2002 Fiscal Year Annual Research Report

HTLV-Iによる自己免疫性慢性関節炎発症機構の解明

Research Project

Project/Area Number	14021022
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) 保田尚孝東京大学, 医科学研究所, 講師 (90323641)
Keywords	HTLV-I / IL-1Rアンタゴニスト / 関節リウマチ / 自己免疫 / トランスジェニックマウス / ノックアウトマウス / IL-1 / IL-6
Research Abstract	我々はHTLV-I遺伝子を導入したTgマウス(HTLV-I-Tg)を作製し、このウイルスが関節リウマチに良く似た自己免疫性の関節炎を引き起こすことを見いだした。また、この関節炎の発症にはIL-1やIL-6などのサイトカインの過剰発現が重要な役割を果たしていることを示し、さらにIL-1レセプターアンタゴニスト(IL-1Ra)KOマウスも同様の自己免疫性の慢性関節炎になることを示した。IL-1やIL-6を欠損させたHTLV-I-Tgマウスでは自己抗体の産生低下が観察されるとともに、自己抗原に対するT細胞の増殖性の低下が観察された。その原因を明らかにする目的で、T細胞表面上の副シグナル分子の発現を調べたところ、CD40LやOX40の発現が低下していることが明かとなり、HTLV-I-Tgマウスのの関節炎発症にはサイトカインを介したT細胞の活性化が重要な役割を果たしていることが示された。また、マイクロアレイを用いてHTLV-I-TgとIL-1RaKOマウスの関節で発現亢進している遺伝子を検索した結果、両モデルマウスでの遺伝子発現には強い相関が見られた。HTLV-I-Tgで特異的に発現の亢進している遺伝子に注目したところ、機能未知の4遺伝子を含む14遺伝子が同定された。

Research Products

(51 results)

All Other

All Publications (51 results)

