2001 Fiscal Year Annual Research Report

サイトカインの制御異常による自己免疫性慢性関節炎発症機序

Research Project

Project/Area Number	12470076
Research Institution	The University of Tokyo
Principal Investigator	岩倉洋一郎東京大学, 医科学研究所, 教授 (10089120)
Co-Investigator(Kenkyū-buntansha)	須藤カツ子東京大学, 医科学研究所, 助手 (50126091) 宝来玲子東京大学, 医科学研究所, 助手 (20313091)
Keywords	関節リウマチ / 自己免疫疾患 / IL-1 / IL-6 / トランスジェニックマウス / ノックアウトマウス / HTLV-1
Research Abstract	我々は、HTLV-Iのtax遺伝子を導入したトランスジェニックマウス(HTLV-I-Tg)を作製し、このウイルスに慢性関節炎を引き起こす能力があることを示し、さらにtaxが原因遺伝子であることを明らかにした。これらのマウスは関節の病理像だけでなく、自己免疫になっている点や、関節での炎症性サイトカインが亢進している点など、リウマチ患者と良く似た病態を示し、関節リウマチの良いモデルとなっている。本研究では、特にサイトカインの病態形成に関わる役割を検討することを目的とした。まず、関節局所で亢進していたIL-1、IL-6、TNF-αに注目し、HTLV-I-Tgのサイトカイン遺伝子を欠損させたところ、IL-1とIL-6は発症に重要な役割を果たしているが、TNF-αの欠損は関節炎の発症に影響しないことが明らかとなった。またこれに関連し、IL-1レセプターアンタゴニストのノックアウトマウスを作製したところ、このマウスも自己免疫性の関節炎を自然発症することを見いだした。この結果はIL-1のシグナルが過剰に伝わることだけで、関節炎を誘起することが可能であることを示す。また、最近関節炎との関連が注目されているCXCR4や、IL-17などのノックアウトマウスを作製した。今後これらのノックアウトマウスを用いて関節炎との関係を明らかにしていく予定である。

Research Products
(25 results)

All Other

All Publications (25 results)

