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Study on molecular mechanism of collagen-induced arthritis in cynomolgus monkeys

Research Project

Project/Area Number 19H03148
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 42040:Laboratory animal science-related
Research InstitutionTokai University

Principal Investigator

Shiina Takashi  東海大学, 医学部, 教授 (00317744)

Co-Investigator(Kenkyū-buntansha) 伊藤 靖  滋賀医科大学, 医学部, 教授 (90324566)
石垣 宏仁  滋賀医科大学, 医学部, 准教授 (90432301)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2021: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2020: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2019: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Keywordsカニクイザル / 疾患モデル / MHC / 関節リウマチ / コラーゲン誘導関節炎 / リウマチ / 自己免疫疾患
Outline of Research at the Start

申請者らは、これまでに5,500頭に及ぶDNA検査から多数のMHC統御ザルを検出した。この次段階として、MHC多型に基づく疾患解析を実施し、その成果を治療法の開発に繋げることが重要課題の一つである。本課題では、RAモデルであるCIAを例として、CIA発症の分子機序を解明することを目的とする。具体的には、遺伝学、免疫学および病理学の多面的な解析から、CIAと関連するMHC多型、CIAの重症度を規定する多型マーカーやバイオマーカーの同定等、CIA発症と関連する遺伝要因を明らかにする。個体数削減と再現性を重視した非臨床試験の実施やCIAとRAとの解析データを対比させながら進める点に独創性がある。

Outline of Final Research Achievements

The development of a collagen-induced arthritis model (CIA) using cynomolgus macaques has been reported about 30 years ago, but its association with major histocompatibility complex (MHC) polymorphism has not been investigated in detail. In this study, we elucidated the molecular mechanism of the CIA onset in the macaques using genetic, immunological and pathological techniques. We identified a CIA-susceptible MHC class II allele by DNA typing of the MHC genes and revealed that the allele has the identical amino acid motif sequence as rheumatoid arthritis-sensitive human leukocyte antigen (HLA) alleles. Furthermore, individuals that have the MHC allele suggested to be produced a large amount of type II collagen-specific Th1 type IgG1 antibody and more strongly induced inflammation of CIA.

Academic Significance and Societal Importance of the Research Achievements

本課題により長年に渡り不明であったCIAと感受性を示すMHC多型が同定され、関節リウマチと類似した遺伝学および免疫学特徴が見出された点に学術的意義があり、他のHLA関連疾患モデルの作出のための貴重な基礎的データを取得できたと考えられる。このMHC多型に基づくCIAモデルの作出から、個体数削減と再現性を重視した非臨床試験への展開、関節リウマチの治療法開発に関する斬新なシーズの創生等が将来的に期待される。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (24 results)

All 2021 2020 2019

All Journal Article (17 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 17 results,  Open Access: 12 results) Presentation (7 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] No Tumorigenicity of Allogeneic Induced Pluripotent Stem Cells in Major Histocompatibility Complex-matched Cynomolgus Macaques.2021

    • Author(s)
      Ishigaki H, Pham VL, Terai J, Sasamura T, Nguyen CT, Ishida H, Okahara J, Kaneko S, Shiina T, Nakayama M, Itoh Y, Ogasawara K.
    • Journal Title

      Cell Transplantation

      Volume: Jan-Dec;30 Pages: 963689721992066-963689721992066

    • DOI

      10.1177/0963689721992066

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Neutralizing antibody-dependent and -independent immune responses against SARS-CoV-2 in cynomolgus macaques2021

    • Author(s)
      Ishigaki Hirohito、Nakayama Misako、Kitagawa Yoshinori、Nguyen Cong Thanh、Hayashi Kaori、Shiohara Masanori、Gotoh Bin、Itoh Yasushi
    • Journal Title

      Virology

      Volume: 554 Pages: 97-105

    • DOI

      10.1016/j.virol.2020.12.013

    • NAID

      120006953803

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy of a Cap-Dependent Endonuclease Inhibitor and Neuraminidase Inhibitors against H7N9 Highly Pathogenic Avian Influenza Virus Causing Severe Viral Pneumonia in Cynomolgus Macaques2020

    • Author(s)
      Suzuki Saori、Nguyen Cong Thanh、Ogata-Nakahara Ayako、Shibata Akihiro、Osaka Hiroyuki、Ishigaki Hirohito、Okamatsu Masatoshi、Sakoda Yoshihiro、Kida Hiroshi、Ogasawara Kazumasa、Itoh Yasushi
    • Journal Title

