TOP > 研究報告検索 > 生体防御のメカニズム 免疫系と神経・内分泌系の立体的分子機構の解明

生体防御のメカニズム 免疫系と神経・内分泌系の立体的分子機構の解明

研究報告コード R990004224
掲載日 2001年2月6日
研究者
  • 奥村 康
研究者所属機関
  • 順天堂大学医学部
研究機関
  • 順天堂大学医学部
報告名称 生体防御のメカニズム 免疫系と神経・内分泌系の立体的分子機構の解明
報告概要 これまで個別の現象として捉えられてきた免疫神経内分泌系の現象のクロスストロークを細胞分子のレベルで明らかにすることを目的とした。我々はかねてよりTNF/TNFRファミリー分子について研究を続けてきており、これらの分子の神経系疾患における役割について検討を加えた。CD27/CD70およびOX40/OX40L相互作用がマウス実験脳炎であるexperimental allergic encephalitisの発病に関与していることが明らかとなった。またTNFRファミリーを介するNF-κBの活性化に関与する新しいシグナル伝達分子TNFR-associated factor(TRAF)5を遺伝子クローニングし、さらにノックアウトマウスを作製し、TRAF5のin vivoにおける役割を明らかにした。さらにアポトーシスを誘導するFasLやTNF-related apoptosis-inducing ligand(TRAIL)といったTNFファミリーに属する分子の標的細胞破壊や腫瘍拒絶における役割を明らかにした。これらの解析を通じて、TNF/TNFRファミリー分子を介する細胞増殖あるいは細胞死などの分子メカニズムを明らかにすることができた。
研究分野
  • 生体防御と免疫系一般
  • 中枢神経系
  • 細胞生理一般
  • サイトカイン
  • 生物学的機能
関連発表論文 (1)Kashiwada, M., Y. Shirakata, J.-I. Inoue, H. Nakano, K. Okazaki, K. Okumura, T. Yamamoto, H. Nagaoka, and T. Takemori. Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) Stimulates Extracellular Signaling Kinase (ERK) Activity in CD40 Signaling Along a Ras-independent Pathway. J. Exp. Med. 187:237-244, 1998.
(2)Akiba, H., M. Atsuta, H. Yagita, and K. Okumura. Identification of rat OX40 ligand by molecular cloning. Biochem. Biophys. Res. Commun. 251, 1:131-6, 1998.
(3)Akiba, H., H. Nakano, S. Nishinaka, M. Shindo, T. Kobata, M. Atsuta, C. Morimoto, C.F. Ware, N.L. Malinin, D. Wallach, H. Yagita, and K. Okumura. 1998. CD27, a member of the tumor necrosis factor receptor superfamily, activates NF-κB and stress-activated protein kinase/c-Jun N-terminal kinase via TRAF2, TRAF5, and NF-kB-inducing kinase. J. Biol. Chem. 273, 21:13353-8, 1998.
(4)Hattori, K., T. Hirano, H. Miyajima, N. Yamakawa, M. Tateno, K. Oshimi, N. Kayagaki, H. Yagita, and K. Okumura. Differential effects of anti-Fas ligand and anti-tumor necrosis factor α antibodies on acute graft-versus-host disease pathologies. Blood 91, 11:4051-5, 1998.
(5)Kawamura, T., K. Takeda, S.K. Mendiratta, H. Kawamura, L. Van Kaer, H. Yagita, T. Abo, and K. Okumura. Critical role of NK1+ T cells in IL-12-induced immune responses in vivo. J. Immunol. 160, 1:16-9, 1998.
(6)Mogi, S., T. Ebata, Y. Setoguchi, M. Fujime, Y. Heike, T. Kohsaka, H. Yagita, K. Okumura, and M. Azuma. Efficient generation of autologous peripheral blood-derived cytotoxic T lymphocytes against poorly immunogenic human tumors using recombinant CD80-adenovirus together with interleukin 12 and interleukin 2. Clin. Cancer Res. 4, 3:713-20, 1998.
(7)Nakajima, A., T. Kodama, S. Morimoto, M. Azuma, K. Takeda, H. Oshima, S. Yoshino, H. Yagita, and K. Okumura. Antitumor effect of CD40 ligand: elicitation of local and systemic antitumor responses by IL-12 and B7. J. Immunol. 161, 4:1901-7, 1998.
(8)Nakano, H., M. Shindo, S. Sakon, S. Nishinaka, M. Mihara, H. Yagita, and K. Okumura. Differential regulation of IκB kinase α and β by two upstream kinases, NF-κB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1. Proc. Natl. Acad. Sci. USA 95, 7:3537-42, 1998.
