1996 Fiscal Year Annual Research Report

担癌宿主T細胞レセプターのシグナル伝達と応答制御

Research Project

Project/Area Number	06282234
Research Institution	Osaka University
Principal Investigator	濱岡利之大阪大学, 医学部, 教授 (60028529)
Co-Investigator(Kenkyū-buntansha)	緒方正人大阪大学, 医学部, 助手 (60224094) 小野史郎大阪大学, 医学部, 講師 (80127208)
Keywords	担癌 / IL-12 / IFN-γ / iNOS / IDO / リンパ球浸潤 / 抗腫瘍免疫
Research Abstract	我々はT細胞機能が低下している後期の担がん宿主でも、ある種のがんのモデル(マウス線維肉腫細胞CSA1M或は卵巣がん細胞OV-HM)ではIL-12を全身投与することにより、抗腫瘍T細胞のIFN-γ産生能の回復が見られ完全な腫瘍退縮効果がもたらされる事を見いだしている。IL-12が担がん宿主免疫系に作用して腫瘍を退縮させる際、腫瘍局所の多数のT細胞の浸潤が認められる。本年度は、IL-12投与によるT細胞の腫瘍局所での抗腫瘍効果発現機構を分子レベルで解析した。1、IL-12投与した担がんマウスの脾細胞を蛍光色素PKH-26にて染色後、無治療の同系担がんマウスに静脈内移入し、12-24時間後に腫瘍塊の凍結切片に於る蛍光細胞数を測定するという実験系を確立し、IL-12はT細胞を活性化するのみならず、活性化T細胞に腫瘍局所への浸潤能力を賦与する事を直接証明した。2、IL-12治療により腫瘍局所で誘導されるIFN-γが如何なる分子機構で腫瘍拒絶を惹起するかについて検討した。1)CSA1M或はOV-HMをIFN-γでin vitro刺激した所、CSA1Mでは誘導型NO-synthase(iNOS)、OV-HMではindolamine 2,3-dioxy-genase(IDO)の発現が誘導された(トリプトファン利用が阻止され増殖抑制に陥ると考えられる)。2)IL-12治療を受けたCSA1M担がんマウス腫瘍局所ではiNOS mRNAの強い発現を認め、OV-HM担がんではIDO mRNAの発現と共に浸潤細胞によるiNOSの発現も認められた。3)L-12投与と共に抗IFN-γ抗体を投与すると腫瘍拒絶は阻止されるが、腫瘍塊へのT細胞浸潤や局所でのIFN-γの発現は抑制されなかった。しかし、腫瘍塊でのiNOSの発現は、抗IFN-γ抗体投与により著明に減少し腫瘍細胞の壊死も誘導されなかった。即ち、IL-12投与により腫瘍局所でIFN-γを介して二次的に誘導されるiNOSやIDOの発現が腫瘍拒絶に必須である事が示された。4)CSA1MやOVA-HMはNOの作用によりG1期に収束或は同期する為に増殖能が低下する事が示唆された。

Research Products

(16 results)

All Other

All Publications (16 results)

[Publications] H.Fujiwara: "Cellular and molecular mechanisms underlying IL-12-induced tumor regression" Annals New York Academy of Science. 32/1067. 447-473 (1996)
[Publications] H.Fujiwara: "Antitumor and antimetastatic effects of interleukin 12" Cancer Chemother.Pharmacol.18(suppl). S22-S26 (1996)
[Publications] W.-G.Yu: "Molecular mechanisms underlying IFN-γ-mediated tumor growth inhibition induced during tumor immunotherapy with rIL-12" Int.Immunology. 8. 855-865 (1996)
[Publications] S.Maruo: "IL-12 produced by antigen-presenting cells induces IL-2-independent proliferation of T helper cell clones" J.Immunol.156. 1748-1755 (1996)
[Publications] X-G.Tai: "A role for CD9 molecules in T cell activation" J.Exp.Med.184. 753-758 (1996)
[Publications] K.Toyooka: "CD28 co-stimulatory signals induce IL-2 receptor expression on antigen-stimulated virgin T cells by an IL-2-independent mechanism" Int.Immunology.8. 159-169 (1996)
[Publications] J.Mu: "Inhibition of growth and metastasis of ovarian carcinoma by administering a drug capable of interferring with vascular endothelial growth factor activity" Jpn.J.Cancer Res.87. 963-971 (1996)
[Publications] S.Noda: "Protection from anti-TCR/CD3-induced apoptosis in immature thymocytes by a signal through thymic shared antigen-1(TSA-1)/stem-cell antigen-2(Sca-2)" J.Exp.Med.183. 2355-2360 (1996)
[Publications] S.Maruo: "B cells regulate CD-40 ligand-induced IL-12 production in antigen-presenting cells(APC) during T cell/APC interactions" J.Immunol.158. 120-126 (1997)
[Publications] Y.Abe: "A defect in cell-to-cell adhesion via integrin-fibronectin interactions in a highly metastatic tumor cell line" Jpn.J.Cancer Res.88. 64-71 (1997)
[Publications] H.Takenaka: "Regulation of T cell-dependent and-independent IL-12 production by three Th2-type cytokines IL-10,IL-6 and IL-4" J.Leukocyte Biol.61. 80-87 (1997)
[Publications] X.-G.Tai: "Expression of inducible type of nitric oxide(NO)synthase in the thymus and involvement of NO in deletion of T cell receptor-stimulated double positive thymocytes" J.Immunol.(in press). (1997)
[Publications] T.Furuyama: "Identification of a novel transmembrane semaphorin expressed on lymphocytes" J.Biol.Chem.(in press). (1997)
[Publications] T.Hirota: "Mouse CD4 and CD8 T-cell clones that recognize xeno-antigens directly on xeno-antigen presenting cells in xeno MHC-restricted ways" Transplant Proc.(in press). (1997)
[Publications] S.Maruo: "Estabishment of an IL-12-dependent T cell clone:Its characterization and utilization to quantitation of IL-12 activity" J.Leukocyte Biol.(in press). (1997)
[Publications] T.Hirota: "Direct recognition of rat MHC antigens on rat antigen-presenting cells by mouse CD4+ and CD8+ T cells and establishment of T cell clones exhibiting a direct recognition pathway" Transplantation. (in press). (1997)

