2000 年度実績報告書

関節リウマチの遺伝要因の解明

研究課題

研究課題/領域番号	12204034
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, 教務職員 (50126091) 宝来玲子東京大学, 医科学研究所, 助手 (20313091) 森本幾夫東京大学, 医科学研究所, 教授 (30119028)
キーワード	関節リウマチ / IL-1レセプターアンタゴニスト / ノックアウトマウス / HTLV-I / トランスジェニックマウス / 自己免疫 / 関節炎 / 遺伝要因
研究概要	我々は、先にHTLV-I遺伝子を導入したトランスジェニック(Tg)マウス、IL-1レセプターアンタゴニスト(IL-1ra)ノックアウト(KO)マウスを作製し、ともに自己免疫性の慢性関節炎になることを明らかにした。これらのマウスはいずれもBALB/c背景では高率に関節炎を発症するが、C57BL/6背景ではほとんど発症しないことから。発症には背景遺伝子が強く関与していることがわかった。本研究では、1.IL-1raの異常がヒトの関節リウマチ患者でも病因となっているかどうか、2.関節炎の病態形成に関与する背景遺伝子は何かを検討した。 1.関節リウマチ患者におけるIL-1ra遺伝子の解析ヒト関節リウマチ患者でIL-1ra遺伝子に異常があるかどうかを明らかにするために、まず患者材料を用い、血清中のIL-1ra蛋白量をELISA法を用いて測定した。リウマチ患者495名中3名に低い値が得られた。健常人9名及び全身性エリテマトーデス、シェグレン症候群患者142名中にはこのように低い値は見られていない。 2.自己免疫感受性遺伝子の同定 1)BALB/c、およびC57BL/6背景のHTLV-I-Tgマウスを掛け合わせ、発症に関与する遺伝子をマップしたところ、少なくとも3本の染色体上に感受性遺伝子が存在することがわかった。これらの染色体についてマイクロサテライトマーカーの数を増やしてさらにマップを行ったが、有意な座位はまだ見つかっていない。 2)IL-1raKOマウスを主要組織適合性複合体(MHC)遺伝子部分が異なるBALB.B及びB10.D2/nマウスに戻し交配し、発症率を検討したが、MHC領域は発症に関与しないことが示唆された。今後もIL-1raのレベルの低いリウマチ患者の遺伝子解析を進めるとともに、モデルマウスを用いた感受性遺伝子の詳細なマッピングを続ける予定である。

研究成果

(28件)

すべてその他

すべて文献書誌 (28件)

