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牛白血病における病態発生機序の解析および新規制御法への応用

Research Project

Project/Area Number 15J01886
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section国内
Research Field Veterinary medical science
Research InstitutionHokkaido University

Principal Investigator

西森 朝美  北海道大学, 獣医学研究科, 特別研究員(DC1)

Project Period (FY) 2015-04-24 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2017: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2016: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2015: ¥1,000,000 (Direct Cost: ¥1,000,000)
Keywordsウシ白血病ウイルス / 免疫抑制因子 / PD-L1 / 治療用抗体 / ウシ投与試験 / 抗ウイルス効果 / 大量培養系 / 牛白血病ウイルス
Outline of Annual Research Achievements

本研究では、牛白血病ウイルス(BLV)に対する新規制御法を開発するため、免疫抑制受容体Programmed death-1 (PD-1) およびそのリガンドであるPD-ligand 1 (PD-L1) を標的とする治療用抗体を作製し、BLV感染牛における抗ウイルス効果を評価することを目的としている。今年度は、前年度に引き続き、生体内での抗ウイルス効果を評価するため、さらに試験頭数を増やした抗体投与試験を行った。
前年度までの報告の通り、本研究で樹立された抗体の安定発現細胞は、培養液1Lあたり738.1 mgの抗体を産生することが可能であるため、この細胞を3L培養することで約1.6 gの抗体精製に成功した。投与試験には病態初期の無症候期 (AL) 、および病態後期のリンパ球増多症 (PL) を呈す感染牛4頭 (AL2頭、PL2頭) を使用し、それぞれをコントロール群1頭、抗体接種群1頭に分けて使用した。抗体投与群にはキメラ抗体を1 mg/kgの用量で静脈内投与し、コントロール群には等量の生理食塩水を投与して2ヶ月間経過を観察した。その結果、AL牛では抗体を接種した牛で有意なプロウイルス量の減少が見られたのに対し、コントロール群では明らかな減少は認められなかった。さらに、コントロール群の個体のプロウイルス量は一部増加傾向にあり、抗PD-L1キメラ抗体の効果を裏付ける結果と考えている。しかしながら、PL牛では抗体接種群においても抗ウイルス効果が認められず、病態後期のウシでも安定して効果を発揮できる投与条件を検討することが必要だと考えられた。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Report

(3 results)
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (27 results)

All 2017 2016 2015 Other

All Int'l Joint Research (3 results) Journal Article (11 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 11 results,  Open Access: 11 results,  Acknowledgement Compliant: 5 results) Presentation (8 results) (of which Int'l Joint Research: 4 results) Patent(Industrial Property Rights) (5 results)

  • [Int'l Joint Research] シドニー大学(オーストラリア)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] フィリピンカラバオセンター(フィリピン)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] モンゴル生命科学大学(モンゴル)

    • Related Report
      2016 Annual Research Report
  • [Journal Article] In vitro and in vivo antivirus activity of an anti-programmed death-ligand 1 (PD-L1) rat-bovine chimeric antibody against bovine leukemia virus infection.2017

    • Author(s)
      Nishimori A, Konnai S, Okagawa T, Maekawa N, Ikebuchi R, Goto S, Sajiki Y, Suzuki Y, Kohara J, Ogasawara S, Kato Y, Murata S, Ohashi K.
    • Journal Title

      PLoS One

      Volume: 印刷中 Issue: 4 Pages: e0174916-e0174916

    • DOI

      10.1371/journal.pone.0174916

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Identification of an atypical enzootic bovine leukosis in Japan by using a novel classification of bovine leukemia based on immunophenotypic analysis.2017

    • Author(s)
      Nishimori, A., Konnai, S., Okagawa, T., Maekawa, N., Goto, S., Ikebuchi, R., Nakahara, A., Chiba, Y., Ikeda, M., Murata, S. and Ohashi, K.
    • Journal Title

      Clin. Vaccine Immunol.

      Volume: CVI.00067-17. Issue: 9

    • DOI

      10.1128/cvi.00067-17

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increase of cells expressing PD-1 and PD-L1 and enhancement of IFN-γ production via PD-1/PD-L1 blockade in bovine mycoplasmosis2017

    • Author(s)
      Goto Shinya、Konnai Satoru、Okagawa Tomohiro、Nishimori Asami、Maekawa Naoya、Gondaira Satoshi、Higuchi Hidetoshi、Koiwa Masateru、Tajima Motoshi、Kohara Junko、Ogasawara Satoshi、Kato Yukinari、Suzuki Yasuhiko、Murata Shiro、Ohashi Kazuhiko
    • Journal Title

      Immunity, Inflammation and Disease

      Volume: 5 Issue: 3 Pages: 355-363

    • DOI

      10.1002/iid3.173

    • NAID

      120006711664

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Anti-Bovine Programmed Death-1 Rat-Bovine Chimeric Antibody for Immunotherapy of Bovine Leukemia Virus Infection in Cattle.2017

    • Author(s)
      Okagawa, T., Konnai, S., Nishimori, A., Maekawa, N., Ikebuchi, R., Goto, S., Nakajima, C., Kohara, J., Ogasawara, S., Kato, Y., Suzuki, Y., Murata, S. and Ohashi, K.
    • Journal Title

      Front Immunol.

