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2010 Fiscal Year Annual Research Report

疾患のシステム的理解を目指したIL―1関連遺伝子欠損マウスライブラリーの作製

Research Project

Project/Area Number 20220009
Research InstitutionThe 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) 西城 忍  千葉大学, 真菌医学研究センター, 特任准教授 (60396877)
角田 茂  信州大学, ヒト環境科学研究支援センター, 助教 (80345032)
海部 知則  東京大学, 医科学研究所, 助教 (90343037)
Keywordsサイトカイン / 疾患モデル動物 / 自己免疫疾患 / Th17細胞 / 関節リウマチ
Research Abstract

動物細胞が分泌するサイトカインと呼ばれる一群の蛋白質は情報伝達物質として機能しており、感染症、自己免疫、肥満、糖尿病、発熱、ストレス応答など種々の疾病の病態形成や生体の恒常性維持において重要な役割を果たしている。そのため、サイトカインを標的とした治療法が開発され、創薬の分子標的として注目されている。これらの疾病は単なる個々の臓器、細胞の異常ではなく、多くの因子が複雑に相互作用し病態発症に至ることから、個体レベルの解析が疾病の理解には必要である。本研究ではこれら疾病の新たな治療法の開発に資するため、実験動物学的立場からIL-1ファミリーおよびその下流遺伝子の系統的な遺伝子欠損マウスライブラリーを作製し、それらの遺伝子の機能と相互関係を解析し、生体システムの恒常性の維持や疾病における役割を解明することを目的とする。平成22年度までに新規3系統の遺伝子改変マウスの作製に成功し、選択した遺伝子背景への戻し交配を完了もしくは完了間近である。新規開発した遺伝子改変マウスの解析により免疫系および内分泌系におけるIL-1関連遺伝子の機能について興味深い結果が出てきている。これらのマウスはこれまでに当グループで開発した遺伝子改変マウスと併せて、利用価値の高いバイオリソースとしてホームページ上に公開し、国内外の当該研究領域の研究者に供給した。さらに、これらの研究成果はImmunityなどを含む雑誌に原著論文として公表された。

  • Research Products

    (75 results)

All 2011 2010 Other

All Journal Article (44 results) (of which Peer Reviewed: 44 results) Presentation (26 results) Book (2 results) Remarks (1 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 2 results)

  • [Journal Article] TNF-{alpha} from inflammatory dendritic cells(DCs)regulates lung IL-17A/IL-5 Levels and neutrophilia versus eosinophilia during persistent fungal infection.2011

    • Author(s)
      Fei, M.
    • Journal Title

      Proc.Natl.Acad..SCI.USA.

      Volume: 108 Pages: 5360-5365

    • Peer Reviewed
  • [Journal Article] Functional specialization of interleukin-17 family members.2011

    • Author(s)
      Iwakura, Y.
    • Journal Title

      Immunity

      Volume: 34 Pages: 149-162

    • Peer Reviewed
  • [Journal Article] The role of Syk/CARD9 coupled C-type lectins in antifungal immunity.2011

    • Author(s)
      Drummond, R.A
    • Journal Title

      Eur.J.Immunol.

      Volume: 41 Pages: 276-281

    • Peer Reviewed
  • [Journal Article] Rapid host defense against Aspergillus fumigatus involves alveolar macrophages with apredominance of alternatively activated phenotype.2011

    • Author(s)
      Bhatia, S.
    • Journal Title

      PLoS One.

      Volume: 6 Pages: E15943

    • Peer Reviewed
  • [Journal Article] Dectin-1 diversifies Aspergillus fumigates-specific T cell responses by inhibiting Thelper type 1 CD4 T cell differentiation.2011

    • Author(s)
      Rives, A
    • Journal Title

      J.Exp.Med.

      Volume: 208 Pages: 369-381

    • Peer Reviewed
  • [Journal Article] Local microbleeding facilitates 1L-6-and IL-17-dependent althritis in the absence of tissue antigen recognition by activated T cells.2011

    • Author(s)
      Murakami, M.
    • Journal Title

      J.Exp.Med.

      Volume: 208 Pages: 103-114

    • Peer Reviewed
  • [Journal Article] IL-1 signalling is dispensable for protective immunity in Leishmania-resistant mice.2011

    • Author(s)
      Kautz-Neu, K
    • Journal Title

      Exp.Dermatol.

