2003 年度実績報告書

慢性関節リウマチの遺伝的要因の解析

研究課題

研究課題/領域番号	15012211
研究機関	東京大学
研究代表者	岩倉洋一郎東京大学, 医科学研究所, 教授 (10089120)
研究分担者	角田茂東京大学, 医科学研究所, 助手 (80345032) 須藤カツ子東京大学, 医科学研究所, 助手 (50126091) 保田尚孝東京大学, 医科学研究所, 講師 (90323641)
キーワード	ゲノム / マイクロアレイ / 免疫学 / 関節リウマチ / 連鎖解析 / トランスジェニックマウス / ノックアウトマウス / IL-1
研究概要	我々はこれまでにHTLV-Iトランスジェニックマウス(HTLV-I-Tg)とIL-1Ra欠損マウス(IL-1RaKO)マウスの2種類の関節リウマチモデルを作製した。何れのモデルでも発症には自己免疫が関与しており、サイトカインが重要な役割を果たしていたが、HTLV-I-Tgの発症はIL-6に依存し、TNF-αには依存しないのに対し、IL-1RaKOは逆にTNF-αに依存しIL-6には依存しなかった。関節リウマチ患者にも抗TNF-α抗体治療や抗IL-6R治療に耐性を示す患者がおり、両者のモデルになると考えちれる。一方、マウスの遺伝的背景が発症率に影響を及ぼすことを見いだした。そこで、本研究では、これらの基盤に立ち、(1)系統間で関節炎発症感受性を決定している遺伝子の同定、(2)新規関節炎発症原因遺伝子の同定を目的とした。その結果、系統間感受性を決定している遺伝子に関しては2本の染色体に連鎖を見いだした。また、マイクロアレイを用いた網羅的解析の結果、発症時には548の遺伝子が有意に発現変動をしていることを見いだし、その内2遺伝子については既にKOマウスを作製した。

研究成果

(38件)

すべてその他

すべて文献書誌 (38件)