      Volume: 8 Pages: 650-650

    • DOI

      10.3389/fimmu.2017.00650

    • NAID

      120006370596

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A canine chimeric monoclonal antibody targeting PD-L1 and its clinical efficacy in canine oral malignant melanoma or undifferentiated sarcoma2017

    • Author(s)
      Maekawa Naoya、Konnai Satoru、Takagi Satoshi、Kagawa Yumiko、Okagawa Tomohiro、Nishimori Asami、Ikebuchi Ryoyo、Izumi Yusuke、Deguchi Tatsuya、Nakajima Chie、Kato Yukinari、Yamamoto Keiichi、Uemura Hidetoshi、Suzuki Yasuhiko、Murata Shiro、Ohashi Kazuhiko
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 8951-8951

    • DOI

      10.1038/s41598-017-09444-2

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Detection of bovine leukemia virus and identification of its genotype in Mongolian cattle.2016

    • Author(s)
      Ochirkhuu N, Konnai S, Odbileg R, Nishimori A, Okagawa T, Murata S, Ohashi K
    • Journal Title

      Archives of Virology

      Volume: 161 Issue: 4 Pages: 985-991

    • DOI

      10.1007/s00705-015-2676-8

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Immunohistochemical Analysis of PD-L1 Expression in Canine Malignant Cancers and PD-1 Expression on Lymphocytes in Canine Oral Melanoma.2016

    • Author(s)
      Maekawa N, Konnai S, Okagawa T, Nishimori A, Ikebuchi R, Izumi Y, Takagi S, Kagawa Y, Nakajima C, Suzuki Y, Kato Y, Murata S, Ohashi K.
    • Journal Title

      PLoS One

      Volume: 11 Issue: 6 Pages: e0157176-e0157176

    • DOI

      10.1371/journal.pone.0157176

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Direct polymerase chain reaction from blood and tissue samples for rapid diagnosis of bovine leukemia virus infection2016

    • Author(s)
      Nishimori A, Konnai S, Ikebuchi R, Okagawa T, Nakahara A, Murata S, Ohashi K
    • Journal Title

      Journal of Veterinary Medical Science

      Volume: 78 Issue: 5 Pages: 791-796

    • DOI

      10.1292/jvms.15-0577

    • NAID

      130005154280

    • ISSN
      0916-7250, 1347-7439
    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Bovine immunoinhibitory receptors contribute to the suppression of Mycobacterium avium subsp. paratuberculosis-specific T-cell responses2015

    • Author(s)
      Okagawa, T., Konnai, S., Nishimori, A., Ikebuchi, R., Mizorogi, S., Nagata, R., Kawaji, S., Tanaka, S., Kagawa, Y., Murata, S., Mori, Y., Ohashi, K.
    • Journal Title

      Infect. Immun.

      Volume: 84 Issue: 1 Pages: 77-89

    • DOI

      10.1128/iai.01014-15

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Increased expression of the regulatory T cell-associated marker CTLA-4 in bovine leukemia virus infection.2015

    • Author(s)
      Suzuki S, Konnai S, Okagawa T, Ikebuchi R, Nishimori A, Kohara J, Mingala CN, Murata S, Ohashi K
    • Journal Title

      Veterinary immunology and immunopathology

      Volume: 163 Issue: 3-4 Pages: 115-124

    • DOI

      10.1016/j.vetimm.2014.10.006

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Bovine leukemia virus reduces anti-viral cytokine activities and NK cytotoxicity by inducing TGF-β secretion from regulatory T cells.2015

    • Author(s)
      Ohira K, Nakahara A, Konnai S, Okagawa T, Nishimori A, Maekawa N, Ikebuchi R, Murata S, Ohashi K.
    • Journal Title

      Immun. Inflamm.

      Volume: 4 Issue: 1 Pages: 52-63

    • DOI

      10.1002/iid3.93

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] 日本国内における牛白血病発症牛の分類と表現型解析2017

    • Author(s)
      西森朝美,今内覚,岡川朋弘,前川直也,後藤伸也,池淵良洋,中原綾子,千葉由純,池田昌穂,村田史郎,大橋和彦
    • Organizer
      第51回日本ウイルス学会北海道支部 夏季シンポジウム
    • Related Report
      2017 Annual Research Report
  • [Presentation] BLV感染症をモデルとした抗ウシPD-L1キメラ抗体の臨床応用試験2017

    • Author(s)
      西森朝美,今内覚,岡川朋弘,前川直也,池淵良洋,後藤伸也,佐治木大和,鈴木定彦,小原潤子,小笠原諭,加藤幸成,村田史郎,大橋和彦
    • Organizer
      第160回日本獣医学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] In vitro and in vivo antivirus activity of an anti-programmed death-ligand 1 (PD-L1) rat-bovine chimeric antibody against bovine leukemia virus infection2017