      Volume: 20 Pages: 76-78

    • Peer Reviewed
  • [Journal Article] Distinct role of T helper Type 17 immune response for Graves'hyperthyroidism in mice with different genetic backgrounds.2011

    • Author(s)
      Horie, I.
    • Journal Title

      Autoimmunity

      Volume: 44 Pages: 159-165

    • Peer Reviewed
  • [Journal Article] Protective role of IL-1β against post-arthroplasty Staphylococcus aureus infection.2011

    • Author(s)
      Bernthal, N.M.
    • Journal Title

      J.Orthop.Res.

      Volume: (in press)(掲載確定)

    • Peer Reviewed
  • [Journal Article] Tumor necrosis factor receptor-associated factor(Traf)2 controls homeostasis of the colon to prevent spontaneous development of murine inflammatory bowel disease.2011

    • Author(s)
      Piao, J.H.
    • Journal Title

      J.Biol.Chem.

      Volume: (in press)(掲載確定)

    • Peer Reviewed
  • [Journal Article] Natural Killer T Cell-Derived IL-17Mediates Lung Ischemia-Reperfusion Injury2011

    • Author(s)
      Sharma, A K
    • Journal Title

      Am.J.Respir.Crit.Care Med.

      Volume: (in press)(掲載確定)

    • Peer Reviewed
  • [Journal Article] Homeostatic defects in interleukin 18-deficient mice contribute to protection against the lethal effects of endotoxin2011

    • Author(s)
      Andrews, D.M.
    • Journal Title

      Immunol.Cell Biol.

      Volume: (in press)(掲載確定)

    • Peer Reviewed
  • [Journal Article] CD30 ligand is a tazget for a novel biological therapy against colitis associated with Th 17 responses.2010

    • Author(s)
      Sun, X
    • Journal Title

      J.Immunol.

      Volume: 185 Pages: 7671-7680

    • Peer Reviewed
  • [Journal Article] The role of endogenous glucocorticoids in lymphocyte development in melanowrtin receptor 2-deficient mice.2010

    • Author(s)
      Sato, Y.
    • Journal Title

      Biochem.Biophys.Res.Commun.

      Volume: 403 Pages: 253-257

    • Peer Reviewed
  • [Journal Article] Development of experimental cerebral malaria is independent of IL-23 and IL-172010

    • Author(s)
      Lshida, H.
    • Journal Title

      Biochem.Biophys.Res.Commun.

      Volume: 402 Pages: 790-795

    • Peer Reviewed
  • [Journal Article] CXC chemokine receptor 4 expressed in T cells plays an important role in the development of collagen-induced arthritis.2010

    • Author(s)
      Chung, S.H.
    • Journal Title

      Arthritis Res.Ther.

      Volume: 12 Pages: R188

    • Peer Reviewed
  • [Journal Article] Apoptotic cells activate NKT cells through T cell Ig-like mucin-like-1 resulting in airway hyperreactivity.2010

    • Author(s)
      Lee, H.H.
    • Journal Title

      J.Immunol.

      Volume: 185 Pages: 5225-5235

    • Peer Reviewed
  • [Journal Article] Functional hypothalamic amenorrhea due to increased CRH tone in melanocortin receptor 2-deficient mice.2010

    • Author(s)
      Matsuwaki, T.
    • Journal Title

      Endocrinology

      Volume: 151 Pages: 5489-5496

    • Peer Reviewed
  • [Journal Article] Periprosthetic osteolysis : characterizing the innate immune response to titanium wear-particles.2010

    • Author(s)
      St Pierre, C.A
    • Journal Title

      J.Orthop.Res.

      Volume: 28 Pages: 1418-1424

    • Peer Reviewed
  • [Journal Article] Critical role of regulatory Tcell in Th17-mediated minor antigen-disparate rejection2010

    • Author(s)
      Vokaer, B.
    • Journal Title

      J.Immunol.

