2003 Fiscal Year Annual Research Report

頭頸部腫瘍に対する養子免疫療法改善のための基礎的検討

Research Project

Project/Area Number	13557160
Research Institution	KYOTO UNIVERSITY
Principal Investigator	梅原久範京都大学, 医学研究科, 助教授 (70247881)
Co-Investigator(Kenkyū-buntansha)	今井俊夫 (株)カン研究所, 所長三森経世京都大学, 医学研究科, 教授 (10157589)
Keywords	フラクタルカイン / NK細胞 / 細胞接着 / CD2 / IFN-γ / 細胞傷害 / 養子免疫療法 / 頭頸部腫瘍
Research Abstract	我々は血管内皮細胞上に発現するケモカインであるfractalkineのreceptor (CX3CR1)を世界に先駆けて同定し,CD14+単球CD16+NK細胞,CD8+T細胞上に発現していること,およびfractalkineが従来のケモカインと異なり接着分子として作用することを報告した.今回,fractalkineのNK細胞に及ぼす効果およびNK細胞と血管内皮細胞との接着や内皮傷害におけるfractalkineの関与を検討した.さらに,NK細胞活性化における細胞膜ラフトの重要性について検討した. 1)可溶型fractalkineはfibonectinやICAM-1に対するNK細胞接着を増強した. 2)fractalkine遺伝子を導入した血管内皮細胞は,NK細胞との接着を増強した. 3)fractalkineは濃度依存性にNK細胞の顆粒放出を増強し抗腫瘍細胞殺傷能を増強した. 4)NK細胞はfractalkine発現細胞を著明に殺傷した. 5)fractalkineによるNK細胞の活性化により,INF-γ産生が著明に増強した. 6)NK細胞上のCD2分子はラフト上に存在した. 7)NK細胞と腫瘍細胞との接着面にCD2の凝集とラフトの凝集が認められた. 8)ラフト破壊作用を有するmethyl-b-cyclodextrinを作用させることにより,NK細胞の腫瘍殺傷機能が著明に抑制された. これらの結果は,炎症反応により産生されたサイトカインで活性化した血管内皮細胞がfractalkineを発現し,NK細胞の接着増強を誘導し,組織中への遊送を増強していることを示している.遊送したNK細胞はfractalkineにより活性化され,抗腫瘍殺傷能が亢進している.このメカニズムを応用することにより,fractalkineによる腫瘍周囲へのNK細胞や細胞障害T細胞の集積を誘導し,養子免疫法の効率を向上させるが可能であろう.NK細胞の腫瘍殺傷機構に,細胞膜上のラフトは深く関わっている.このラフト機能を増強する薬剤は,養子免疫療法を増強させる可能性がある.

Research Products
(14 results)

All Other

All Publications (14 results)

[Publications] Yamaoka S, et al.: "Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells"J Biol Chem. (印刷中).
[Publications] Uchicda Y, et al.: "Anthracycline resistance in HL-60/ADR cells via transcriptional up-regulation of glucosyclceramide synthase and reversal by Sp1 decoyoligodeoxynucleotides"J.Biol.Chem. (印刷中).
[Publications] Umehara H, et al.: "Fractalkine and vascular biology : from basic research to clinical diseases"Arterio.Thromb.Vasc.Biol. (Review). 24. 34-40 (2004)
[Publications] Watanabe I, et al.: "Increase of the ceramide content in nuclei through caspase-3 dependent inhibition of sphingomyelin synthase in Fas-induced Jurkat T cell apoptosis"Cancer Res.. 60. 1000-1007 (2004)
[Publications] Kawabata D, et al.: "Ameliorative effects of follistatin-related protein/TSC-36 on joint inflammation in a mouse model of arthritis"Arthritis Rheum. 50. 660-607 (2004)
[Publications] Iwai K, et al.: "Ceramide increases oxidative damage due to inhibition of catalase by caspase-3-dependent proteolysis in HL-60 cell apoptosts"J.Biol.Chem.. 278. 9813-9822 (2003)
[Publications] Yoneda O, et al.: "Membrane bound form of fractalkine induces IFN-γ production by NK cells : A role for Th1 response"Eur.J.Immunol.. 33. 53-58 (2003)
[Publications] Umehara H, et al.: "Role for adapter proteins in costimulatory signals of CD2 and IL-2 on NK cells activation"Mol.Tmmunol.. 38. 587-596 (2002)
[Publications] Tanaka Y, et al.: "H-Ras/Mitogen-activated protein kinase pathway inhibits integrin-mediated adhesion and induces apoptosis in osteoblasts"J.Biol.Chem.. 277. 21446-21452 (2002)
[Publications] Nishimura M, et al.: "Dualfunctions of fractalkino/CX3CR1 in trafficking of circulating cytotoxic effector lymphocytes that are defined by CX3CR1 expression"J.Immunol.. 168. 6173-6180 (2002)
[Publications] Kondo T, et al.: "Vesnarinone causes oxidative damage by inhibiting catalase function through ceramide action in myeloid cell apoptosis"Mol.Pharm.. 61. 620-627 (2002)
[Publications] Kondo T, et al.: "Control of ceramide-induced apoptosis by IGF-1 : involvement of PI-3 kinase caspase-3 and catalase"Cell Death Differnt. 9. 682-692 (2002)
[Publications] Kawase M, et al.: "Increase of ceramide in adriamycin-induced HL-60 cell apoptosis detection by a novel anti-ceramido antibody"Biochimica et Biophysica Acta. 1584. 104-114 (2002)
[Publications] Inoue H, et al.: "Lipid rafts as the signaling scaffold for NK cell activation : Tyrosine phosphorylation and association of LAT with PI 3-kinase and PLC-γ following CD2 stimulation"Eur.J.Immunol.. 32. 2188-2198 (2002)