[文献書誌] Hayakawa,Y.: "Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells."Nat Med.. 7. 94-100 (2001)
[文献書誌] Fukamauchi,F.: "TAG-1-deficient mice have marked elevation of adenosine Al receptors in the hippocampus."Biochem.Biphys.Res.Commun.,. 281. 220-226 (2001)
[文献書誌] Horai,R.: "Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in IL-1 receptor antagonist-deficient mice."J.Exp.Med.. 191. 313-320 (2000)
[文献書誌] Serizawa,S.: "Mutually exclusive expression of odorant receptor transgenes."Nat.Neurosci.. 3. 687-693 (2000)
[文献書誌] Uetani,N.: "Impaired learning with enhanced hippocampal long-term potentiation in PTPδ-deficient mice."EMBO J.. 19. 2775-2785 (2000)
[文献書誌] Tanaka,J.: "Lipopolysaccharide-induced HIV-1 expression in transgenic mice is mediated by tumor necrosis factor-alpha and interleukin-1, but not by interferon-gamma nor interleukin-6."AIDS. 14. 1299-1307 (2000)
[文献書誌] Hayashi,K.: "Diminution of the AML1 transcription factor function causes differential effects on the fates of CD4 and CD8 single-positive T cells."J.Immunol.. 165. 6816-6824 (2000)
[文献書誌] Tagawa,Y.: "Bimodal role of endogenous interleukin-6 in concanavalin A-induced hepatitis in mice."J.Leukoc.Biol.. 67. 90-96 (2000)
[文献書誌] Hino,A.: "Interferon γ priming is not critical for IL-12 production of murine spleen cells."Cytokine. 12. 12-20 (2000)
[文献書誌] Miyazato,A.: "Chemokine synthesis and cellular inflammatory changes in lungs of mice bearing p40tax of human T-lymphotropic virus type 1."Clin.Exp.Immunol.. 120. 113-124 (2000)
[文献書誌] Takikawa,O.: "Interferon-γ-dependent/independent expression of indoleamine 2,3-dioxygenase. Studies with interferon-γ-knockout mice."Adv.Exp.Med.Biol.. 467. 553-557 (2000)
[文献書誌] Nishihori,H.: "Participation of endogenously produced IFN-γ in interleukin 4-mediated tumor rejection."Human Gene Therapy. 11. 659-668 (2000)
[文献書誌] Yamaguchi,K.: "Involvement of interleukin-1 in the inflammatory actions of aminobisphosphonates in mice."Br.J.Pharmacol.. 130. 1646-1654 (2000)
[文献書誌] Ohta,A.: "Indispensable role for TNF-α and IFN-γ at the effector phase of liver injury mediated by Th1 cells specific to hepatitis B virus surface antigen."J.Immunol.. 165. 956-961 (2000)
[文献書誌] Kawakami,K.: "IL-18 contributes to host resistance against infection with Cryptococcus neoformans in mice with defective IL-12 synthesis through induction of IFN-γ production by NK cells."J.Immunol.. 165. 941-947 (2000)
[文献書誌] Yamada,H.: "Protective role of interleukin-1 in mycobacterial infection in IL-1 α/β double-knockout mice."Lab.Invest.. 80. 759-767 (2000)
[文献書誌] Ohkusu,K.: "Potentiality of interleukin-18 as a useful reagent for treatment and prevention of Leishmania major infection."Infect.Immun.. 68. 2449-2456 (2000)
[文献書誌] Sasaki,S.: "Interleukin-4 and interleukin-10 are involved in host resistance to Staphylococcus aureus infection through regulation of gamma interferon."Infect.Immun.. 68. 2424-2430 (2000)
[文献書誌] Kido,M.: "Presence of a higher molecular weight β-1, 4-galactosyltransferase in mouse liver."Acta Histochem.Cytochem.. 33. 215-221 (2000)
[文献書誌] Igarashi,I.: "Immunization with recombinant surface antigens p26 with Freund's adjuvants against Babesia rodhaini infection."J.Vet.Med.Sci.. 62. 717-723 (2000)
[文献書誌] Miura,T.: "Roles of endogenous cytokines in liver apoptosis of mice in lethal Listeria monocytogenes infection."FEMS Immunol.Med.Microbiol.. 28. 335-341 (2000)
[文献書誌] Mun,H.-S.: "Toxoplasma gondii Hsp70 as a danger signal in Toxoplasma gondii-infected mice."Cell Stress & Chaperones. 5. 328-335 (2000)
[文献書誌] Sugawara,I.: "IL-4 is required for defense against Mycobacterial infection."Microbiol.Immunol.. 44. 971-979 (2000)
[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.).
[文献書誌] Seino,K.: "Requirement for NKT cells in the induction of allograft tolerance."Proc.Natl.Acad.U.S.A.,. (in press.).
[文献書誌] Naruse-Nakajima,C.: "Involvement of EphA2 in the formation of the tail notochord via interaction with ephrin A1."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 infection."J.Immunol.. (in press.).

2000 年度 実績報告書

関節リウマチの遺伝要因の解明

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] Hayakawa,Y.: "Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells."Nat Med.. 7. 94-100 (2001)

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

[文献書誌] Horai,R.: "Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in IL-1 receptor antagonist-deficient mice."J.Exp.Med.. 191. 313-320 (2000)

[文献書誌] Serizawa,S.: "Mutually exclusive expression of odorant receptor transgenes."Nat.Neurosci.. 3. 687-693 (2000)

[文献書誌] Uetani,N.: "Impaired learning with enhanced hippocampal long-term potentiation in PTPδ-deficient mice."EMBO J.. 19. 2775-2785 (2000)