      Volume: 185 Pages: 3417-3425

    • Peer Reviewed
  • [Journal Article] Lipid-cytokine-chemokine cascade drives neutrophil recruitment in a marine model of inflammatory arthritis.2010

    • Author(s)
      Chou, R C.
    • Journal Title

      Immunity

      Volume: 33 Pages: 266-278

    • Peer Reviewed
  • [Journal Article] IL-1 plays an important role in the bone metabolism under physiological conditions.2010

    • Author(s)
      Lee, Y.M.
    • Journal Title

      Int.Immunol

      Volume: 22 Pages: 805-816

    • Peer Reviewed
  • [Journal Article] Role of interleukin-17A in cell-mediated protection against Staphylococcus aureus infection in mice immunized with the fibrinogen-binding domain of clumping factor A2010

    • Author(s)
      Narita, K
    • Journal Title

      Infect.Immun.

      Volume: 78 Pages: 4234-4242

    • Peer Reviewed
  • [Journal Article] 1α, 25-Dihydroxyvitamin D3 and all-traps retinoic acid synergistically inhibit the differentiation and expansion of Th17 cells2010

    • Author(s)
      Ikeda, U.
    • Journal Title

      Immunol.Lett.

      Volume: 134 Pages: 7-16

    • Peer Reviewed
  • [Journal Article] Inflammasome activation by adenylate cyclase toxin directs Th 17 responses and protection against Bordetella pertussis.2010

    • Author(s)
      Dunne, A.
    • Journal Title

      J.Immunol.

      Volume: 185 Pages: 1711-1719

    • Peer Reviewed
  • [Journal Article] TNF but not IL-6 and IL17, is crucial for the development of T cell-independent psoriasis-like dermatitis in Ill rn-/-mice.2010

    • Author(s)
      Nakajima, A.
    • Journal Title

      J.Immunol.

      Volume: 185 Pages: 1887-1893

    • Peer Reviewed
  • [Journal Article] Interleukin-17A during local and systemic Staphylococcus aureus-induced arthritis in mice.2010

    • Author(s)
      Henningsson, L.
    • Journal Title

      Infect.Immun.

      Volume: 78 Pages: 3783-3790

    • Peer Reviewed
  • [Journal Article] Altered effector CD4+ T cell function in IL-21R-/-CD4+ T cell-mediated graft-versus-host disease.2010

    • Author(s)
      Oh, I.
    • Journal Title

      J Immunol

      Volume: 185 Pages: 1920-1926

    • Peer Reviewed
  • [Journal Article] IL-17 is necessary for host protection against acute-phase Trypanosoma cruzi infection.2010

    • Author(s)
      Miyazaki, Y.
    • Journal Title

      J.Immunol.

      Volume: 185 Pages: 1150-1157

    • Peer Reviewed
  • [Journal Article] The mechanism of lipopolysaccharide-induced human immunodefieiency virus type I activation in transgenic mouse macrophages.2010

    • Author(s)
      Kadoki, M.
    • Journal Title

      Int.Immunol.

      Volume: 22 Pages: 469-478

    • Peer Reviewed
  • [Journal Article] Genetic background and gender effects on gross phenotypes in congenic lines of ALS2/alsin-deficient mice.2010

    • Author(s)
      Hadano, S.
    • Journal Title

      Neurosci.Res.

      Volume: 68 Pages: 131-136

    • Peer Reviewed
  • [Journal Article] AT(h)17-polarized cell population that has infiltrated the lung requires cells that convert to IFN-{gamma}production in order to induce airway hyperresponsiveness.2010

    • Author(s)
      Ashino, S.
    • Journal Title

      Int.Immunol.

      Volume: 22 Pages: 503-513

    • Peer Reviewed
  • [Journal Article] Dectin-2 recognition of alpha-mannans and induction of Th 17 cell differentiation is essential for host defense against Candida albicans.2010

    • Author(s)
      Saijo, S.
    • Journal Title

      Immunity

      Volume: 32 Pages: 681-691

    • Peer Reviewed
  • [Journal Article] Activation of myeloid dendritic cells by deoxynucleic acids from Cordyceps sinensisvia a Toll-like receptor 9-dependent pathway.2010

    • Author(s)
      Xiao, G
    • Journal Title

      Cell Immunol

      Volume: 263 Pages: 241-250

    • Peer Reviewed
  • [Journal Article] Stem cell mobilization with G-CSF induces type 17 differentiation and promotes scleroderma.2010

    • Author(s)
      Hill, G.R.
    • Journal Title

      Blood

      Volume: 116 Pages: 819-828

    • Peer Reviewed
  • [Journal Article] IL-23 suppresses innate immune response independently of IL-17A duringcar cinogenesis and metastasis.2010

    • Author(s)
      Teng, M.W.
    • Journal Title

      Proc.Natl.Acad.Sci.U S A.