[文献書誌] Li, Y.: "IL-18 gene therapy develops Th1-type immune responses in Leishmania major-infected BALB/c mice : is the effect mediated by the CpG signaling TLR9?"Gene Ther.. (in press). (2004)
[文献書誌] Kobari, Y.: "T cells accumulating in the inflamed joints of a spontaneous murine model of rheumatoid arthritis become restricted to common clonotypes during disease progression."Int.Immunol.. 16. 131-138 (2004)
[文献書誌] Ozaki, H.: "Six1 controls patterning of the mouse otic vesicle."Development. 131. 551-562 (2004)
[文献書誌] Ishida, Y.: "The Essential Involvement of Cross-Talk between IFN-γ and TGF-β in the Skin Wound-Healing Process."J.Immunol.. 172. 1848-1855 (2004)
[文献書誌] Kurohara, K.: "Essential roles of Meltrin β (ADAM19) in heart development."Dev.Biol.. 267. 14-28 (2004)
[文献書誌] Ishihara, K.: "The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTL-V-I pX in promoting rheumatoid arthritis-like arthritis."Int.Immunol.. 16. 455-465 (2004)
[文献書誌] Ishida, Y.: "Essential Involvement of IFN-γ in Clostridium difficile Toxin A-induced Enteritis."J.Immunol.. 172. 3018-3925 (2004)
[文献書誌] Nakaya, T.A.: "Panax ginseng Induces Production of Proinflammatory Cytokines via Toll-like Receptor."J.Inerferon Cytokine Res.. 24. 93-100 (2004)
[文献書誌] Ikegaya, Y.: "Interleukin-1 β abrogates long-term depression of hippocampal CA1 synaptic transmission."Synapse. 47. 54-57 (2003)
[文献書誌] Kurisaki, T.: "Phenotypic analysis of Meltrinα (ADAM12)-deficient mice : involvement of Meltrin a in adipogenesis and myogenesis."Mol.Cell.Riot.. 23. 55-61 (2003)
[文献書誌] Sashinami, H.: "Effective Induction of Acquired Resistance to Lisferia monocyto genes by Immunizing Mice with In Vivo-Infected Dendritic Cells."Infect.Immun.. 71. 117-125 (2003)
[文献書誌] Nakae, S.: "IL-1-induced TNFα elicits inflammatory cell infiltration in the skin by inducing interferon-γ-inducible protein-10 in the elicitation phase of contact hypersensitivity response."Int.Immunol.. 15. 251-260 (2003)
[文献書誌] Tanaka, J.: "Latent HLV-1 reactivation in transgenic mice requires cell cycle-dependent demethylation of CREB/ATF sites in the LTR."AIDS. 24. 167-175 (2003)
[文献書誌] Li, H.: "Aberrant responses to acoustic stimuli in mice deficient for neural recognition molecule NB-2."Eur.J.Neurosci.. 17. 483-490 (2003)
[文献書誌] Ohtaki, H.: "Suppression of oxidative neuronal damage after transient middle cerebral artery occlusion in mice lacking interleukin-1."Neuroscience Res.. 45. 313-324 (2003)
[文献書誌] Nakae, S.: "Interleukin-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response."Int Immunol.. 15. 483-490 (2003)
[文献書誌] Voronoy, B.: "Interleukin 1 is required for tumor invasiveness and angiogenesis."Proc.Natl.Acad.Sd.USA. 100. 2645-2650 (2003)
[文献書誌] Kirii, H.: "Lack of interleukin-1 β decreases the severity of atherosclerosis in apolipoprotein E-deficient mice."Arterioscler.Thromb.Vasc.Blol.. 23. 656-660 (2003)
[文献書誌] Kyuwa, S.: "Differences between BALB/c and C57BL/6 mice in mouse hepatitis virus replication in primary hepatocyte culture."Exp.Anim.. 52. 81-84 (2003)
[文献書誌] Nakae, S.: "IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist."Proc.Natl.Acad.Sci.USA. 100. 5986-5990 (2003)
[文献書誌] Asano, M.: "Impaired selectin ligand biosynthesis and reduced inflammatory responses in β-1,4-galactosyltransferase-I-deflcient mice."Blood. 102. 1678-1685 (2003)
[文献書誌] Wheeler, R.D.: "Interleukin-18 induces expression and release of cytokines from murine glial cells : interactions with interleukin-1β."J.Neurochem.. 85. 1412-1420 (2003)
[文献書誌] Isoda, K.: "Deficiency of interleukin-1 receptor antagonist promotes neointimal formation after injury."Circulation. 108. 516-518 (2003)
[文献書誌] Miyake-Nishijima, R.: "Role of Crk-associated substrate lymphocyte type in the pathophysiology of the rheumatoid arthritis in tax transgenic mice and in humans."Arthritis Rheum.. 48. 1890-1900 (2003)
[文献書誌] Takeda, Y.: "Impaired motor coordination in mice lacking neural recognition molecule NB-3 of the contaction/F3 subgroup."J.Neurobiol.. 56. 252-265 (2003)
[文献書誌] Matsuki, T.: "IL-1 plays an important role in lipid metabolism by regulating insulin levels under physiological conditions."J.Exp.Med.. 198. 877-888 (2003)
[文献書誌] Mun, HS.: "Pathogenicity of Toxoplasma gondii through B-2 cell-mediated downregulation of host defense responses."Microbiol.Iminunol.. 47. 533-542 (2003)
[文献書誌] Traka, M.: "Association of Tag-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers."J.Cell.Biol. 162. 1161-1172 (2003)
[文献書誌] Kariyone, A.: "Immunogenicity of Peptide-25 of Ag85B in Th1 development : role of IFN-γ."Int.Immunol.. 15. 1183-1194 (2003)
[文献書誌] Norose, K.: "IFN- γ -Regulated Toxoplasma gondii Distribution and Load in the Murine Eye."Invest.Ophthalmol.Vis.Sci.. 44. 4375-4381 (2003)
[文献書誌] Nakae, S.: "Suppression of immune induction of collagen-induced arthritis in IL-17- deficient mice."J.Immunol.. 171. 6173-6177 (2003)
[文献書誌] Ohtaki, H.: "Suppression of oxidative stress after transient faocal ischemia in interleukin-1 knocknout mice."Acta Neurochir.Suppl.. 86. 191-194 (2003)
[文献書誌] Iwakura, Y.: "Autoimmune chronic inflammatory arthropathy in mice transgenic for the HTLV-I tax gene."Gann Monograph on Cancer Res.. 50. 95-109 (2003)
[文献書誌] 西城忍: "自然免疫と関節炎"医学のあゆみ. 205. 92-96 (2003)
[文献書誌] 角田茂: "トランスジェニックマウスとノックアウトマウスの作製法の最近の進歩"生物工学会誌. 81. 345-357 (2003)
[文献書誌] 岩倉洋一郎: "炎症、アレルギー病態におけるIL-17の役割"Molecular Medicinc(臨時増刊号)免疫2004. 40. 252-258 (2003)
[文献書誌] Nakae, S.: "Cytokine Knockouts"Humana Press. 15 (2003)
[文献書誌] 安田二朗: "改訂第4版新遺伝子工学ハンドブック(松村正實,山本雅編集)実験医学別冊"羊土社. 18 (2003)