(9)Oshima, H., H. Nakano, C. Nohara, T. Kobata, A. Nakajima, N.A. Jenkins, D.J. Gilbert, N.G. Copeland, T. Muto, H. Yagita, and K. Okumura. Characterization of murine CD70 by molecular cloning and mAb. Int. Immunol. 10, 4:517-26, 1998.
(10)Saito, K., J. Sakurai, J. Ohata, T. Kohsaka, H. Hashimoto, K. Okumura, R. Abe, and M. Azuma. Involvement of CD40 ligand-CD40 and CTLA4-B7 pathways in murine acute graft-versus-host disease induced by allogeneic T cells lacking CD28. J. Immunol. 160, 9:4225-31, 1998.
(11)Seino, K., K. Iwabuchi, N. Kayagaki, R. Miyata, I. Nagaoka, A. Matsuzawa, K. Fukao, H. Yagita, and K. Okumura. Chemotactic activity of soluble Fas ligand against phagocytes. J. Immunol. 161, 9:4484-8, 1998.
(12)Shindo, M., H. Nakano, S. Sakon, H. Yagita, M. Mihara, and K. Okumura. Assignment of IκB kinase β (IKBKB) to human chromosome band 8p12→p11 by in situ hybridization. Cytogenet. Cell Genet. 82, 1-2:32-3, 1998.
(13)Shindo, M., H. Nakano, H. Kuroyanagi, T. Shirasawa, M. Mihara, D.J. Gilbert, N.A. Jenkins, N.G. Copeland, H. Yagita, and K. Okumura. CDNA cloning, expression, subcellular localization, and chromosomal assignment of mammalian aurora homologues, aurora-related kinase (ARK) 1 and 2. Biochem. Biophys. Res. Commun. 244, 1:285-92, 1998.
(14)Hong, N.M., K. Masuko-Hongo, H. Sasakawa, T. Kato, T. Shirai, K. Okumura, K. Nishioka, and T. Kobat. Amelioration of lymphoid hyperplasia and hypergammaglobulinemia in lupus-prone mice, gld by Fas ligand gene transfer. J. Autoimmunity, 11; 301-307, 1998.
(15)Tsukada, N., T. Kobata, Y. Aizawa, H. Yagita, and K. Okumura. Graft-versus-leukemia (GVL) effect and graft-versus-host disease (GVHD) can be differentiated by cytotoxic mechanisms in a murine model of allogeneic bone marrow transplantation. Blood, 93: 2738-2747, 1999.
(16)Suzuki, N., A. Nakajima, S. Yoshino, K. Matsushima, H. Yagita, and K. Okumura Selective accumulation of CCR5+ T lymphocytes into inflamed jount of rheumatoid arthritis. Int. Immunol., 11: 553-559, 1999.
(17)Kayagaki, N., N. Yamaguchi, M. Nakayama, A. Kawasai, H. Akiba, K. Okumura, and H. Yagita. Involvement of TRAIL in human CD4+ T cell-mediated cytotoxicity. J. Immunol., 162; 2639-2647, 1999.
(18)Kayagaki, N., Yamaguchi, N., Nakayama, M., Eto, H., Okumura, K. and H. Yagita. Type I Interferones(IFNs) Regulate Tumor Necrosis Factor-related Apoptosis-inducing Ligand(TRAIL) Expression on Human T Cells: A Novel Mechanism for the Antitumor Effects of Type I IFNs. J. Exp. Med. 189:1451-1460, 1999.
(19)Kodama, T., K. Takeda, O. Shimozato, Y. Hayakawa, M. Atsuta, K. Kobayashi, M. Ito, H. Yagita, and K. Okumura. Perforin-dependent NK cell cytotoxicity is sufficient for anti-metastatic effect of IL-12. Eur. J. Immunol. 29:1-7, 1999.
(20)Hatakeyama, S., M. Kitagawa, K. Nakayama, M. Shirane, M. Matsumoto, K. Hattori, H. Higashi, H. Nakano, K. Okumura, K. Onoe, R.A. Good, and K.-I. Nakayama. Ubiquitin-dependent degradation of IκB is mediated by a novel ubiquitin ligase SCFFWD1. Proc. Natl. Acad. Sci. 96: 3859-3863, 1999.
(21)Shimozato, O., K. Takeda, H. Yagita, and K. Okumura Expression of CD30 ligand (CD153) on murine activated T cells. Biochem. Biophys. Res. Commun. 256: 519-526, 1999.