[Publications] Voronov, E.: "Interleukin 1 is required for tumor invasiveness and angiogenesis"Proc. Natl. Acad. Sci. USA. (in press). (2003)
[Publications] Nakae, S.: "Interleukin-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response"Int. Immunol.. (in press). (2003)
[Publications] Ohtaki, H.: "Suppression of oxidative neuronal damage after transient middle cerebral artery occlusion in mice lacking interleukin-1"Neuroscience Res.. (in press). (2003)
[Publications] Sashinami, H.: "Effective induction of acquired resistance to Listeria monocytogenes by immunizing mice with in vivo-infected dendritic cells"Infect. Immun.. 71. 117-125 (2003)
[Publications] Li, H.: "Aberrant responses to acoustic stimuli in mice deficient for neural recognition molecule NB-2. Aberrant responses to acoustic stimuli in mice deficient for neural recognition molecule NB-2"Eur. J. Neurosci.. (in press). (2003)
[Publications] Tanaka, J.: "Latent HIV-1 reactivation in transgenic mice requires cell cycle-dependent demethylation of CREB/ATF sites in the LTR"AIDS. 17. 167-175 (2003)
[Publications] Iwakura, Y.: "Autoimmune chronic inflammatory arthropathy in mice transgenic for the HTLV-I tax gene"Gann Monograph. (in press). (2003)
[Publications] 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)
[Publications] Ikegaya. Y.: "Interleukin-1β abrogates long-term depression of hippocampal CA1 synaptic transmission"Synapse. 47. 54-57 (2003)
[Publications] Kurisaki, T.: "Phenotypic analysis of Meltrin α (ADAM12)-deficient mice : involvement of Meltrin α in adipogenesis and myogenesis"Mol. Cell. Biol.. 23. 55-61 (2003)
[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] Yano, A.: "Roles of IFN-γ on stage conversion of an obligate intracellular protozoan parasite, Toxoplasma gondii"Int. Rev. Immunol.. 21. 405-421 (2002)
[Publications] Desaki, M.: "Role of interferon-γ in the development of murine bronchus-associated lymphoid tissues induced by silica in vivo"Toxicol. Appl. Pharmacol.. 185. 1-7 (2002)
[Publications] Yoshida, M.: "Differential localization of colitogenic Th1 and Th2 cells monospecific to a microflora-associated antigen in mice"Gastroenterology. 123. 1949-1961 (2002)
[Publications] Oguri, S.: "Primary role of interleukin-1α and Interleukin-1β in lipopolysaccharide-induced hypoglycemia in mice"Clin. Diagn. Lab. Immunol.. 9. 1307-1312 (2002)
[Publications] Kakuta, S.: "Genomic structure of the mouse 2',5'-oligoadenylate synthetase gene family"J. Interferon Cytokine Res.. 22. 981-993 (2002)
[Publications] Sakamaki, K.: "Ex vivo whole-embryo culture of caspase-8-deficient embryos normalize their aberrant phenotypes in the developing neural tube and heart"Cell Death and Differentiation. 11. 1196-1206 (2002)
[Publications] 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)
[Publications] Yan, X.: "Antibacterial effect of Kampo herbal formulation Hochu-ekki-to (Bu-Zhong-Yi-Qi-Tang) on Helicobacter pylori infection in mice"Microbiol. Immunol.. 46. 475-482 (2002)
[Publications] Iwakura, Y.: "Roles of IL-1 in the development of rheumatoid arthritis : Consideration from mouse models"Cytokine Growth Factor Rev.. 13. 341-355 (2002)
[Publications] Mizuki, M.: "Comparison of host resistance to primary and secondary Listeriamonocytogenes infections in mice by intranasal and intravenous routes"Infect. Immun.. 70. 4805-4811 (2002)
[Publications] Shiraishi, K.: "Roles of RecJ, RecO, and RecR in RecET-mediated illegitimate recombination in Escherichia coli"J. Bacteriol.. 184. 4715-4721 (2002)
[Publications] Minami, M.: "Role of IFN-γ and tumor necrosis factor-α in herpes simplex virus type 1 infection"J. Interferon Cytokine Res.. 22. 671-676 (2002)