[Publications] Takeda, K: "Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells"Nature Medicine. 7. 94-100 (2001)
[Publications] Fukamauchi, F: "TAG-1-deficient mice have marked elevation of adenosine A1 receptors in the hippocampus"Biochem.Biphys.Res.Commun. 281. 220-226 (2001)
[Publications] Seino, K: "Requirement for NKT cells in the induction of allograft tolerance"Proc.Natl.Acad.U.S.. 98. 2577-2581 (2001)
[Publications] Ishii, T: "Projection of three subsets of olfactory neurons expressing the odorant receptor transgene and the two cognate endogenous alleles"Genes to Cell. 6. 71-78 (2001)
[Publications] Naruse-Nakajima, C: "Involvement of EphA2 in the formation of the tail notochord via interaction with ephrinA1"Mecha. Develop. 102. 95-105 (2001)
[Publications] Ozaki, H: "Six-4, a putative myogenin gene regulator, is not essential for mouse embryonal development"Mol.Cell.Biol. 21. 3343-3350 (2001)
[Publications] Kotani, N: "Knockout of mouse β1, 4-galactosyltransferase-1 gene results in a dramatic shift of outer chain moieties of N-glycans from type 2 to type 1 chains in hepatic membrane and plasma glycoproteins"Biochem J.. 357. 827-834 (2001)
[Publications] Boutin, H.: "Role of IL-1α and IL-1β in ischaemic brain damage"J.Neuroscience. 21. 5528-5534 (2001)
[Publications] Morita, Y: "Caspase-2 deficiency prevents programmed germ cell death resulting from cytokine insufficiency but not meiotic defects caused by loss of ataxia telangiectasia-mutated (Atm) gene function"Cell Death Differ. 8. 614-620 (2001)
[Publications] Sato, M: "Th1 cytokine-conditioned bone marrow-derived dendritic cells can bypass the requirement for Th functions during the generation of CD8(+ CTL"J.Immunol.. 167. 3687-3691 (2001)
[Publications] Imaizumi, Y: "Increased expression of interleukin-1β in mouse hippocampus after global cerebral ischemia"Acta Histochem. Cytochem.. 34. 357-362 (2001)
[Publications] Dal, J.H.: "Glycyrrhizin enhances interleukin-12 production in peritoneal macrophage"Immunology. 103. 235-243 (2001)
[Publications] Norose, K: "Organ infectivity of Toxoplasma gondii in interferon-γ knockout mice"J. Parasitol. 87. 447-452 (2001)
[Publications] Yoneto, T: "A critical role of Fc receptor-mediated antibody-dependent phagocytosis in the host resistance to blood-stage Plasmodium berghei XAT infection"J.Immunol.. 166. 6236-6241 (2001)
[Publications] Hayakawa, Y: "Critical contribution of INF-gamma and NK cells, but not perforin-mediated cytotoxicity, to anti-metastatic effect of alpha-galactosylceramide"Eur J Immunol.. 31. 1720-1727 (2001)
[Publications] Shibata, S: "Cloning of a novel 2', 5'-oligoadenylate synthetase-like molecule, Oasl5 in mice"Gene. 271. 261-271 (2001)
[Publications] Nakae, S: "IL-1 enhances T cell-dependent antibody production through induction of CD40L and OX40 on T cells"J.Immunol.. 167. 90-97 (2001)
[Publications] Yasuda, J: "T cell apoptosis causes peripheral T cell depletion in mice transgenic for the HIV-1 vpr"Virology. 285. 181-192 (2001)
[Publications] Miura, T.: "Effect of 6-Hydroxydopamine on host resistance against Listeria monocytogenes infection. Infect"Infect Immun.. 69. 7234-7241 (2001)
[Publications] Le Feuvre, R.A: "Priming of macrophages with LPS potentiates P2X7 mediated cell death via a caspase-1 dependent mechanism, independently of cytokine production"J.Biol.Chem. (2001)
[Publications] Nakae, S: "IL-1α, but not IL-1β, is required for contact-allergen-specific T cell activation during the sensitization phase in contact hypersensitivity"Int.Immunol.. 13. 1471-1478 (2001)
[Publications] Kyuwa, S.: "The severity of hepatic lesion after intraperitoneal JHMV infection in IFN-gamma deficient mice is parallel to viral replication in hepatocytes in vitro"Adv Exp Med Biol.. 494. 95-99 (2001)
[Publications] Moshkin, M.P.: "Social behavior in male mice deficient in genes for interleukin-1"Med.Immunolo.. 3. 449-457 (2001)
[Publications] Yokoyama, H.: "Pathological changes of renal epithelial cells in mice transgenic for the TT virus ORF1 gene"J.Gen.Virol.. 83. 141-150 (2002)
[Publications] Saijo, S.: "Suppression of autoimmune arthritis in IL-1-deficient mice in which T cell activation is impaired due to low levels of CD40L and OX40 expression on T cells"Arth.Rheum.. 46. 533-544 (2002)

2001 Fiscal Year Annual Research Report

サイトカインの制御異常による自己免疫性慢性関節炎発症機序

Principal Investigator

岩倉 洋一郎 東京大学, 医科学研究所, 教授 (10089120)

Research Products

[Publications] Takeda, K: "Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells"Nature Medicine. 7. 94-100 (2001)

[Publications] Fukamauchi, F: "TAG-1-deficient mice have marked elevation of adenosine A1 receptors in the hippocampus"Biochem.Biphys.Res.Commun. 281. 220-226 (2001)

[Publications] Seino, K: "Requirement for NKT cells in the induction of allograft tolerance"Proc.Natl.Acad.U.S.. 98. 2577-2581 (2001)

[Publications] Ishii, T: "Projection of three subsets of olfactory neurons expressing the odorant receptor transgene and the two cognate endogenous alleles"Genes to Cell. 6. 71-78 (2001)

[Publications] Naruse-Nakajima, C: "Involvement of EphA2 in the formation of the tail notochord via interaction with ephrinA1"Mecha. Develop. 102. 95-105 (2001)