2003 Fiscal Year Annual Research Report

頭頸部腫瘍に対する養子免疫療法改善のための基礎的検討

Principal Investigator

梅原 久範 京都大学, 医学研究科, 助教授 (70247881)

Research Products

[Publications] Yamaoka S, et al.: "Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells"J Biol Chem. (印刷中).

[Publications] Uchicda Y, et al.: "Anthracycline resistance in HL-60/ADR cells via transcriptional up-regulation of glucosyclceramide synthase and reversal by Sp1 decoyoligodeoxynucleotides"J.Biol.Chem. (印刷中).

[Publications] Umehara H, et al.: "Fractalkine and vascular biology : from basic research to clinical diseases"Arterio.Thromb.Vasc.Biol. (Review). 24. 34-40 (2004)

[Publications] Watanabe I, et al.: "Increase of the ceramide content in nuclei through caspase-3 dependent inhibition of sphingomyelin synthase in Fas-induced Jurkat T cell apoptosis"Cancer Res.. 60. 1000-1007 (2004)

[Publications] Kawabata D, et al.: "Ameliorative effects of follistatin-related protein/TSC-36 on joint inflammation in a mouse model of arthritis"Arthritis Rheum. 50. 660-607 (2004)

[Publications] Iwai K, et al.: "Ceramide increases oxidative damage due to inhibition of catalase by caspase-3-dependent proteolysis in HL-60 cell apoptosts"J.Biol.Chem.. 278. 9813-9822 (2003)

[Publications] Yoneda O, et al.: "Membrane bound form of fractalkine induces IFN-γ production by NK cells : A role for Th1 response"Eur.J.Immunol.. 33. 53-58 (2003)

[Publications] Umehara H, et al.: "Role for adapter proteins in costimulatory signals of CD2 and IL-2 on NK cells activation"Mol.Tmmunol.. 38. 587-596 (2002)

[Publications] Tanaka Y, et al.: "H-Ras/Mitogen-activated protein kinase pathway inhibits integrin-mediated adhesion and induces apoptosis in osteoblasts"J.Biol.Chem.. 277. 21446-21452 (2002)

[Publications] Nishimura M, et al.: "Dualfunctions of fractalkino/CX3CR1 in trafficking of circulating cytotoxic effector lymphocytes that are defined by CX3CR1 expression"J.Immunol.. 168. 6173-6180 (2002)

[Publications] Kondo T, et al.: "Vesnarinone causes oxidative damage by inhibiting catalase function through ceramide action in myeloid cell apoptosis"Mol.Pharm.. 61. 620-627 (2002)

[Publications] Kondo T, et al.: "Control of ceramide-induced apoptosis by IGF-1 : involvement of PI-3 kinase caspase-3 and catalase"Cell Death Differnt. 9. 682-692 (2002)

[Publications] Kawase M, et al.: "Increase of ceramide in adriamycin-induced HL-60 cell apoptosis detection by a novel anti-ceramido antibody"Biochimica et Biophysica Acta. 1584. 104-114 (2002)

[Publications] Inoue H, et al.: "Lipid rafts as the signaling scaffold for NK cell activation : Tyrosine phosphorylation and association of LAT with PI 3-kinase and PLC-γ following CD2 stimulation"Eur.J.Immunol.. 32. 2188-2198 (2002)

梅原久範京都大学, 医学研究科, 助教授 (70247881)