    • Author(s)
      Nishimori A, Konnai S, Okagawa, Maekawa N, Ikebuchi R, Goto S, Sajiki Y, Suzuki Y, Kohara J, Ogasawara S, Kato Y, Murata S, Ohashi K
    • Organizer
      The 5th Sapporo Summer Seminar for One Health
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] In vivo analysis of anti-bovine PD-L1 antibody for clinical application in BLV infection.2016

    • Author(s)
      Nishimori A, Konnai S, Okagawa, Maekawa N, Suzuki Y, Nakajima C, Kohara J, Kato Y, Murata S, Ohashi K.
    • Organizer
      The 4th Sapporo Summer Seminar for One Health
    • Place of Presentation
      北海道札幌市北海道大学
    • Year and Date
      2016-09-20
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Phenotypic analysis using flow cytometry provides novel character of B-cell lymphoma caused by bovine leukemia virus (BLV) in cattle.2016

    • Author(s)
      Nishimori A, Konnai S, Okagawa T, Maekawa N, Goto S, Murata S, Ohashi K.
    • Organizer
      International Veterinary Immunology Symposium 2016
    • Place of Presentation
      Gold Coast, Australia
    • Year and Date
      2016-08-16
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Field survey for phenotypic analysis of juvenile cattle with lymphoma in Japan.2015

    • Author(s)
      Nishimori A, Konnai S, Okagawa, Murata S, Ohashi K.
    • Organizer
      The 3rd Sapporo Summer Seminar for One Health
    • Place of Presentation
      北海道札幌市北海道大学
    • Year and Date
      2015-09-16
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 日本国内における牛白血病若齢発症牛の実態調査と表現型解析.2015

    • Author(s)
      西森朝美,今内覚,池渕良洋,岡川朋弘,中原綾子,千葉由純,戸塚千恵,村田史郎,大橋和彦.
    • Organizer
      第158回日本獣医学会学術集会
    • Place of Presentation
      青森県十和田市北里大学
    • Year and Date
      2015-09-07
    • Related Report
      2015 Annual Research Report
  • [Presentation] 牛白血病ウイルス感染症における疲弊化T細胞の動態とその再活性化.2015

    • Author(s)
      岡川朋弘,今内覚,西森朝美,前川直也,池渕良洋,村田史郎,大橋和彦.
    • Organizer
      第158回日本獣医学会学術集会
    • Place of Presentation
      青森県十和田市北里大学
    • Year and Date
      2015-09-07
    • Related Report
      2015 Annual Research Report
  • [Patent(Industrial Property Rights)] PD-L1検出用抗PD-L1抗体2017

    • Inventor(s)
      今内 覚, 大橋和彦, 村田史郎, 岡川朋弘, 西森朝美, 他
    • Industrial Property Rights Holder
      今内 覚, 大橋和彦, 村田史郎, 岡川朋弘, 西森朝美, 他
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-061389
    • Filing Date
      2017-03-27
    • Related Report
      2016 Annual Research Report
  • [Patent(Industrial Property Rights)] 抗PD-L1抗体2016

    • Inventor(s)
      今内 覚, 大橋和彦, 村田史郎, 鈴木定彦, 中島千絵, 他
    • Industrial Property Rights Holder
      今内 覚, 大橋和彦, 村田史郎, 鈴木定彦, 中島千絵, 他
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2016-159088
    • Filing Date
      2016-08-15
    • Related Report
      2016 Annual Research Report
  • [Patent(Industrial Property Rights)] ウシ用抗PD-L1抗体2016

    • Inventor(s)
      今内 覚, 大橋和彦, 村田史郎, 鈴木定彦, 中島千絵, 他
    • Industrial Property Rights Holder
      今内 覚, 大橋和彦, 村田史郎, 鈴木定彦, 中島千絵, 他
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2016-159089
    • Filing Date
      2016-08-15
    • Related Report
      2016 Annual Research Report
  • [Patent(Industrial Property Rights)] 抗PD-1抗体2016

    • Inventor(s)
      今内 覚, 大橋和彦, 村田史郎, 鈴木定彦, 中島千絵, 他
    • Industrial Property Rights Holder
      今内 覚, 大橋和彦, 村田史郎, 鈴木定彦, 中島千絵, 他
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2016-159090
    • Filing Date
      2016-08-15
    • Related Report
      2016 Annual Research Report
  • [Patent(Industrial Property Rights)] 抗LAG-3抗体2016

    • Inventor(s)
      今内 覚, 大橋和彦, 村田史郎, 鈴木定彦, 中島千絵, 他
    • Industrial Property Rights Holder
      今内 覚, 大橋和彦, 村田史郎, 鈴木定彦, 中島千絵, 他
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2016-159091
    • Filing Date
      2016-08-15
    • Related Report
      2016 Annual Research Report

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Published: 2015-11-26   Modified: 2024-03-26  

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