1996 Fiscal Year Annual Research Report

担癌宿主T細胞レセプターのシグナル伝達と応答制御

Principal Investigator

濱岡 利之 大阪大学, 医学部, 教授 (60028529)

Research Products

[Publications] H.Fujiwara: "Cellular and molecular mechanisms underlying IL-12-induced tumor regression" Annals New York Academy of Science. 32/1067. 447-473 (1996)

[Publications] H.Fujiwara: "Antitumor and antimetastatic effects of interleukin 12" Cancer Chemother.Pharmacol.18(suppl). S22-S26 (1996)

[Publications] W.-G.Yu: "Molecular mechanisms underlying IFN-γ-mediated tumor growth inhibition induced during tumor immunotherapy with rIL-12" Int.Immunology. 8. 855-865 (1996)

[Publications] S.Maruo: "IL-12 produced by antigen-presenting cells induces IL-2-independent proliferation of T helper cell clones" J.Immunol.156. 1748-1755 (1996)

[Publications] X-G.Tai: "A role for CD9 molecules in T cell activation" J.Exp.Med.184. 753-758 (1996)

[Publications] K.Toyooka: "CD28 co-stimulatory signals induce IL-2 receptor expression on antigen-stimulated virgin T cells by an IL-2-independent mechanism" Int.Immunology.8. 159-169 (1996)

[Publications] J.Mu: "Inhibition of growth and metastasis of ovarian carcinoma by administering a drug capable of interferring with vascular endothelial growth factor activity" Jpn.J.Cancer Res.87. 963-971 (1996)

[Publications] S.Noda: "Protection from anti-TCR/CD3-induced apoptosis in immature thymocytes by a signal through thymic shared antigen-1(TSA-1)/stem-cell antigen-2(Sca-2)" J.Exp.Med.183. 2355-2360 (1996)

[Publications] S.Maruo: "B cells regulate CD-40 ligand-induced IL-12 production in antigen-presenting cells(APC) during T cell/APC interactions" J.Immunol.158. 120-126 (1997)

[Publications] Y.Abe: "A defect in cell-to-cell adhesion via integrin-fibronectin interactions in a highly metastatic tumor cell line" Jpn.J.Cancer Res.88. 64-71 (1997)

[Publications] H.Takenaka: "Regulation of T cell-dependent and-independent IL-12 production by three Th2-type cytokines IL-10,IL-6 and IL-4" J.Leukocyte Biol.61. 80-87 (1997)

[Publications] X.-G.Tai: "Expression of inducible type of nitric oxide(NO)synthase in the thymus and involvement of NO in deletion of T cell receptor-stimulated double positive thymocytes" J.Immunol.(in press). (1997)

[Publications] T.Furuyama: "Identification of a novel transmembrane semaphorin expressed on lymphocytes" J.Biol.Chem.(in press). (1997)

[Publications] T.Hirota: "Mouse CD4 and CD8 T-cell clones that recognize xeno-antigens directly on xeno-antigen presenting cells in xeno MHC-restricted ways" Transplant Proc.(in press). (1997)

[Publications] S.Maruo: "Estabishment of an IL-12-dependent T cell clone:Its characterization and utilization to quantitation of IL-12 activity" J.Leukocyte Biol.(in press). (1997)

[Publications] T.Hirota: "Direct recognition of rat MHC antigens on rat antigen-presenting cells by mouse CD4+ and CD8+ T cells and establishment of T cell clones exhibiting a direct recognition pathway" Transplantation. (in press). (1997)

濱岡利之大阪大学, 医学部, 教授 (60028529)