[Publications] Ishida, Y.: "A pivotal involvement of IFN-γ in the pathogenesis of acetaminophen-induced acute liver injury"FASEB J.. 16. 1227-1236 (2002)
[Publications] Konishi, H.: "IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions"Proc. Natl. Acad. Sci. USA. 99. 11340-11345 (2002)
[Publications] Sasaki, S.: "Roles of gamma interferon and tumor necrosis factor-alpha in shiga toxin lethality"Microb. Pathog.. 33. 43-47 (2002)
[Publications] Nagai, Y.: "Essential role of MD-2 in LPS responsiveness and TLR4 distribution"Nat. Immunol.. 3. 667-672 (2002)
[Publications] Yamamoto, S.: "Mice deficient in nervous system-specific carbohydrate epitope HNK-1 exhibit impaired synaptic plasticity and spatial learning"J. Biol. Chem.. 277. 27227-27231 (2002)
[Publications] Mizushima, H.: "Reduced postischemic apoptosis in the hippocampus of mice deficient in interleukin-1"J. comparative Neurol.. 448. 203-216 (2002)
[Publications] Asada, H.: "Significant antitumor effects obtained by autologous tumor cell vaccine engineered to secrete interleukin(IL)-12 and IL-18 by means of the EBV/lipoplex"Molec. Therapy. 5. 609-616 (2002)
[Publications] Oguro, T.: "Involvement of tumor necrosis factorα、rather than interleukin-1 or nitric oxides in the HEME Oxygenase-1 gene expression by lipopolysaccharide in the mouse liver"FEBS Letters. 516. 63-66 (2002)
[Publications] Battsetseg, B.: "Immune responses of interferon γ (IFN-γ) knock out mice to repeated Haemaphysalis longicomis (Acari : Ixodidae) nymph infestations"J. Med. Entomol.. 39. 173-176 (2002)
[Publications] Asahi, Y.: "Protection against influenza virus infection in polymeric Ig receptor knockout mice immunized intranasally with adjuvant-combined vaccines"J. Immunol.. 168. 2930-2938 (2002)
[Publications] Furuzawa, M.: "Diurnal variation of heart rate, locomotor activity, and body temperature in interleukin-1 α/β doubly deficient mice"Exp. Anim.. 51. 49-56 (2002)
[Publications] Shinozawa, Y.: "Role of interferon-gamma in inflammatory responses in murine respiratory infection with Legionella pneumophila"J. Med. Microbiol.. 51. 225-230 (2002)
[Publications] Kyuwa, S.: "Acute hepatic failure in IFN-γ-deficient BALB/c mice after murine coronavirus infection"Virus Research. 83. 169-177 (2002)
[Publications] Nagai, Y.: "Requirement for MD-1 in cell surface expression of RP105/CD180 and B-cell responsiveness to lipopolysaccharide"Blood. 99. 1699-1705 (2002)
[Publications] Brough, D.: "Purinergic (P2X7) receptor activation of microglia induces cell death via an interleukin-1-independent mechanism"Mol. Cell. Neurosci.. 19. 272-280 (2002)
[Publications] Kakuta, S.: "Inhibition of B16 melanoma experimental metastasis by interferon-γ through direct inhibition of cell proliferation and activation of antitumour host mechanisms"Immunology. 105. 92-100 (2002)
[Publications] Saijo, S.: "Suppression of autoimmune arthritis in IL-4-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)
[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.. 277. 3210-3218 (2002)
[Publications] 岩倉洋一郎: "関節リウマチモデルマウス"医学のあゆみ. (印刷中). (2003)
[Publications] 岩倉洋一郎: "関節リウマチモデルマウスと創薬への応用"日本薬理学雑誌. 120. 303-313 (2002)
[Publications] 中江進: "接触型過敏症におけるサイトカインの役割"臨床免疫. 38. 171-178 (2002)
[Publications] 岩倉洋一郎: "IL-1の過剰シグナルによる自己免疫の誘導"蛋白質・核酸・酵素. 47(増刊). 2349-2354 (2002)
[Publications] 岩倉洋一郎: "関節炎発症に於けるIL-1の役割"最新医学. 57. 840-818 (2002)
[Publications] 岩倉洋一郎: "ヒトレトロウイルス感染症モデル:エイズおよび関節リウマチモデル"病理と臨床. 20. 291-299 (2002)
[Publications] 宝来玲子: "IL-1Raノックアウトマウスの関節炎"炎症と免疫. 10. 85-89 (2002)
[Publications] 岩倉洋一郎: "動物発生工学"朝倉書店. 254 (2002)
[Publications] 浅島誠: "バイオサイエンスの新世紀 15「生命工学・新しい生命へのアプローチ」"共立出版社. 291 (2002)
[Publications] 井上達: "ヒト型モデル動物"シュプリンガー・フェアラーク東京. 221 (2002)