(22)Akiba, H., H. Oshima, K. Takeda, M. Atsuta, H. Nakano, A. Nakanjima, C. Nohara, H. Yagita, and K. Okumura. CD28-independent costimulation of T cells by OX40 ligand and CD70 on activated B cells. J. Immunol. 162: 7058-7066, 1999.
(23)Takumi, T., C. Matsubara, Y. Shigeyoshi, K. Taguchi, K. Yagita, Y. Maebayashi, Y. Sakakida, K. Okumura, N. Takashima and H. Okamura. A new mammalian period gene predominantly expressed in the suprachiasmatic nucleus. Genes Cells, 3, 167-176, 1998.
(24)Takumi, T., K. Taguchi, S. Miyake, Y. Sakakida, N. Takashima, C. Matsubara, Y. Maebayashi, K. Okumura, S. Takekida, S. Yamamoto, K. Yagita, L. Yan, M. W. Young and H. Okamura. A light independent oscillatory gene mPer3 in mouse SCN and OVLT. EMBO J., 17, 4753-4759, 1998.
(25)Morimoto, S., Y. Kanno, Y. Tanaka, Y. Tokano, H. Hashimoto, S. Jacquot, C. Morimoto, S. F. Schlossman, H. Yagita, K. Okumura, and T. Kobata. CD134L engagement enhances human B cell Ig production: CD154/CD40, DC70/CD27, and CD134/CD134L interactions coordinately regulate T cell-dependent B cell responses. J Immunol. 164:4097-104, 2000.
(26)Satake, Y., H. Akiba, K. Takeda, M. Atsuta, H. Yagita, and K. Okumura. Characterization of rat OX40 ligand by monoclonal antibody. Biochem Biophys Res Commun. 270:1041-8, 2000.
(27)Takeda, K., Y. Hayakawa, L. Van Kaer, H. Matsuda, H. Yagita, and K. Okumura. Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proc Natl Acad Sci USA, in press.
(28)Takeda, K., H. Oshina, Y. Hayakawa, H. Akiba, M. Atsuta, T. Kobata, K. Kobayashi, M. Ito, H. Yagita, and K. Okumura. CD27-mediated activation of murine NK cells. J Immunol. 164:1741-5, 2000.
(29)Tsukada, N., H. Akiba, T. Kobata, Y. Aizawa, H. Yagita, and K. Okumura. Blockade of CD134 (OX40)-CD134L interaction ameliorates lethal acute graft-versus-host disease in a murine model of allogeneic bone marrow transplantation. Blood, 95:2434-9, 2000.
(30)Akiba, H., Miyahira, Y., Atsuta, M., Takeda, K., Nohara, C., Futagawa, T., Matsuda, H., Aoki, T., Yagita, H. and Okumura, K. Critical contribution of OX40 ligand to T helper 2 cell type 2 differentiation in experimental leishmeniasis. J. Exp. Med. 191:375-380, 2000.
(31)Sanz, L. M., t. Diaz-Meco, H. Nakano, and J. Moscat. The Atypical PKC-interacting Protein p62 Channels NF-κB Activation by the IL-1/TRAF6 Pathway. EMBO, 19;1576-1586, 2000.
(32)Morio, T., S. H. Hanissian, L. B. Bacharier, H. Teraoka, S. Nonoyama, M. Seki, J. Kondo, H. Nakano, S. K. Lee, R. S. Geha, and J.-I. Yata. Ku in the Cytoplasm Associates with CD40 in Human B Cells and Translocates into the Nucleus Following Incubation with IL-4 and Anti-CD40 mAb. Immunity 11; 339-348, 1999.
(33)Nakano H., S. Sakon, H. Koseki, T. Takemori, K. Tada, M. Matsumoto, E. Munechika, T. Sakai, T. Shirasawa, H. Akiba, T. Kobata, S. M. Santee, C. F. Ware, P. D. Rennert, M. Taniguchi, H. Yagita, and K. Okumura. Targeted Disruption of Traf5 gene Causes Defects in CD40- and CD27-mediated Lymphocyte Activation. Proc. Natl. Acad. Sci. USA 96:9803-9808, 1999.
(34)Jin, D.-Y., V. Giordano, K. V. Kibler, H. Nakano, and K.-T. Jeang. Role of Adapter Function in Oncoprotein-mediated Activation of NF-κB. HUMAN T-CELL LEUKEMIA VIRUS TYPE I Tax INTERACTS DIRECTLY WITH IκB KINASEγ. J. Biol. Chem. 274 17402-17405, 1999.