[Publications] Ozaki, H: "Six-4, a putative myogenin gene regulator, is not essential for mouse embryonal development"Mol.Cell.Biol. 21. 3343-3350 (2001)

[Publications] Kotani, N: "Knockout of mouse β1, 4-galactosyltransferase-1 gene results in a dramatic shift of outer chain moieties of N-glycans from type 2 to type 1 chains in hepatic membrane and plasma glycoproteins"Biochem J.. 357. 827-834 (2001)

[Publications] Boutin, H.: "Role of IL-1α and IL-1β in ischaemic brain damage"J.Neuroscience. 21. 5528-5534 (2001)

[Publications] Morita, Y: "Caspase-2 deficiency prevents programmed germ cell death resulting from cytokine insufficiency but not meiotic defects caused by loss of ataxia telangiectasia-mutated (Atm) gene function"Cell Death Differ. 8. 614-620 (2001)

[Publications] Sato, M: "Th1 cytokine-conditioned bone marrow-derived dendritic cells can bypass the requirement for Th functions during the generation of CD8(+ CTL"J.Immunol.. 167. 3687-3691 (2001)

[Publications] Imaizumi, Y: "Increased expression of interleukin-1β in mouse hippocampus after global cerebral ischemia"Acta Histochem. Cytochem.. 34. 357-362 (2001)

[Publications] Dal, J.H.: "Glycyrrhizin enhances interleukin-12 production in peritoneal macrophage"Immunology. 103. 235-243 (2001)

[Publications] Norose, K: "Organ infectivity of Toxoplasma gondii in interferon-γ knockout mice"J. Parasitol. 87. 447-452 (2001)

[Publications] Yoneto, T: "A critical role of Fc receptor-mediated antibody-dependent phagocytosis in the host resistance to blood-stage Plasmodium berghei XAT infection"J.Immunol.. 166. 6236-6241 (2001)

[Publications] Hayakawa, Y: "Critical contribution of INF-gamma and NK cells, but not perforin-mediated cytotoxicity, to anti-metastatic effect of alpha-galactosylceramide"Eur J Immunol.. 31. 1720-1727 (2001)

[Publications] Shibata, S: "Cloning of a novel 2', 5'-oligoadenylate synthetase-like molecule, Oasl5 in mice"Gene. 271. 261-271 (2001)

[Publications] Nakae, S: "IL-1 enhances T cell-dependent antibody production through induction of CD40L and OX40 on T cells"J.Immunol.. 167. 90-97 (2001)

[Publications] Yasuda, J: "T cell apoptosis causes peripheral T cell depletion in mice transgenic for the HIV-1 vpr"Virology. 285. 181-192 (2001)

[Publications] Miura, T.: "Effect of 6-Hydroxydopamine on host resistance against Listeria monocytogenes infection. Infect"Infect Immun.. 69. 7234-7241 (2001)

[Publications] Le Feuvre, R.A: "Priming of macrophages with LPS potentiates P2X7 mediated cell death via a caspase-1 dependent mechanism, independently of cytokine production"J.Biol.Chem. (2001)

[Publications] Nakae, S: "IL-1α, but not IL-1β, is required for contact-allergen-specific T cell activation during the sensitization phase in contact hypersensitivity"Int.Immunol.. 13. 1471-1478 (2001)

[Publications] Kyuwa, S.: "The severity of hepatic lesion after intraperitoneal JHMV infection in IFN-gamma deficient mice is parallel to viral replication in hepatocytes in vitro"Adv Exp Med Biol.. 494. 95-99 (2001)

[Publications] Moshkin, M.P.: "Social behavior in male mice deficient in genes for interleukin-1"Med.Immunolo.. 3. 449-457 (2001)

[Publications] Yokoyama, H.: "Pathological changes of renal epithelial cells in mice transgenic for the TT virus ORF1 gene"J.Gen.Virol.. 83. 141-150 (2002)

[Publications] Saijo, S.: "Suppression of autoimmune arthritis in IL-1-deficient mice in which T cell activation is impaired due to low levels of CD40L and OX40 expression on T cells"Arth.Rheum.. 46. 533-544 (2002)

岩倉洋一郎東京大学, 医科学研究所, 教授 (10089120)