2003 年度 実績報告書

慢性関節リウマチの遺伝的要因の解析

研究代表者

岩倉 洋一郎 東京大学, 医科学研究所, 教授 (10089120)

研究成果

[文献書誌] Li, Y.: "IL-18 gene therapy develops Th1-type immune responses in Leishmania major-infected BALB/c mice : is the effect mediated by the CpG signaling TLR9?"Gene Ther.. (in press). (2004)

[文献書誌] Kobari, Y.: "T cells accumulating in the inflamed joints of a spontaneous murine model of rheumatoid arthritis become restricted to common clonotypes during disease progression."Int.Immunol.. 16. 131-138 (2004)

[文献書誌] Ozaki, H.: "Six1 controls patterning of the mouse otic vesicle."Development. 131. 551-562 (2004)

[文献書誌] Ishida, Y.: "The Essential Involvement of Cross-Talk between IFN-γ and TGF-β in the Skin Wound-Healing Process."J.Immunol.. 172. 1848-1855 (2004)

[文献書誌] Kurohara, K.: "Essential roles of Meltrin β (ADAM19) in heart development."Dev.Biol.. 267. 14-28 (2004)

[文献書誌] Ishihara, K.: "The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTL-V-I pX in promoting rheumatoid arthritis-like arthritis."Int.Immunol.. 16. 455-465 (2004)

[文献書誌] Ishida, Y.: "Essential Involvement of IFN-γ in Clostridium difficile Toxin A-induced Enteritis."J.Immunol.. 172. 3018-3925 (2004)

[文献書誌] Nakaya, T.A.: "Panax ginseng Induces Production of Proinflammatory Cytokines via Toll-like Receptor."J.Inerferon Cytokine Res.. 24. 93-100 (2004)

[文献書誌] Ikegaya, Y.: "Interleukin-1 β abrogates long-term depression of hippocampal CA1 synaptic transmission."Synapse. 47. 54-57 (2003)

[文献書誌] Kurisaki, T.: "Phenotypic analysis of Meltrinα (ADAM12)-deficient mice : involvement of Meltrin a in adipogenesis and myogenesis."Mol.Cell.Riot.. 23. 55-61 (2003)

[文献書誌] Sashinami, H.: "Effective Induction of Acquired Resistance to Lisferia monocyto genes by Immunizing Mice with In Vivo-Infected Dendritic Cells."Infect.Immun.. 71. 117-125 (2003)

[文献書誌] Nakae, S.: "IL-1-induced TNFα elicits inflammatory cell infiltration in the skin by inducing interferon-γ-inducible protein-10 in the elicitation phase of contact hypersensitivity response."Int.Immunol.. 15. 251-260 (2003)

[文献書誌] Tanaka, J.: "Latent HLV-1 reactivation in transgenic mice requires cell cycle-dependent demethylation of CREB/ATF sites in the LTR."AIDS. 24. 167-175 (2003)

[文献書誌] Li, H.: "Aberrant responses to acoustic stimuli in mice deficient for neural recognition molecule NB-2."Eur.J.Neurosci.. 17. 483-490 (2003)

[文献書誌] Ohtaki, H.: "Suppression of oxidative neuronal damage after transient middle cerebral artery occlusion in mice lacking interleukin-1."Neuroscience Res.. 45. 313-324 (2003)

[文献書誌] Nakae, S.: "Interleukin-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response."Int Immunol.. 15. 483-490 (2003)

[文献書誌] Voronoy, B.: "Interleukin 1 is required for tumor invasiveness and angiogenesis."Proc.Natl.Acad.Sd.USA. 100. 2645-2650 (2003)

