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

• 研究課題/領域番号: 12470076
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 免疫学
• 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: 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)
• 研究期間 (年度): 2000 – 2002
• 研究課題ステータス: 完了 (2002年度)
• 配分額: 14,100千円 (直接経費: 14,100千円); 2002年度: 4,000千円 (直接経費: 4,000千円); 2001年度: 4,000千円 (直接経費: 4,000千円); 2000年度: 6,100千円 (直接経費: 6,100千円)
• キーワード: 関節リウマチ / モデルマウス / IL-1 / HTLV-I / IL-6 / TNF-α / IL-17 / IL-IRアンタゴニスト / 自己免疫疾患 / トランスジェニックマウス / ノックアウトマウス / HTLV-1

研究概要

我々はこれまでに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マウス)、およびIL-1Ra欠損(KO)マウスを作製し、これらのマウスが共に自己免疫性の関節炎を自然発症することを見いだした。これまでの解析から、これらのマウスの関節炎の発症にはT細胞に依存した自己免疫が関与することを明らかにしてきた。本研究では特にサイトカインの病態形成における役割を検討することを目的とした。これまでの研究ではHTLV-I-Tgの場合はIL-1やIL-6などのサイトカインを欠損させると発症が抑制され、一方、IL-1Ra-KOマウスの場合はTNFαを欠損させることにより、発症を抑制できることを示した。ところで、IL-17は他の炎症性サイトカインとは異なり、主に活性化CD4T細胞を産生細胞とし、種々のケモカインや他のサイトカインを誘導することが知られる。さらに、関節リウマチ患者の病変部位でも検出され疾患との関連が示唆されていた。そこで、IL-17の関節炎発症における役割を明らかにする目的で、KOマウスを作製した。その結果、IL-1RaKOマウスではIL-17を欠損させることにより関節炎発症は完全に抑制された。またコラーゲン誘導関節炎の発症も強く抑えることが明かとなった。

研究成果

• [文献書誌] Nakae, S.: "IL-1-induced TNE elicits inflammatory cell infiltration in the skin by inducing interferon-g-inducible protein-10 in the elicitation phase of CHS"Int. Immunol.. 15. 251-260 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Nakae, S.: "Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, resulting in the suppression of allergic cellular and humoral responses"Immunity. 17. 375-387 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [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. USA. 100. 5986-5990 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Iwakura, Y.: "Roles of IL-1 in the development of rheumatoid arthritis : Consideration from mouse models"Cytokine Growth Factor Rev.. 13. 341-355 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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 cell"Arth. Rheum.. 13. 533-544 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Iwakura, Y.: "Autoimmune chronic inflammatory arthropathy in mice transgenic for the HTLV-I tax gene"Gann Monograph. (in press). (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Nakae, S., Komiyama, Y., Narumi, S., Sudo, K., Horai, R., Tagawa, Y., Sekikawa, K., Matsushima, K., Asano, M., and Iwakura. Y.: "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 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nakae, S., Komiyama, K., Yokoyama, H., Nambu, A., Umeda, M., Iwase, M., Homma, I., Sudo, K., Horai, R., Asano, M. and Iwakura. Y.: "Interleukin-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response"Int. Immunol.. 15. 483-490 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nakae, S., Komiyama, Y., Nambu, A., Sudo, K., Iwase, M., Homma, I., Sekikawa, K., Asano, M., and Iwakura, Y.: "Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, resulting in the suppression of allergic cellular and humoral responses"Immunity. 17. 375-387 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nakae, S., Saijo, S., Horai, R., Sudo, K., Mori, S., and Iwakura, Y.: "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 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Iwakura, Y.: "Roles of IL-1 in the development of rheumatoid arthritis : Consideration from mouse models"Cytokine Growth Factor Rev.. 13. 341-355 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Saijo, S., Asano, M., Horai, R., Yamamoto, H., and Iwakura. Y.: "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)
  • 説明: 「研究成果報告書概要(欧文)」より
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• [文献書誌] Morita,Y.: "Caspase-2 deficiency rescues female germ cells from death due to cytokine insufficiency but not meiotic defects caused by Ataxia Telangiectasia-mutated (Atm) gene inactivation."Endocrinology. (in press).
• [文献書誌] Ishii,T.: "Projection of three subsets of olfactory neurons expressing the odorant receptor transgene and the two cognate endogenous alleles."Genes to Cells.. (in press).
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• [文献書誌] Naruse-Nakajima,C.: "Involvement of EphA2 in the formation of the tail notochord via interaction with ephrinA1."Mechanisms of Development.. (in press).
• [文献書誌] Yoneto,T.: "A critical role of Fc receptor-mediated antibody-dependent phagocytosis in the host resistance to blood-stage plasmodium berghei XAT infecion."J.Immunol.. (in press).