2002 Fiscal Year Annual Research Report

新規樹立マウスバセドウ病モデルを用いた病態の解析及び治療法の開発

Research Project

Project/Area Number	14571069
Research Institution	Nagasaki University
Principal Investigator	永山雄二長崎大学, 医歯薬学総合研究科, 助教授 (30274632)
Keywords	甲状腺自己免疫 / 甲状腺刺激ホルモン受容体 / アデノウイルス / 自己抗体 / バセドウ病 / サイトカイン
Research Abstract	バセドウ病の病態解析 (1)遺伝背景:我々は以前、TSH受容体発現アデノウイルスを連続筋注することによってBALB/c(H-2d)マウスに高頻度にバセドウ病を誘導できることを報告した。今回遺伝的背景のバセドウ病発症に及ぼす影響を検討するため、BALB/cと主要組織適合抗原(MHC)のみが異なるマウス(即ち、congenic mice ; BALB/K (H-2k))と、MHC以外が異なるマウス(DBA/2J)を同様に免疫した。前者での発症率はBALB/cと同等であったが、後者では発症率低下の著しい認められた。よって、バセドウ病発症を規定する遺伝子はMHC外に存在することが示唆される。 (2)環境因子:環境中の微生物感染のバセドウ病発症に及ぼす影響を検討するため、Specific pathogen freeの状態或いは通常の環境中で飼育したBALB/cマウスを免役した。しかし発症率に有意な差は認められなかった。疾患発症に及ぼす微生物暴露の影響は小さいと考えらる。 (3)Th1/Th2バランス:Th1サイトカイン(interleukin-12 ; IL-12)とTh2サイトカイン(IL-4)の影響を検討するため、これらサイトカインを発現するアデノウイルスを作成し、TSH受容体発現アデノウイルスと共に筋注した。IL-4はTSH受容体に対する免疫反応をTh2にシフトさせ(抗TSH受容体抗体IgG1/IgG2a比上昇、脾細胞からの抗原特異的interferon-γ分泌低下)、疾患発症を抑制したが、IL-12は免疫反応をTh1にシフトさせたものの(脾細胞からの抗原特異的interferon-γ分泌増加)、疾患発症は不変であった。バセドウ病発症におけるTh1反応の重要性が示唆される。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] Tamada Y.: "p48 overexpression enhances interferon-mediated expression and activity of double-stranded RNA-dependent protein kinase (PKR) in human hepatoma cells"Journal of Hepatology. 37(4). 493-499 (2002)
[Publications] Schwarz-Lauer L.L.: "Evidence for a simplified view of autoantibody interactions with the TSH receptor"Thyroid. 12(2). 115-120 (2002)
[Publications] Nagayama Y.: "A novel murine model of Graves' hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor"Journal of Immunology. 168(6). 2789-2794 (2002)
[Publications] Kakinuma A.: "Multiple messenger ribonucleic acid transcripts and revised gene organization of human TSH receptor"Endocrine Journal. 49(2). 175-180 (2002)
[Publications] Kuroda H.: "Distinctive gene expression of receptor-type tyrosine kinase families during rat hepatocarcinogenesis"International Journal of Molecular Medicine. 9(5). 473-480 (2002)
[Publications] Kawamata Y.: "Receptor-independent augmentation of adenovirus-mediated gene transfer with chitosan in vitro"Biomaterials. 23(23). 4573-4579 (2002)
[Publications] Ando T.: "A monoclonal thyroid-stimulating antibody"Journal of Clinical Investigation. 110(11). 1667-1674 (2002)
[Publications] Ito M.: "Expression of receptor-type tyrosine kinase, Axl, and its ligand, Gas6, in pediatric thyroid carcinomas around Chernobyl"Thyroid. 12(11). 971-975 (2002)
[Publications] Yanagi K.: "Immuno-gene therapy with adenoviruses expressing fms-like tyrosine kinase 3 ligand and CD40 ligand for mouse hepatoma cells in vivo"International Journal of Oncology. 22(2). 345-351 (2002)
[Publications] Kita-Furuyama M.: "Dendritic cells infected with adenovirus expressing the thyrotropin receptor induce Graves' hyperthyroidism in BALB/c mice"Clinical and Experimental Immunology. 131(2). 234-240 (2002)
[Publications] Nagayama Y.: "A major role for non-MHC genes, but not for microorganisms, in a novel murine model of Graves' hyperthyroidism"Thyroid. (In press). (2003)
[Publications] Nagayama Y.: "Enhanced antitumor effect of combined replicative adenovirus and non-replicative adenovirus expressing interlerkin-12 in an immunocompetent mouse model"Gene Therapy. (In press). (2003)
[Publications] Schwarz-Lauer L.L.: "The cysteine-rich amino-terminus of the thyrotropin receptor is the immunodominant linear antibody epitope in mice immunized using naked DNA or adenovirus vectors"Endocrinology. (In press). (2002)
[Publications] Nagayama Y.: "Prevention of autoantibody-mediated Graves'-like hyperthyroidism in mice by IL-4, a Th2 cytokine"Journal of Immunology. (In press). (2003)
[Publications] Nagayama Y.: "Thyroid Eye Disease : Diagnosis and Treatment"Marcel Dekker. 9 (2002)
[Publications] Nagayama Y.: "The encyclopedia of Endocrinology and Endocrine Diseases"Academic Press (In press). (2003)