2002 Fiscal Year Annual Research Report

HTLV-Iによる自己免疫性慢性関節炎発症機構の解明

Principal Investigator

岩倉 洋一郎 東京大学, 医科学研究所, 教授 (10089120)

Research Products

[Publications] Voronov, E.: "Interleukin 1 is required for tumor invasiveness and angiogenesis"Proc. Natl. Acad. Sci. USA. (in press). (2003)

[Publications] Nakae, S.: "Interleukin-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response"Int. Immunol.. (in press). (2003)

[Publications] Ohtaki, H.: "Suppression of oxidative neuronal damage after transient middle cerebral artery occlusion in mice lacking interleukin-1"Neuroscience Res.. (in press). (2003)

[Publications] Sashinami, H.: "Effective induction of acquired resistance to Listeria monocytogenes by immunizing mice with in vivo-infected dendritic cells"Infect. Immun.. 71. 117-125 (2003)

[Publications] Li, H.: "Aberrant responses to acoustic stimuli in mice deficient for neural recognition molecule NB-2. Aberrant responses to acoustic stimuli in mice deficient for neural recognition molecule NB-2"Eur. J. Neurosci.. (in press). (2003)

[Publications] Tanaka, J.: "Latent HIV-1 reactivation in transgenic mice requires cell cycle-dependent demethylation of CREB/ATF sites in the LTR"AIDS. 17. 167-175 (2003)

[Publications] Iwakura, Y.: "Autoimmune chronic inflammatory arthropathy in mice transgenic for the HTLV-I tax gene"Gann Monograph. (in press). (2003)

[Publications] 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)

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

[Publications] Kurisaki, T.: "Phenotypic analysis of Meltrin α (ADAM12)-deficient mice : involvement of Meltrin α in adipogenesis and myogenesis"Mol. Cell. Biol.. 23. 55-61 (2003)

[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] Yano, A.: "Roles of IFN-γ on stage conversion of an obligate intracellular protozoan parasite, Toxoplasma gondii"Int. Rev. Immunol.. 21. 405-421 (2002)

[Publications] Desaki, M.: "Role of interferon-γ in the development of murine bronchus-associated lymphoid tissues induced by silica in vivo"Toxicol. Appl. Pharmacol.. 185. 1-7 (2002)

[Publications] Yoshida, M.: "Differential localization of colitogenic Th1 and Th2 cells monospecific to a microflora-associated antigen in mice"Gastroenterology. 123. 1949-1961 (2002)

[Publications] Oguri, S.: "Primary role of interleukin-1α and Interleukin-1β in lipopolysaccharide-induced hypoglycemia in mice"Clin. Diagn. Lab. Immunol.. 9. 1307-1312 (2002)

[Publications] Kakuta, S.: "Genomic structure of the mouse 2',5'-oligoadenylate synthetase gene family"J. Interferon Cytokine Res.. 22. 981-993 (2002)

[Publications] Sakamaki, K.: "Ex vivo whole-embryo culture of caspase-8-deficient embryos normalize their aberrant phenotypes in the developing neural tube and heart"Cell Death and Differentiation. 11. 1196-1206 (2002)

[Publications] 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)

[Publications] Yan, X.: "Antibacterial effect of Kampo herbal formulation Hochu-ekki-to (Bu-Zhong-Yi-Qi-Tang) on Helicobacter pylori infection in mice"Microbiol. Immunol.. 46. 475-482 (2002)

[Publications] Iwakura, Y.: "Roles of IL-1 in the development of rheumatoid arthritis : Consideration from mouse models"Cytokine Growth Factor Rev.. 13. 341-355 (2002)

[Publications] Mizuki, M.: "Comparison of host resistance to primary and secondary Listeriamonocytogenes infections in mice by intranasal and intravenous routes"Infect. Immun.. 70. 4805-4811 (2002)

[Publications] Shiraishi, K.: "Roles of RecJ, RecO, and RecR in RecET-mediated illegitimate recombination in Escherichia coli"J. Bacteriol.. 184. 4715-4721 (2002)

[Publications] Minami, M.: "Role of IFN-γ and tumor necrosis factor-α in herpes simplex virus type 1 infection"J. Interferon Cytokine Res.. 22. 671-676 (2002)

[Publications] Ishida, Y.: "A pivotal involvement of IFN-γ in the pathogenesis of acetaminophen-induced acute liver injury"FASEB J.. 16. 1227-1236 (2002)

[Publications] Konishi, H.: "IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions"Proc. Natl. Acad. Sci. USA. 99. 11340-11345 (2002)

[Publications] Sasaki, S.: "Roles of gamma interferon and tumor necrosis factor-alpha in shiga toxin lethality"Microb. Pathog.. 33. 43-47 (2002)

[Publications] Nagai, Y.: "Essential role of MD-2 in LPS responsiveness and TLR4 distribution"Nat. Immunol.. 3. 667-672 (2002)

[Publications] Yamamoto, S.: "Mice deficient in nervous system-specific carbohydrate epitope HNK-1 exhibit impaired synaptic plasticity and spatial learning"J. Biol. Chem.. 277. 27227-27231 (2002)