[文献書誌] Kirii, H.: "Lack of interleukin-1 β decreases the severity of atherosclerosis in apolipoprotein E-deficient mice."Arterioscler.Thromb.Vasc.Blol.. 23. 656-660 (2003)

[文献書誌] Kyuwa, S.: "Differences between BALB/c and C57BL/6 mice in mouse hepatitis virus replication in primary hepatocyte culture."Exp.Anim.. 52. 81-84 (2003)

[文献書誌] Nakae, S.: "IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist."Proc.Natl.Acad.Sci.USA. 100. 5986-5990 (2003)

[文献書誌] Asano, M.: "Impaired selectin ligand biosynthesis and reduced inflammatory responses in β-1,4-galactosyltransferase-I-deflcient mice."Blood. 102. 1678-1685 (2003)

[文献書誌] Wheeler, R.D.: "Interleukin-18 induces expression and release of cytokines from murine glial cells : interactions with interleukin-1β."J.Neurochem.. 85. 1412-1420 (2003)

[文献書誌] Isoda, K.: "Deficiency of interleukin-1 receptor antagonist promotes neointimal formation after injury."Circulation. 108. 516-518 (2003)

[文献書誌] Miyake-Nishijima, R.: "Role of Crk-associated substrate lymphocyte type in the pathophysiology of the rheumatoid arthritis in tax transgenic mice and in humans."Arthritis Rheum.. 48. 1890-1900 (2003)

[文献書誌] Takeda, Y.: "Impaired motor coordination in mice lacking neural recognition molecule NB-3 of the contaction/F3 subgroup."J.Neurobiol.. 56. 252-265 (2003)

[文献書誌] Matsuki, T.: "IL-1 plays an important role in lipid metabolism by regulating insulin levels under physiological conditions."J.Exp.Med.. 198. 877-888 (2003)

[文献書誌] Mun, HS.: "Pathogenicity of Toxoplasma gondii through B-2 cell-mediated downregulation of host defense responses."Microbiol.Iminunol.. 47. 533-542 (2003)

[文献書誌] Traka, M.: "Association of Tag-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers."J.Cell.Biol. 162. 1161-1172 (2003)

[文献書誌] Kariyone, A.: "Immunogenicity of Peptide-25 of Ag85B in Th1 development : role of IFN-γ."Int.Immunol.. 15. 1183-1194 (2003)

[文献書誌] Norose, K.: "IFN- γ -Regulated Toxoplasma gondii Distribution and Load in the Murine Eye."Invest.Ophthalmol.Vis.Sci.. 44. 4375-4381 (2003)

[文献書誌] Nakae, S.: "Suppression of immune induction of collagen-induced arthritis in IL-17- deficient mice."J.Immunol.. 171. 6173-6177 (2003)

[文献書誌] Ohtaki, H.: "Suppression of oxidative stress after transient faocal ischemia in interleukin-1 knocknout mice."Acta Neurochir.Suppl.. 86. 191-194 (2003)

[文献書誌] Iwakura, Y.: "Autoimmune chronic inflammatory arthropathy in mice transgenic for the HTLV-I tax gene."Gann Monograph on Cancer Res.. 50. 95-109 (2003)

[文献書誌] 西城忍: "自然免疫と関節炎"医学のあゆみ. 205. 92-96 (2003)

[文献書誌] 角田茂: "トランスジェニックマウスとノックアウトマウスの作製法の最近の進歩"生物工学会誌. 81. 345-357 (2003)

[文献書誌] 岩倉洋一郎: "炎症、アレルギー病態におけるIL-17の役割"Molecular Medicinc(臨時増刊号)免疫2004. 40. 252-258 (2003)

[文献書誌] Nakae, S.: "Cytokine Knockouts"Humana Press. 15 (2003)

[文献書誌] 安田二朗: "改訂第4版 新 遺伝子工学ハンドブック(松村正實,山本雅 編集)実験医学別冊"羊土社. 18 (2003)

2003 年度実績報告書

岩倉洋一郎東京大学, 医科学研究所, 教授 (10089120)

[文献書誌] 安田二朗: "改訂第4版新遺伝子工学ハンドブック(松村正實,山本雅編集)実験医学別冊"羊土社. 18 (2003)