2002 Fiscal Year Annual Research Report

新規樹立マウスバセドウ病モデルを用いた病態の解析及び治療法の開発

Principal Investigator

永山 雄二 長崎大学, 医歯薬学総合研究科, 助教授 (30274632)

Research Products

[Publications] Tamada Y.: "p48 overexpression enhances interferon-mediated expression and activity of double-stranded RNA-dependent protein kinase (PKR) in human hepatoma cells"Journal of Hepatology. 37(4). 493-499 (2002)

[Publications] Schwarz-Lauer L.L.: "Evidence for a simplified view of autoantibody interactions with the TSH receptor"Thyroid. 12(2). 115-120 (2002)

[Publications] Nagayama Y.: "A novel murine model of Graves' hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor"Journal of Immunology. 168(6). 2789-2794 (2002)

[Publications] Kakinuma A.: "Multiple messenger ribonucleic acid transcripts and revised gene organization of human TSH receptor"Endocrine Journal. 49(2). 175-180 (2002)

[Publications] Kuroda H.: "Distinctive gene expression of receptor-type tyrosine kinase families during rat hepatocarcinogenesis"International Journal of Molecular Medicine. 9(5). 473-480 (2002)

[Publications] Kawamata Y.: "Receptor-independent augmentation of adenovirus-mediated gene transfer with chitosan in vitro"Biomaterials. 23(23). 4573-4579 (2002)

[Publications] Ando T.: "A monoclonal thyroid-stimulating antibody"Journal of Clinical Investigation. 110(11). 1667-1674 (2002)

[Publications] Ito M.: "Expression of receptor-type tyrosine kinase, Axl, and its ligand, Gas6, in pediatric thyroid carcinomas around Chernobyl"Thyroid. 12(11). 971-975 (2002)

[Publications] Yanagi K.: "Immuno-gene therapy with adenoviruses expressing fms-like tyrosine kinase 3 ligand and CD40 ligand for mouse hepatoma cells in vivo"International Journal of Oncology. 22(2). 345-351 (2002)

[Publications] Kita-Furuyama M.: "Dendritic cells infected with adenovirus expressing the thyrotropin receptor induce Graves' hyperthyroidism in BALB/c mice"Clinical and Experimental Immunology. 131(2). 234-240 (2002)

[Publications] Nagayama Y.: "A major role for non-MHC genes, but not for microorganisms, in a novel murine model of Graves' hyperthyroidism"Thyroid. (In press). (2003)

[Publications] Nagayama Y.: "Enhanced antitumor effect of combined replicative adenovirus and non-replicative adenovirus expressing interlerkin-12 in an immunocompetent mouse model"Gene Therapy. (In press). (2003)

[Publications] Schwarz-Lauer L.L.: "The cysteine-rich amino-terminus of the thyrotropin receptor is the immunodominant linear antibody epitope in mice immunized using naked DNA or adenovirus vectors"Endocrinology. (In press). (2002)

[Publications] Nagayama Y.: "Prevention of autoantibody-mediated Graves'-like hyperthyroidism in mice by IL-4, a Th2 cytokine"Journal of Immunology. (In press). (2003)

[Publications] Nagayama Y.: "Thyroid Eye Disease : Diagnosis and Treatment"Marcel Dekker. 9 (2002)

[Publications] Nagayama Y.: "The encyclopedia of Endocrinology and Endocrine Diseases"Academic Press (In press). (2003)

永山雄二長崎大学, 医歯薬学総合研究科, 助教授 (30274632)