      Antimicrobial Agents and Chemotherapy

      Volume: 65 Issue: 3 Pages: 1825-1820

    • DOI

      10.1128/aac.01825-20

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Immune profiling of influenza‐specific B‐ and T‐cell responses in macaques using flow cytometry‐based assays2020

    • Author(s)
      Koutsakos Marios、Ishigaki Hirohito、Itoh Yasushi、Kedzierska Katherine et al.
    • Journal Title

      Immunology & Cell Biology

      Volume: 99 Issue: 1 Pages: 97-106

    • DOI

      10.1111/imcb.12383

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Experimental techniques for the development of a uterus transplantation model in cynomolgus macaques2020

    • Author(s)
      Kisu Iori、Ishigaki Hirohito、Shiina Takashi、Aoki Daisuke et al.
    • Journal Title

      Journal of Obstetrics and Gynaecology Research

      Volume: 46 Issue: 11 Pages: 2251-2260

    • DOI

      10.1111/jog.14477

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Embryonal Carcinoma and Glioblastoma Cell Lines Derived from Monkey Induced Pluripotent Stem Cells2020

    • Author(s)
      Ishigaki Hirohito、Itoh Yasushi
    • Journal Title

      Methods in Molecular Biology

      Volume: 25 Pages: 1-17

    • DOI

      10.1007/7651_2020_303

    • ISBN
      9781071621189, 9781071621196
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Clinical features of irreversible rejection after allogeneic uterus transplantation in cynomolgus macaques2020

    • Author(s)
      Kisu Iori、Ishigaki Hirohito、Shiina Takashi et al.
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 13910-13910

    • DOI

      10.1038/s41598-020-70914-1

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Natural History of Spontaneously Occurred Endometriosis in Cynomolgus Monkeys by Monthly Follow-Up Laparoscopy for Two Years2020

    • Author(s)
      Hayashi Kaori、Nakayama Misako、Iwatani Chizuru、Tsuchiya Hideaki、Nakamura Shinichiro、Nonoguchi Kosuke、Itoh Yasushi、Tsuji Shunichiro、Ishigaki Hirohito、Mori Takahide、Murakami Takashi、Ogasawara Kazumasa
    • Journal Title

      The Tohoku Journal of Experimental Medicine

      Volume: 251 Issue: 4 Pages: 241-253

    • DOI

      10.1620/tjem.251.241

    • NAID

      130007879339

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characterization of tumour-infiltrating lymphocytes in a tumour rejection cynomolgus macaque model2020

    • Author(s)
      Satooka Hiroki、Ishigaki Hirohito、Todo Kagefumi、Terada Koji、Agata Yasutoshi、Itoh Yasushi、Ogasawara Kazumasa、Hirata Takako
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 8414-8414

    • DOI

      10.1038/s41598-020-65488-x

    • NAID

      120006862372

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Low replicative fitness of neuraminidase inhibitor-resistant H7N9 avian influenza A virus with R292K substitution in neuraminidase in cynomolgus macaques compared with I222T substitution.2020

    • Author(s)
      Suzuki S, Shichinohe S, Itoh Y, Nakayama M, Ishigaki H, Mori Y, Ogata-Nakahara A, Nguyen TC, Okamatsu M, Sakoda Y, Kida H, Ogasawara K.
    • Journal Title

      Antiviral Research

      Volume: 178 Pages: 104790-104790

    • DOI

      10.1016/j.antiviral.2020.104790

    • NAID

      120006845305

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] First Successful Delivery after Uterus Transplantation in MHC-Defined Cynomolgus Macaques2020

    • Author(s)
      Kisu Iori、Ishigaki Hirohito、Shiina Takashi et al.
    • Journal Title

      Journal of Clinical Medicine

      Volume: 9 Issue: 11 Pages: 3694-3694

    • DOI

      10.3390/jcm9113694

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Histological analysis of fundic gland polyps enlarged by proton pump inhibitors2019

    • Author(s)
      Fukuda M, Ishigaki H, Sugimoto M, Mukaisho K, Matsubara A, Ishida H, Moritani S, Itoh Y, Sugihara H, Andoh A, Ogasawara K, Murakami K, Kushima R
    • Journal Title

      Histopathology

      Volume: 75 Issue: 4 Pages: 537-545

    • DOI

      10.1111/his.13902

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Long-Term Outcome and Rejection After Allogeneic Uterus Transplantation in Cynomolgus Macaques2019

