyltransferase gene in xenotranplantation" Transplantation Proceeding. 29. 2213-2213 (1997)

[文献書誌] Y Namii, I Yokoyama, H Takagi: "Evidence that the adenoviral vector containing the CTLA-Ig gene improves transgene expression and graft survival" Transplantation Proceeding. 29. 1738-1739 (1997)

[文献書誌] H Asano, I Yokoyama, H Takagi: "Significance of tumor necrosis factor microsatellite polymorphism in renal transplantation" Tissue Antigens. 50. 484-488 (1997)

[文献書誌] Negita M, Yokoyama I, Takagi H: "Protective Effect of Human Superoxide Dismutase cDNA Transfection in the Prevention of Cold Preservation Injury" Transplantation Proceeding. 29. 1363-1363 (1997)

[文献書誌] Yokoyama I Takagi H: "Apoptosis in Pig Endothelial Cells After Reperfusion and Its Prevention by Induction of Human Cu, Zn-SOD cDNA" Transplantation Proceeding. 29. 1364-1364 (1997)

[文献書誌] Hayashi S, Yokoyama I, Takagi H: "Effect of CTL4-Ig Gene Transfer Using Adenovial Vector in Organ and Cell transplantation" Transplantation Proceedings. 29. 2212-2212 (1997)

[文献書誌] Katayama A, Yokoyama I, Takagi H: "Studies of α-Gal Dependent Hyperacute Xenotransplant Reiection Using DOuble Knockout Embryonic Stem Cells" Transplantation Proceedings. 29. 2262-2262 (1997)

[文献書誌] C Koike, I Yokoyama, H Takagi: "Direct gene replacement of the mouse α(1,3)-galactsyltransgferase gene with human α(1,2)-fucosyltransgferase gene : Converting α galactsyl epitopes into H antigens" Xenotransplantation. 4. 147-153 (1997)

[文献書誌] H Asano, I Yokoyama, H Takagi: "Significance of tumor necrosis factor microsatellite polymorphism in renal transplantation" TISSUE ANTIGENS. 50. 484-488 (1997)

[文献書誌] T Kojima, I Yokoyama,: "Inhibition of completment-mediated immune hemolysis by the constant domain of immunoglobuin" Peptido Chemistry. (in press).

[文献書誌] Yokoyama I, Takagi H: "Transplant Portal venous flow velocity measured by the implantable miniature Doppler probe in pig liver transplantation." Interntional. (in press).

[文献書誌] Yokoyama I, Takagi H: "Fas antigen expression and its modification by immunosuppressants" Dig Dis Sci. (in press).

[文献書誌] Yokoyama I, Takagi H: "Prevention of endothelial cell apoptosis with genetic induction of human Cu, Zn-SOD cDNA." Transplantation. (in press).

[文献書誌] Yokoyama I, Takagi H: "Portal venous flow velocity measured by the implantable miniature Doppler probe in pig liver transplantation" International. (in press).

[文献書誌] Yokoyama I, Takagi H: "Fas antigen expression and its modification by immunosuppressants." Dig Dis Sci. (in press).

1997 年度実績報告書

横山逸男名古屋大学, 医学部, 講師 (60240206)