サイトカイン研究のための遺伝子改変マウスライブラリーの作製

• Project/Area Number: 08408037
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: The University of Tokyo
• Principal Investigator: 岩倉 洋一郎 東京大学, 医科学研究科, 教授 (10089120)
• Co-Investigator(Kenkyū-buntansha): 須藤 カツ子 東京大学, 医科学研究科, 教務職員 (50126091) ; 浅野 雅秀 東京大学, 医科学研究科, 助手 (50251450) ; 松澤 昭雄 東京大学, 医科学研究科, 教授 (50012745) ; 田川 陽一 東京大学, 医科学研究所, 教務職員 (70262079)
• Project Period (FY): 1996 – 1998
• Project Status: Completed (Fiscal Year 1998)
• Budget Amount: ¥20,300,000 (Direct Cost: ¥20,300,000); Fiscal Year 1998: ¥4,700,000 (Direct Cost: ¥4,700,000); Fiscal Year 1997: ¥5,200,000 (Direct Cost: ¥5,200,000); Fiscal Year 1996: ¥10,400,000 (Direct Cost: ¥10,400,000)
• Keywords: トランスジェニックマウス / ノックアウトマウス / IL-1α / IL-1β / IFN-γ / IL-6 / HTLV-I / 関節リウマチ / IL-1レセプターアンタゴニスト / HTLV-L Tgマウス / HIV-Tgマウス / HTLV-I Tgマウス / IL-12 / HTLV-I-Tgマウス / HIV-I-Tgマウス

Research Abstract

1.炎症や免疫応答において重要な役割を果たすと考えられている、IL-1α、IL-1β、IL-1α/β、IL-1レセプターアンタゴニスト、およびIFN-γの遺伝子欠損マウスを作製することに成功した。
2.IL-1欠損マウスを用い、IL-1が末梢だけでなく中枢で発熱やグルココルチコイドの分泌制御に重要な役割を果たしていることを明らかにした。この結果は、IL-1が生体の恒常性の維持に主要な役割を果たしていることを示唆する。
3.IL-1レセプターアンタゴニスト欠損マウスは、関節リウマチによく似た自己免疫性の関節炎を発症することを明らかにした。この結果は、IL-1が免疫系の恒常性維持にも重要な役割を果たしていることを初めて示したものであり、ヒトの関節リウマチの原因の1つとして、IL-1系の異常が考えられることを示唆した。
4.関節リウマチの発症機構を、我々が独自に開発したHTLV-Iトランスジェニックマウス関節炎モデルを用いて検討し、IL-1およびIL-6が病態形成に重要な役割を果たしていることを明らかにした。この結果は、関節リウマチの治療に1つの示唆を与えるものである。
5.同じく、IFN-γ欠損マウスを用い、肝炎の発症にIFN-γが大きな役割を果たしていることを明らかにした。
6.多くの研究者との共同研究により、Mycobacteria、マウス肝炎ウイルス、Helicobacterpylori、Babesia、HSV-1、Toxoplasma、Lieshmaniaなど種々の感染症におけるIFN-γの役割を検討し、重要な役割を果たしていることを示した。また、サイトカインネットワークにおける役割を検討した。
7.IL-1についても、炎症や、HIV、マラリア、Leishmaniaなどの感染における役割を検討し、このサイトカインが病態形成に重要であることを示した。