[文献書誌] Tanaka,J.: "Lipopolysaccharide-induced HIV-1 expression in transgenic mice is mediated by tumor necrosis factor-alpha and interleukin-1, but not by interferon-gamma nor interleukin-6."AIDS. 14. 1299-1307 (2000)

[文献書誌] Hayashi,K.: "Diminution of the AML1 transcription factor function causes differential effects on the fates of CD4 and CD8 single-positive T cells."J.Immunol.. 165. 6816-6824 (2000)

[文献書誌] Tagawa,Y.: "Bimodal role of endogenous interleukin-6 in concanavalin A-induced hepatitis in mice."J.Leukoc.Biol.. 67. 90-96 (2000)

[文献書誌] Hino,A.: "Interferon γ priming is not critical for IL-12 production of murine spleen cells."Cytokine. 12. 12-20 (2000)

[文献書誌] Miyazato,A.: "Chemokine synthesis and cellular inflammatory changes in lungs of mice bearing p40tax of human T-lymphotropic virus type 1."Clin.Exp.Immunol.. 120. 113-124 (2000)

[文献書誌] Takikawa,O.: "Interferon-γ-dependent/independent expression of indoleamine 2,3-dioxygenase. Studies with interferon-γ-knockout mice."Adv.Exp.Med.Biol.. 467. 553-557 (2000)

[文献書誌] Nishihori,H.: "Participation of endogenously produced IFN-γ in interleukin 4-mediated tumor rejection."Human Gene Therapy. 11. 659-668 (2000)

[文献書誌] Yamaguchi,K.: "Involvement of interleukin-1 in the inflammatory actions of aminobisphosphonates in mice."Br.J.Pharmacol.. 130. 1646-1654 (2000)

[文献書誌] Ohta,A.: "Indispensable role for TNF-α and IFN-γ at the effector phase of liver injury mediated by Th1 cells specific to hepatitis B virus surface antigen."J.Immunol.. 165. 956-961 (2000)

[文献書誌] Kawakami,K.: "IL-18 contributes to host resistance against infection with Cryptococcus neoformans in mice with defective IL-12 synthesis through induction of IFN-γ production by NK cells."J.Immunol.. 165. 941-947 (2000)

[文献書誌] Yamada,H.: "Protective role of interleukin-1 in mycobacterial infection in IL-1 α/β double-knockout mice."Lab.Invest.. 80. 759-767 (2000)

[文献書誌] Ohkusu,K.: "Potentiality of interleukin-18 as a useful reagent for treatment and prevention of Leishmania major infection."Infect.Immun.. 68. 2449-2456 (2000)

[文献書誌] Sasaki,S.: "Interleukin-4 and interleukin-10 are involved in host resistance to Staphylococcus aureus infection through regulation of gamma interferon."Infect.Immun.. 68. 2424-2430 (2000)

[文献書誌] Kido,M.: "Presence of a higher molecular weight β-1, 4-galactosyltransferase in mouse liver."Acta Histochem.Cytochem.. 33. 215-221 (2000)

[文献書誌] Igarashi,I.: "Immunization with recombinant surface antigens p26 with Freund's adjuvants against Babesia rodhaini infection."J.Vet.Med.Sci.. 62. 717-723 (2000)

[文献書誌] Miura,T.: "Roles of endogenous cytokines in liver apoptosis of mice in lethal Listeria monocytogenes infection."FEMS Immunol.Med.Microbiol.. 28. 335-341 (2000)

[文献書誌] Mun,H.-S.: "Toxoplasma gondii Hsp70 as a danger signal in Toxoplasma gondii-infected mice."Cell Stress & Chaperones. 5. 328-335 (2000)

[文献書誌] Sugawara,I.: "IL-4 is required for defense against Mycobacterial infection."Microbiol.Immunol.. 44. 971-979 (2000)

[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.).

[文献書誌] Seino,K.: "Requirement for NKT cells in the induction of allograft tolerance."Proc.Natl.Acad.U.S.A.,. (in press.).

[文献書誌] Naruse-Nakajima,C.: "Involvement of EphA2 in the formation of the tail notochord via interaction with ephrin A1."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 infection."J.Immunol.. (in press.).

2000 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)