    • Author(s)
      Kisu、Ishigaki、Emoto、Kato、Yamada、Matsubara、Obara、Masugi、Matoba、Adachi、Banno、Saiki、Itagaki、Kawamoto、Iwatani、Nakagawa、Tsuchiya、Sasamura、Urano、Ema、Ogasawara、Aoki、Nakagawa、Shiina
    • Journal Title

      Journal of Clinical Medicine

      Volume: 8 Issue: 10 Pages: 1572-1572

    • DOI

      10.3390/jcm8101572

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inactivated whole virus particle vaccine with potent immunogenicity and limited IL-6 production is ideal for influenza2019

    • Author(s)
      Sekiya T, Mifsud EJ, Ohno M, Nomura N, Sasada M, Fujikura D, Daito T, Shingai M, Ohara Y, Nishimura T, Endo M, Mitsumata R, Ikeda T, Hatanaka H, Kitayama H, Motokawa K, Sobue T, Suzuki S, Itoh Y, Brown LE, Ogasawara K, Kino Y, Kida H
    • Journal Title

      Vaccine

      Volume: 37 Issue: 15 Pages: 2158-2166

    • DOI

      10.1016/j.vaccine.2019.02.057

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The Cynomolgus Macaque MHC Polymorphism in Experimental Medicine2019

    • Author(s)
      Shiina、Blancher
    • Journal Title

      Cells

      Volume: 8 Issue: 9 Pages: 978-978

    • DOI

      10.3390/cells8090978

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cynomolgus macaque IL37 polymorphism and control of SIV infection2019

    • Author(s)
      Shiina Takashi、Suzuki Shingo、Congy-Jolivet Nicolas、Aarnink Alice、Garchon Henri-Jean、Dereuddre-Bosquet Nathalie、Vaslin Bruno、Tchitchek Nicolas、Desjardins Delphine、Autran Brigitte、Lambotte Olivier、Theodorou Ioannis、Le Grand Roger、Blancher Antoine
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 7981-7981

    • DOI

      10.1038/s41598-019-44235-x

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Nomenclature report 2019: major histocompatibility complex genes and alleles of great and small ape and old and new world monkey species2019

    • Author(s)
      de Groot NG, Otting N, Maccari G, Robinson J, Hammond JA, Blancher A, Lafont BAP, Guethlein LA, Wroblewski EE, Marsh SGE, Shiina T, Walter L, Vigilant L, Parham P, O'Connor DH, Bontrop RE
    • Journal Title

      Immunogenetics

      Volume: 72 Pages: 25-36

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] カニクイザルを用いた組織適合抗原複合体一致他家iPS細胞移植においてteratomaは形成されない2020

    • Author(s)
      石垣宏仁、寺井淳、仲山美沙子、伊藤靖、小笠原一誠
    • Organizer
      第109回 日本病理学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] カニクイザルを用いたH7N9亜型高病原性鳥インフルエンザウイルスの病原性解析2020

    • Author(s)
      緒方綾子、鈴木沙織、 グエン タン・コン、伊藤靖、石垣宏仁、仲山美沙子、小笠原一誠
    • Organizer
      第109回 日本病理学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] H7N9高病原性鳥インフルエンザウイルスに対するバロキサビルの有効性評価および免疫反応の解析2020

    • Author(s)
      鈴木沙織、Than Cong Nguyen、緒方(中原)綾子、石垣宏仁、仲山美沙子、伊藤靖
    • Organizer
      第163回 日本獣医学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] カニクイザルを用いた H5N6 亜型高病原性鳥インフルエンザウイルスによる重症肺炎の解析2019

    • Author(s)
      伊藤靖、Cong Nguyen Thanh、鈴木紗織、石垣宏仁、仲山美沙子、小笠原一誠
    • Organizer
      第108回 日本病理学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] LAP陽性細胞吸着カラムの癌治療への応用2019

    • Author(s)
      寺本和雄、石垣宏仁、仲山美沙子、伊藤靖、小笠原一誠
    • Organizer
      第78回日本癌学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Investigation of effects of the vaccine for influenza virus in cynomolgus macaques2019

    • Author(s)
      Yasushi Itoh, Saori Suzuki, Hirohito Ishigaki, Misako Nakayama, Takaaki Kinoshita, Kazumasa Ogasawara
    • Organizer
      Asian-African Research Forum on Emerging and Reemerging Infections 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Donor lymphoid cells remain in the skin graft until 14 days after allogeneic transplantation in macaques2019

    • Author(s)
      Hirohito Ishigaki, Cong Thanh Nguyen, Misako Nakayama, Yasushi Itoh, Kazumasa Ogasawara
    • Organizer
      第48回 日本免疫学会総会
    • Related Report
      2019 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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