A comparative analysis of HAM/TSP using novel animal model and patients samples for understanding pathogenesis and identifying potential targets for future therapy.

• Project/Area Number: 18K07541
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Kawasaki Medical School
• Principal Investigator: Saito Mineki 川崎医科大学, 医学部, 教授 (40398285)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: HTLV-1 / HAM/TSP / 動物モデル / T細胞受容体 / 自己抗原特異的T細胞

Outline of Final Research Achievements

In HTLV-1 associated myelopathy (HAM), various autoantibodies are frequently detected in peripheral blood, and there are many cases of complications with other inflammatory diseases including autoimmune diseases. In this study, we generated double transgenic (Tg) mice by crossing the myelin oligodendrocyte glycoprotein -specific T-cell receptor-Tg mouse with mice expressing one of the two HTLV-1 viral regulatory genes (i.e., tax or HBZ) under control of a murine CD4-specific promoter/enhancer/silencer (2D2-Tax-Tg or 2D2-HBZ-Tg mouse). These mice spontaneously develop HAM-like lower limb paraplegia (HAM mice). Using both HAM mice and HAM patient specimens, we searched for host cell factors that reflect the pathophysiology. As a result, multiple host cell factors containing tax or HBZ target genes were identified. These factors can be new biomarkers and therapeutic target candidates that reflect the pathophysiology of HAM.

Academic Significance and Societal Importance of the Research Achievements

HTLV-1はマウスに感染しないため、従来HAMの小動物モデルは存在しなかった。我々が先行研究で独自に開発したHAM病態モデルマウスの病理学的・免疫学的解析結果は、HAM患者の特徴とよく一致しており、本マウスと患者検体との統合的な比較解析を通して新規治療標的や治療薬候補を探索することは、病態解析、発症予防・治療法の開発において極めて重要であり、学術的・社会的意義が大きい。今回の研究で、両者の病態に共通して関与する宿主細胞因子を同定できたことから、今後さらなる解析を通じて、HAMにおける慢性炎症形成の分子機構解明と新規発症予防法・治療法の開発に資する成果が得られる可能性がある。

Research Products

• [Journal Article] Genome wide association study of HTLV-1 associated myelopathy/tropical spastic paraparesis in the Japanese population (2021)
  • Author(s): Penova Marina et al.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 118 Issue: 11
  • DOI: 10.1073/pnas.2004199118
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of ABL1 tyrosine kinase reduces HTLV-1 proviral loads in peripheral blood mononuclear cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (2020)
  • Author(s): Kodama Daisuke, Tanaka Masakazu, Matsuzaki Toshio, Izumo Kimiko, Nakano Nobuaki, Matsuura Eiji, Saito Mineki, Nagai Masahiro, Horiuchi Masahisa, Utsunomiya Atae, Takashima Hiroshi, Kubota Ryuji, Izumo Shuji
  • Journal Title: PLOS Neglected Tropical Diseases Volume: 14 Issue: 7 Pages: e0008361-e0008361
  • DOI: 10.1371/journal.pntd.0008361
  • Peer Reviewed / Open Access
• [Journal Article] EOS, an Ikaros family zinc finger transcription factor, interacts with the HTLV-1 oncoprotein Tax and is downregulated in peripheral blood mononuclear cells of HTLV-1-infected individuals, irrespective of clinical statuses. (2019)
  • Author(s): Naito T, Ushirogawa H, Fukushima T, Tanaka Y, Saito M.
  • Journal Title: Virology Journal Volume: 16 Issue: 1 Pages: 160-160
  • DOI: 10.1186/s12985-019-1270-1
  • NAID: 120006937799
  • Peer Reviewed / Open Access
• [Journal Article] Association between HTLV-1 genotypes and risk of HAM/TSP. (2019)
  • Author(s): Saito M.
  • Journal Title: Frontiers in Microbiology Volume: 10 Pages: 1101-1101
  • DOI: 10.3389/fmicb.2019.01101
  • Peer Reviewed / Open Access
• [Journal Article] Association of high levels of plasma OX40 with acute adult T-cell leukemia. (2019)
  • Author(s): Tanaka Y, Takahashi Y, Tanaka R, Miyagi T, Saito M, Fukushima T.
  • Journal Title: International Journal of Hematology Volume: 109 Issue: 3 Pages: 319-327
  • DOI: 10.1007/s12185-018-02580-z
  • Peer Reviewed / Open Access
• [Journal Article] Diversity of cell phenotypes among MT-2 cell lines affects the growth of U937 cells and cytokine production (2018)
  • Author(s): Nomura Hajime、Umekita Kunihiko、Hashikura Yuuki、Umeki Kazumi、Yamamoto Ikuo、Aratake Yatsuki、Saito Mineki、Hasegawa Hiroo、Yanagihara Katsunori、Okayama Akihiko
  • Journal Title: Human Cell Volume: 32 Issue: 2 Pages: 185-192
  • DOI: 10.1007/s13577-018-00231-3
  • Peer Reviewed
• [Journal Article] Distinct gene expression signatures induced by viral transactivators of different HTLV-1 subgroups that confer a different risk of HAM/TSP. (2018)
  • Author(s): Naito T, Yasunaga JI, Mitobe Y, Shirai K, Sejima H, Ushirogawa H, Tanaka Y, Nakamura T, Hanada K, Fujii M, Matsuoka M, Saito M.
  • Journal Title: Retrovirology Volume: 15 Issue: 1 Pages: 72-72
  • DOI: 10.1186/s12977-018-0454-x
  • NAID: 120006847301
  • Peer Reviewed / Open Access
• [Presentation] HTLV-1サブグループによるHAM感受性の違い (2019)
  • Author(s): 齊藤峰輝, 後川 潤, 内藤忠相
  • Organizer: 第6回日本HTLV-1学会学術集会
• [Presentation] 免疫老化を制御するMenin-Bach2経路にHTLV-1が及ぼす影響の解析 (2018)
  • Author(s): 瀬島寛恵, 内藤忠相, 齊藤峰輝
  • Organizer: 第5回日本HTLV-1学会学術集会
• [Remarks] 川崎医科大学微生物学教室ホームページ
  • URL: http://www.kawasaki-m.ac.jp/microbiology/index.html
• [Remarks] 川崎医科大学微生物学教室ホームページ
  • URL: http://www.kawasaki-m.ac.jp/microbiology/