      Volume: 107 Pages: 8328-8333

    • Peer Reviewed
  • [Journal Article] Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor by promoting angiogenesis.2010

    • Author(s)
      Wakita, D.
    • Journal Title

      Eur.J.Immunol.

      Volume: 40 Pages: 1927-1937

    • Peer Reviewed
  • [Journal Article] Lung CD4-CD8-double-negative T cell are prominent producer of IL-17A and IFN-gamma during primary respiratory murine infection with Francisella tularensis live vaccine strain.2010

    • Author(s)
      Cowley, S.C.
    • Journal Title

      J.Immunol.

      Volume: 184 Pages: 5791-5891

    • Peer Reviewed
  • [Journal Article] Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy.2010

    • Author(s)
      Baldeviano, G.C.
    • Journal Title

      Circ.Res.

      Volume: 106 Pages: 1636-1655

    • Peer Reviewed
  • [Journal Article] Th17 cells promote autoimmune anti-myeloperoxidase glomerulonephritis.2010

    • Author(s)
      Gan, P.Y.
    • Journal Title

      J.Am.Soc.Nephrol

      Volume: 21 Pages: 925-931

    • Peer Reviewed
  • [Journal Article] Identification of the cellular sensor that stimulates the inflammatory response to sterilecell death.2010

    • Author(s)
      Kono, H.
    • Journal Title

      J Immunol

      Volume: 184 Pages: 4470-4478

    • Peer Reviewed
  • [Journal Article] Essential role of Il-17A in the formation of a mycobacterial infection-induced granuloma in the lung.2010

    • Author(s)
      Okamoto, Yoshida, Y.
    • Journal Title

      J.Immunol.

      Volume: 184 Pages: 4414-4422

    • Peer Reviewed
  • [Journal Article] Neural tube defects and impaired neural progenitor cell proliferation in Gbetal-deficient mice.2010

    • Author(s)
      Okae, H.
    • Journal Title

      Dev Dyn.

      Volume: 239 Pages: 1089-1010

    • Peer Reviewed
  • [Journal Article] Type I IFN signaling constrains IL-17A/F secretion by gammadelta T cells during bacterial infections.2010

    • Author(s)
      Henry, T.
    • Journal Title

      J.Immunol.

      Volume: 184 Pages: 3755-3767

    • Peer Reviewed
  • [Presentation] The role of IL-1 and 17 family genes in development of intestinal polyps.2010

    • Author(s)
      Shigeru Kakuta
    • Organizer
      第33回日本分子生物学会年会 第83回日本生化学会大会合同大会
    • Place of Presentation
      神戸ポートアイランド
    • Year and Date
      20101207-20101210
  • [Presentation] 病原微生物による潜伏HIV-1再活性化の分子機構2010

    • Author(s)
      角木基彦
    • Organizer
      第33回日本分子生物学会年会 第83回日本生化学会大会合同大会
    • Place of Presentation
      神戸ポートアイランド
    • Year and Date
      20101207-20101210
  • [Presentation] HIV感受性マウス作製に向けたヒトLEDGFトランスジェニックマウス(Tg)の作製2010

    • Author(s)
      多田卓哉
    • Organizer
      第58回日本ウイルス学会学術集会
    • Place of Presentation
      徳島県郷土文化会館
    • Year and Date
      20101107-20101109
  • [Presentation] IL-17A and IL-17F are important for the development of intestinal polyps in APC^<MIN> mice by accelerating blood vessel formation.2010

    • Author(s)
      Shigeru Kakuta
    • Organizer
      8th Joint Conference of the ICS and ISICR, Cytokines 2010
    • Place of Presentation
      Chicago, USA
    • Year and Date
      20101003-20101007
  • [Presentation] IL-17F promotes type 1 immunity by directly enhancing CD4+ T cell activation.2010