Research Products

• [Publications] Horai、R.: "Development of chronic inflammatory arthropathy resembling rtheumatoid arthritis in IL-1 receptor antagonist-deficient mice."J.Exp.Med.. 191. 313-320 (2000)
• [Publications] Kotani、M.: "Involvement of autoimmunity against type II collagen in the development of arthritis in mice transgenic for the human T cell leukemia virus type I tax gene."Eur.J.Immunol.. 29. 54-64 (1999)
• [Publications] Saijo、S.: "Bone marrow derived cells are responsible for the development of auto-immume arthritis in HTLV-I transgenic mice and those of normal mice can suppress the disease."J.Immunol.. 163. 5700-5707 (1999)
• [Publications] Habu、K.: "The HTLV-I-tax gene is responsible for the development of both inflammatory polyarthropathy resembling rheumatoid arthritis and non-inflammatory ankylotic arthropathy in transgenic mice."J.Immunol.. 162. 2956-2963 (1999)
• [Publications] Shimada、S.: "Generation of polymeric immunoglobulin receptor-deficient mouse with marked reduction of secretory IgA."J.Immunol.. 163. 5367-5373 (1999)
• [Publications] Hyodo、Y.: "Interleukin 18 upregulates perforin-mediated NK activity without increasing perforin mRNA expression by binding to constituively expressed IL-18R."J.Immunol.. 162. 1662-1668 (1999)
• [Publications] Tsuji、H.: "Alleviation of lipopolysaccharide-induced acute liver injury in Propionibacterium acnes-primed interferon γ deficient mice with a concomitant reduction of tumor necrosis factor-α、interleukin-12 and interleukin-18 production"J.Immunol.. 162. 1049-1055 (1999)
• [Publications] Igarashi、I: "Roles of CD4+ T cells and IFN-γ in protective immunity against Babesia microti infection in mice."Infection and Immunity. 67. 4143-4148 (1999)
• [Publications] Kobayashi、M: "Toxoplasma gondii : difference of invasion into tissue of digestive organs between susceptible and resistant stran and influence of IFN-γ in mice inoculated with the cyst per orally."J.Parasitology. 85. 973-975 (1999)
• [Publications] Sawai、N.: "The role of interferon-γ in Helicobacter pylor-induced gastric inflammatory responses in a mouse model."Infection and Immunity. 67. 279-285 (1999)
• [Publications] Kawakami、K: "Induction of lympocytic inflammatory changes in the lung interstitium by human T lymphotropic virus type I."Am.J.Respir.Crit.Csre Med. 160. 995-1000 (1999)
• [Publications] Tagawa、Y: "Bimpdal rple of endogenous interleukin-6 in concanavalin A-induced hepatitis in mice."J.Leukocyte Biology. 67. 90-96 (2000)
• [Publications] Hino、A.: "Interferon-γ primimg is not critical for IL-12 production of murine spleen cells."Cytokine. 12. 12-20 (2000)
• [Publications] Horai, R,.et al.: "Production of mice deficient in genes for IL-1α, IL-1β, IL-1α/β, and IL-1ra shous that IL-1β is cruciao in turpentine-induced fever development" J.Exp.Med.187. 1463-1475 (1998)
• [Publications] Iwakura, Y., et al: "The development of autoimmure arthropathy in mice transgenio for the HTLV-I env-pX region is not dependent on H-2 haplotypes and madiliot by Frsantrgen" J.Immunol.161. 6592-6598 (1998)
• [Publications] Kotani, M.et al: "Involvement of Autoimmunity. Against type II collgen in the development of arthritis in mice transgenic for the HTLV-I tax gene." Eur.J.Immuinol.29. 54-64 (1999)
• [Publications] Habu, K., et al: "The HTLV-I-taxgene is responsible for the development of both infrainnatory polyarthropathy and non-inflammatory ankyloticar thropathy in transgenic imce" J.Immunol. (in press).
• [Publications] Flamand, V.et al: "CD40 ligation prevents neonatal induction of transplan tation tolerance." J.Immunol. 160. 4666-4669 (1998)
• [Publications] Kyuwa, S.et al: "Murine coronaviru s-induced subacute fatal poitonitis in C57346 mice deficient in gamma interferon." J.Virol.72. 9286-9290 (1998)
• [Publications] Kyuwa, S.et al: "MHV-induced fatal peritonitis in mice lacking IFV-γ." Adv.Exp.Med.Biol.440. 445-450 (1998)
• [Publications] Miwa, K.et al: "Caspasel-independent IL-1β release and inflammation induced by the apoptosis inducer Fras ligand." Nat Med.4. 1287-1292 (1998)
• [Publications] Kido, M.et al: "Presence of polysialic acid and HNK-1 carloohydrate on lorain glycoproteins from β-1, 4 gal T-krockout mice" Biochem.Biophys, Res.Commun. 245. 860-864 (1998)
• [Publications] Sugawara, I.et al: "Induction of granulomas.in interferon-γ gene-disrupted nice by aviralent but not by virulent strain of Mycobactinum Tuberavosis" J.Med.Microbiol.47. 871-877 (1998)
• [Publications] Tagawa, Y.et al.: "lnvolvement of Fas/Fas ligard system-mediated apoptosis in the development of Con A-induced hepatitis." Eur.J.Immunol.28. 4105-4113 (1998)
• [Publications] Tsuji, H.et al: "Alleviation of LPS-induced acute liver injury in P.ac nes・primed・IFN′-r-deficient mice by a concomitant reduce on of DVR a, 2L-12 and IL-18 Production" J.Immunol.162. 1049-1055 (1999)