[Publications] Mizushima, H.: "Reduced postischemic apoptosis in the hippocampus of mice deficient in interleukin-1"J. comparative Neurol.. 448. 203-216 (2002)

[Publications] Asada, H.: "Significant antitumor effects obtained by autologous tumor cell vaccine engineered to secrete interleukin(IL)-12 and IL-18 by means of the EBV/lipoplex"Molec. Therapy. 5. 609-616 (2002)

[Publications] Oguro, T.: "Involvement of tumor necrosis factorα、rather than interleukin-1 or nitric oxides in the HEME Oxygenase-1 gene expression by lipopolysaccharide in the mouse liver"FEBS Letters. 516. 63-66 (2002)

[Publications] Battsetseg, B.: "Immune responses of interferon γ (IFN-γ) knock out mice to repeated Haemaphysalis longicomis (Acari : Ixodidae) nymph infestations"J. Med. Entomol.. 39. 173-176 (2002)

[Publications] Asahi, Y.: "Protection against influenza virus infection in polymeric Ig receptor knockout mice immunized intranasally with adjuvant-combined vaccines"J. Immunol.. 168. 2930-2938 (2002)

[Publications] Furuzawa, M.: "Diurnal variation of heart rate, locomotor activity, and body temperature in interleukin-1 α/β doubly deficient mice"Exp. Anim.. 51. 49-56 (2002)

[Publications] Shinozawa, Y.: "Role of interferon-gamma in inflammatory responses in murine respiratory infection with Legionella pneumophila"J. Med. Microbiol.. 51. 225-230 (2002)

[Publications] Kyuwa, S.: "Acute hepatic failure in IFN-γ-deficient BALB/c mice after murine coronavirus infection"Virus Research. 83. 169-177 (2002)

[Publications] Nagai, Y.: "Requirement for MD-1 in cell surface expression of RP105/CD180 and B-cell responsiveness to lipopolysaccharide"Blood. 99. 1699-1705 (2002)

[Publications] Brough, D.: "Purinergic (P2X7) receptor activation of microglia induces cell death via an interleukin-1-independent mechanism"Mol. Cell. Neurosci.. 19. 272-280 (2002)

[Publications] Kakuta, S.: "Inhibition of B16 melanoma experimental metastasis by interferon-γ through direct inhibition of cell proliferation and activation of antitumour host mechanisms"Immunology. 105. 92-100 (2002)

[Publications] Saijo, S.: "Suppression of autoimmune arthritis in IL-4-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)

[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.. 277. 3210-3218 (2002)

[Publications] 岩倉洋一郎: "関節リウマチモデルマウス"医学のあゆみ. (印刷中). (2003)

[Publications] 岩倉洋一郎: "関節リウマチモデルマウスと創薬への応用"日本薬理学雑誌. 120. 303-313 (2002)

[Publications] 中江進: "接触型過敏症におけるサイトカインの役割"臨床免疫. 38. 171-178 (2002)

[Publications] 岩倉洋一郎: "IL-1の過剰シグナルによる自己免疫の誘導"蛋白質・核酸・酵素. 47(増刊). 2349-2354 (2002)

[Publications] 岩倉洋一郎: "関節炎発症に於けるIL-1の役割"最新医学. 57. 840-818 (2002)

[Publications] 岩倉洋一郎: "ヒトレトロウイルス感染症モデル:エイズおよび関節リウマチモデル"病理と臨床. 20. 291-299 (2002)

[Publications] 宝来玲子: "IL-1Raノックアウトマウスの関節炎"炎症と免疫. 10. 85-89 (2002)

[Publications] 岩倉洋一郎: "動物発生工学"朝倉書店. 254 (2002)

[Publications] 浅島誠: "バイオサイエンスの新世紀 15「生命工学・新しい生命へのアプローチ」"共立出版社. 291 (2002)

[Publications] 井上達: "ヒト型モデル動物"シュプリンガー・フェアラーク東京. 221 (2002)

岩倉洋一郎東京大学, 医科学研究所, 教授 (10089120)