    • Author(s)
      Ce Tang
    • Organizer
      8th Joint Conference of the ICS and ISICR, Cytokines 2010
    • Place of Presentation
      Chicago, USA
    • Year and Date
      20101003-20101007
  • [Presentation] The roles of C-type lectins in the host defense against fungal infection.2010

    • Author(s)
      Shinobu Saijo
    • Organizer
      8th Joint Conference of the ICS and ISICR, Cytokines 2010
    • Place of Presentation
      Chicago, USA
    • Year and Date
      20101003-20101007
  • [Presentation] A novel arthritis-regulatory gene identified by using two mouse rheumatoid arthritis models.2010

    • Author(s)
      Masanori A.Murayama
    • Organizer
      8th Joint Conference of the ICS and ISICR, Cytokines 2010
    • Place of Presentation
      Chicago, USA
    • Year and Date
      20101003-20101007
  • [Presentation] IL-17-producing γδ T cells are important for the development of arthritis in arheumatoid arthritis model.2010

    • Author(s)
      Aoi Akitsu
    • Organizer
      8th Joint Conference of the ICS and ISICR, Cytokines 2010
    • Place of Presentation
      Chicago, USA
    • Year and Date
      20101003-20101007
  • [Presentation] CXC chemokine receptor 4 expressed in T cells plays an important role in the development of collagen-induced arthritis.2010

    • Author(s)
      Soo-hyuq Chung
    • Organizer
      8th Joint Conference of the ICS and ISICR, Cytokines 2010
    • Place of Presentation
      Chicago, USA
    • Year and Date
      20101003-20101007
  • [Presentation] DCIR : A new therapeutic target for autoimmune disorders.2010

    • Author(s)
      Guangyu Ma
    • Organizer
      8th Joint Conference of the ICS and ISICR, Cytokines 2010
    • Place of Presentation
      Chicago, USA
    • Year and Date
      20101003-20101007
  • [Presentation] Develqpment of TH 17-dependent athritis in IL-6-deficient IL-1 receptor antagonist-deficient mice.2010

    • Author(s)
      Satoshi Ikeda
    • Organizer
      8th Joint Conference of the ICS and ISICR, Cytokines 2010
    • Place of Presentation
      Chicago, USA
    • Year and Date
      20101003-20101007
  • [Presentation] Oral administration of β-glucan stimulates mucosal immune system and improves immunological homeostasis oral tolerance.2010

    • Author(s)
      Huimin Yan
    • Organizer
      14^<th> interntional congress of immunology
    • Place of Presentation
      Kobe神戸ポートピアホテル神戸国際展示場
    • Year and Date
      20100822-20100827
  • [Presentation] CXC chemokine receptor 4 expressed in T cells plays an important role in the development of collagen-induced arthritis.2010

    • Author(s)
      Soo-hyun Chung
    • Organizer
      14^<th> interntional congress of immunology
    • Place of Presentation
      Kobe神戸ポートピアホテル神戸国際展示場
    • Year and Date
      20100822-20100827
  • [Presentation] Generation and analysis of oligoadenylate synthetase family genes-deficient mice.2010

    • Author(s)
      Shigeru Kakuta
    • Organizer
      14^<th> interntional congress of immunology
    • Place of Presentation
      Kobe神戸ポートピアホテル神戸国際展示場
    • Year and Date
      20100822-20100827
  • [Presentation] IL-17-producing gamma-delta T cells is important for the development of arthritis in arheumatoid arthribs model.2010

    • Author(s)
      Aoi Akitsu
    • Organizer
      14^<th> interntional congress of immunology
    • Place of Presentation
      Kobe神戸ポートピアホテル神戸国際展示場
    • Year and Date
      20100822-20100827
  • [Presentation] IL-17F promotes Th 1-type immunity by inducing IL-2 production.2010

    • Author(s)
      Ce Tang
    • Organizer
      14^<th> interntional congress of immunology
    • Place of Presentation
      Kobe神戸ポートピアホテル神戸国際展示場
    • Year and Date
      20100822-20100827
  • [Presentation] Development of Tb17-dependent arthritis in IL-6-deficient IL-1 receptor antagonist-deficient mice.2010