(35)Kayagaki, N., Yamaguchi, N., Nakayama, M., Takeda, K., Akiba, H., Tsutsui, H., Okamura, H., Nakanishi, K., Okumura, K. and H. Yagita. Expression and Function of TNF-related Apoptosis-Inducing Ligand on Murine Activated NK Cells. J. Immunol. 163:1906-1913, 1999.
(36)Kotani, M., Y. Tagawa, and Y. Iwakura. Involvement of autoimmunity against type II collagen in the development of arthritis in mice transgenic for the human T cell Ieukemia virus type I tax gene. Eur. J. Immunol. 29, 54-64, 1999.
(37)Habu, K., J. Nakayama-Yamada, M. Asano, S. Saijo, K. Itagaki, R. Horai, H. Yamamoto, T. Sekiguchi, T. Nosaka, M. Hatanaka, and Y. Iwakura. The HTLV-I-tax gene is responsible for the development of both inflammatory polyarthropathy resembling rheumatoid arthritis and non-inflammatory ankylotic arthropathy in transgenic mice. J. Immunol., 162, 2956-2963, 1999.
(38)Saijo, S., Kotani, M., Habu, K., Ishitsuka, C., Yamamoto, H., Sekiguchi, T. and. lwakura, Y. Bone marrow derived cells are responsible for the development of autoimmune arthritis in HTLV-I transgenic mice and those of normal mice can suppress the disease. J. Immunol., 1 63, 5700-5707, 1999.
(39)Horai, R., Saijo, S., Tanioka, H., Nakae, S., Sudo, K., Okahara, A., Ikuse, T., Asano, M., and lwakura, Y. Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in IL-1 receptor antagonist-deficient mice. J. Exp, Med., 191 , 313 -320, 2000.
(40)Ozaki, H., Tanaka, J., Yasuda, J., Horai, R., Tagawa, Y., Asano, M., Saijo, S., Imai, M., Sekikawa, K., Kopf, M., and Iwakura, Y. LPS-induced HIV-I expression in transgenic mice is mediated by TNF-α and IL-1, but not by IFN-γ nor IL-6. AIDS, in press
(41)Tsurui. H., Lerner, J. M., Takahashi, K., Hirose, S., Mitsui, K., Okumura, K. and Shirai, T. : Hyperspectral imaging of pathology samples. Proceedings of Three-Dimensional and Multidimensional Microscopy: Image Acquisition and Processing VI. Volume 3605, 273-281, 1999.
(42)Tsurui, H., Nishimura, H., Hattori, S., Hirose, S., Okumura K. and Shirai, T. Seven-color Fluorescence Imaging of Tissue Samples Based on Fourier Spectroscopy and Singular Value Decomposition. J. Histo. Cyto., 48: 653-622, 2000.
(43)Jjang, Y., Hirose, S., Sanokawa-Akakura, R., Abe, M., Mi, X., Li, N., Miura,Y., Shirai, J., Zhang, D., Hamano, Y. and Shirai, T., : Genetically determined aberrant down-regulation of FcγRIIB1 in germinal center B cells associated with hyper-IgG and IgG autoantibodies in murine systemic lupus erythematosus, Int. Immunol. 11, 1685-1691. 1999.
(44)Shirai, J., Ida, A., Jiang, Y., Sanokawa-Akakura, R., Miura, Y., Yan, K., Hamano, Y., Hirose, S. and Shirai, T. : Genetic polymorphism of murine tissue plaminogen activator associated with antiphospholipid syndrome. Genes and Immunity 1, 130-136, 1999.
(45)Ochiai, K., Ozaki, S., Tanino, A., Watanabe, S., Ueno, T., Mitsui, K., Toei, J., Inada, Y., Hirose, S., Shirai, T. and Nishimura, H. : Genetic regulation of anti-erythrocyte autoantibodies and splenomegaly in autoimmune hemolytic anemia-prone New Zealand Black mice. Int. Immunol. 12, 1-8, 2000.
(46)Takumi, T., Y. Nagamine, S. Miyake, C. Matsubara, K. Taguchi, S. Takekida, Y. Sakakida, K. Nishikawa, T. Kishimoto, S. Niwa, K. Okumura and H. Okamura. A mammalian ortholog of Drosophila timeless, highly expressed in SCN and retina, forms a complex with mPER1. Genes Cells, 4, 67-75, 1999.
研究制度
  • 戦略的基礎研究推進事業、研究領域「生体防御のメカニズム」研究代表者 奥村 康(順天堂大学医学部)/科学技術振興事業団
研究報告資料
  • 奥村 康. 生体防御のメカニズム 免疫系と神経・内分泌系の立体的分子機構の解明. 戦略的基礎研究推進事業 平成10年度 研究年報,1999. p.144 - 148.

PAGE TOP