• [Publications] Hyodo, Y.et al: "IL-18 upregulates exocytosis-mediated NK activity without uffecting parforin mRNA expression by binding to constitulively expressed IL IFR" J.Immunol.162. 8662-8668 (1999)
• [Publications] Sawai,N.et al: "Role of gamma interferon in Hlicobacter pylori-induced gastric inflammatory responses in a mouse model" Infect.Immun.67. 279-285 (1999)
• [Publications] Asano,M.: "Growth retardation and early death of b-1,4-galactosyltransferase knockout mice with augumented proliferation and abnormal differentiation of epithelial cells." EMBOJ.16. 1850-1857 (1997)
• [Publications] Tagawa,Y.: "Suppression of Concanavalin A induced hepatitis in IFN-g-/-,but not in TNF-a-/-,mice : role for IFN-g in activating apoptosis of hepatocytes." J.Immunol.159. 1418-1428 (1997)
• [Publications] Ozaki,H.: "TNF-a,but not IL-1,IL-6,or IFN-g,is the major mediator of LPS-induced HIV activation in mice transgenic for HIV." J.Interferon Cytokine Res.17. s105 (1997)
• [Publications] Yoshimoto,T.: "Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-g production from activated B cells." Proc.Natl.Acad.Sci.USA. 94. 3948-3953 (1997)
• [Publications] Kishi,S.: "Resistance to Fas-mediated apoptosis of peripheral T cells in human T lymphocyte virus type I (HTLV-I) transgenic mice with autoimmune arthropathy." J.Exp.Med.186. 57-64 (1997)
• [Publications] Sugawara,I.: "Granulomas in interferon-g gene-disrupted mice are inducible by avirurent Mycobacterium,but not by virulent Mycobacterium." J.Medical Microbiology. (in press). (1998)
• [Publications] Arakawa,H: "Extrachromosomal circular DNAs from differentiating embryonic stem cells" Cell Struc.Funct. (in press). (1997)
• [Publications] Asano,M: "Growth retardation and early death of β-1,4-galactosyltransferase knockout mice with augmented proliferation and abnormal differentiation of epithelial cells" EMBO.J.(in press). (1997)
• [Publications] Asano,M: "Growth retardation and early death of β-1,4-galactosyltransferase knockout mice with augumented proliteration and abnormal differentiation of epithelial cells" In“Mouse Molecular Genetics". 26 (1996)
• [Publications] Fujisawa,K: "Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-I tax transgenic mice" J.Clin.Invest. 98. 271-278 (1996)
• [Publications] Kidani,Y: "Orally active DACH-Pt(IV)compounds" IN“Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy". 45-51 (1996)
• [Publications] Kizu,R: "An orally active antitumor cyclohexanedimine-Pt(IV)complex:trans,cis,cis-bis(n-valerato)(oxalato)(1R,2R-cyclohexanediamine)PT(IV)" Anti-CancerDrugs. 7. 248-256 (1996)
• [Publications] Matsuzawsa,A: "Establishment of tumor dormant state following clinically complete cure of disseminated leukemia by chemotherapy in mice." In“Premalignancy and Tumor Dormancy". 89-103 (1996)
• [Publications] Miez,M: "Selective reduction of vα14^+NK cells associated with disease development in autoimmune-prone mice" J.Immunol.156. 4035-4040 (1996)
• [Publications] Nakano,H: "Genetic defect in T Iymphocyte-specific homing into peripheral lymph nodes." Eur.J.Immunol. (in press). (1997)
• [Publications] Nakano,H: "Deletion of peripheral vβ14^+T cells by Mtv-2-encoded viral superantigen preceded by blastogenesis and DNA synthesis but not by specific expansion." Cell.Immunol.168. 281-290 (1996)
• [Publications] Nanbu,H: "Fas-independent apoptosis of photoreceptor cells in C3H mice." Exp.Anim. 45. 309-315 (1996)
• [Publications] Oyaizu,T: "Studies on the mechanism of dimethylnitrosamine-induced acute lever inJury in mice" Exp.Toxical.Pathol. (in press). (1997)
• [Publications] Saijo,S: "Involvement of autoimmunity in inflammatory arthropathy that developed in HTLV-1 transgenic mice." Eur.Cytokine Netw.7. 606 (1996)
• [Publications] Shimizu.M: "Augmentation of antitumor immunity with bacterial superantigen Staphylococcal enterotoxin B-bond tumor cells" Cancer Res.56. 3731-3736 (1996)
• [Publications] Suzuki A.: "Involvement of Fas inregression of vaginal epithelia after ovaricetomy and during an estrus cycle." EMBO J.15. 211-215 (1996)
• [Publications] Suzuki,A: "Down regulation of Bc1-2 is the first step on Fas-mediated apoptosis of male reproductive tract." Oncogene. 13. 31-37 (1996)
• [Publications] Tagawa,Y: "Resistance of interferon-r deficient mice against in a T-cell dependent manner." Eur.Cytokine Netw. 7. 505 (1996)
• [Publications] Tanaka,S.: "Genetic regulation of border zone formation in female mastomys(Praoumys coucha)adrenal cortex." J.Heredit.87. 70-74 (1996)
• [Publications] Yoshimoto,T: "Deletion of CD4^+T cells by murine mammary tumor virus(FM)superantigen with broad specificity of T cell receptor β-chain variable region," Virology. 223. 387-391 (1996)
• [Publications] Yoshimoto,T: "Interleukin-18(IL-18)together with IL-12 inhibits IgE synthesis by induction of IFN-γ Production from activated B cells." Proc.Nat Acad.Sci.USA. (in press). (1997)