    • Author(s)
      Satoshi Ikeda
    • Organizer
      14^<th> interntional congress of immunology
    • Place of Presentation
      Kobe神戸ポートピアホテル神戸国際展示場
    • Year and Date
      20100822-20100827
  • [Presentation] The roles of C-type lectins in the host defense against fungal infecrion.2010

    • Author(s)
      Shinobu Saijo
    • Organizer
      14^<th> interntional congress of immunology
    • Place of Presentation
      Kobe神戸ポートピアホテル神戸国際展示場
    • Year and Date
      20100822-20100827
  • [Presentation] The roles of Dcir in bone metabolic diseases2010

    • Author(s)
      Guangyu Ma
    • Organizer
      14^<th> interntional congress of immunology
    • Place of Presentation
      Kobe神戸ポートピアホテル神戸国際展示場
    • Year and Date
      20100822-20100827
  • [Presentation] 腸管ポリープ形成におけるIL-17の役割の検討2010

    • Author(s)
      角田茂
    • Organizer
      第75回日本インターフェロン・サイトカイン学会学術集会
    • Place of Presentation
      小倉北北九州国際会議場
    • Year and Date
      20100625-20100626
  • [Presentation] C型レクチンによるサイトカイン産生と生体防御機構2010

    • Author(s)
      西城忍
    • Organizer
      第75回日本インターフェロン・サイトカイン学会学術集会
    • Place of Presentation
      小倉北北九州国際会議場
    • Year and Date
      20100625-20100626
  • [Presentation] IL-17産生性γδT細胞は自己免疫性関節炎モデルマウスにおける関節炎発症に重要である.2010

    • Author(s)
      秋津葵
    • Organizer
      第75回日本インターフェロン・サイトカイン学会学術集会
    • Place of Presentation
      小倉北北九州国際会議場
    • Year and Date
      20100625-20100626
  • [Presentation] IL-17産生性γδT細胞は自己免疫性関節炎モデルマウスにおける関節炎発症に重要である2010

    • Author(s)
      秋津葵
    • Organizer
      第57回日本実験動物学会
    • Place of Presentation
      京都テレサ
    • Year and Date
      20100512-20100514
  • [Presentation] 東京大学医科学研究所システム疾患モデル研究センターにおける遺伝子改変マウスの供給について2010

    • Author(s)
      角田茂
    • Organizer
      第57回日本実験動物学会
    • Place of Presentation
      京都号テレサ
    • Year and Date
      20100512-20100514
  • [Presentation] インターロイキン-17の腸管ポリープ形成における役割の解析2010

    • Author(s)
      角田茂
    • Organizer
      第5回核酸・核タンパク機能性研究会学術集会
    • Place of Presentation
      北海道恵庭リサーチビジネスパーク
    • Year and Date
      2010-08-06
  • [Presentation] 発生工学的アプローチによるIL-17ファミリーを中心としたサイトカインの機能解析2010

    • Author(s)
      角田茂
    • Organizer
      東海医学会講演会・例会
    • Place of Presentation
      伊勢原東海大学
    • Year and Date
      2010-07-13
  • [Book] アグリゲーション法によるキメラマウスの作製改訂第5版新2010

    • Author(s)
      角田茂
    • Total Pages
      289-296
    • Publisher
      遺伝子工学ハンドブック
  • [Book] コンディショナルターゲティング法改訂第5版新2010

    • Author(s)
      角田茂
    • Total Pages
      297-302
    • Publisher
      遺伝子工学ハンドブック
  • [Remarks]

    • URL

      http://www.ims.u-tokyo.ac.ip/cem_dcb/index.html

  • [Patent(Industrial Property Rights)] 樹状細胞免疫受容体刺激剤2011

    • Inventor(s)
      岩倉洋一郎、藤門範行、馬光宇
    • Industrial Property Rights Holder
      東京大学
    • Industrial Property Number
      優先権、PCTIJP20111053980
    • Filing Date
      2011-02-23
    • Overseas
  • [Patent(Industrial Property Rights)] 腸疾患の治療方法および治療用医薬組成物2011

    • Inventor(s)
      岩倉洋一郎、角田茂、鈴木俊佐
    • Industrial Property Rights Holder
      東京大学
    • Industrial Property Number
      優先権、PCTIJP20111052156
    • Filing Date
      2011-02-02
    • Overseas

URL: 

Published: 2012-07-19  

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