Development of treatment for Takayasu arteritis using multiomics approach through rheumatic and musculoskeletal diseases

• Project/Area Number: 21K16306
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Keio University
• Principal Investigator: Matsumoto Kotaro 慶應義塾大学, 医学部(信濃町), 助教 (00815425)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2022: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2021: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 高安動脈炎 / 巨細胞性動脈炎 / バイオマーカー / 分子的寛解 / マルチオミックス / マクロファージ / 治療抵抗性メカニズム

Outline of Research at the Start

高安動脈炎は大動脈および大動脈の分枝血管に肉芽腫性炎症を伴う全身性の血管炎症候群であり、血管の閉塞や破綻による臓器障害をきたす難病である。治療戦略はステロイドに依存するが、巨細胞の残存が予後不良の病態に関与している可能性があり、血管壁マクロファージおよび巨細胞を標的とした治療は根治療法につながる。本研究は希少膠原病横断的なマルチオミックス解析を実施し、大型血管炎と疾患コントロールとの共通シグナルおよび差次的シグナルを明らかにする。特に、高安動脈炎の治療標的分子を同定し、病態モデルマウスを用いて治療標的分子の役割を明らかにする。

Outline of Final Research Achievements

The purpose of this project is to elucidate the significant molecule to reflect the landscape of Takayasu arteritis. We have identified the novel molecule to reflect the pathogenesis of vasculitis using multiomics analysis. We screened vasculitis-specific molecules by combining the findings from serum proteome analysis and whole blood bulk RNA sequencing. Then, we validated the results using immunohistochemical staining and spatial transcriptome analysis. The molecule we identified can distinguish vasculitis from other rheumatic and musculoskeletal diseases. The longitudinal testing of it can predict clinical response in patients with LVV, and also monitor insidious disease activity. It may have potential as a target for diagnostic or therapeutic agents.

Academic Significance and Societal Importance of the Research Achievements

血管炎病態の重症度と関連し、予後の層別化、再燃の予測に有用な分子を同定した。IL-6を指標としないため、IL-6阻害治療下であっても再燃に先行して病勢を反映するバイオマーカーとなり得る。さらに、これを治療標的とした新規治療が奏功すれば、高安動脈炎の根治的治療となり得る。

Research Products

• [Journal Article] Distinct gene signatures of monocytes and B cells in patients with giant cell arteritis: a longitudinal transcriptome analysis (2023)
  • Author(s): Kotaro Matsumoto, Katsuya Suzuki, Hiroto Yoshida, Mayu Magi, Yoshihiro Matsumoto, Mariko Noguchi-Sasaki, Keiko Yoshimoto, Tsutomu Takeuchi, Yuko Kaneko
  • Journal Title: Arthritis Res Ther. Volume: 25 Issue: 1 Pages: 1-1
  • DOI: 10.1186/s13075-022-02982-9
  • Peer Reviewed / Open Access
• [Journal Article] Longitudinal monitoring of circulating immune cell phenotypes in anti-neutrophil cytoplasmic antibody-associated vasculitis (2023)
  • Author(s): Matsumoto Kotaro、Suzuki Katsuya、Yasuoka Hidekata、Hirahashi Junichi、Yoshida Hiroto、Magi Mayu、Noguchi-Sasaki Mariko、Kaneko Yuko、Takeuchi Tsutomu
  • Journal Title: Autoimmunity Reviews Volume: 22 Issue: 3 Pages: 103271-103271
  • DOI: 10.1016/j.autrev.2023.103271
  • Peer Reviewed / Open Access
• [Journal Article] Changes in the molecular profiles of large-vessel vasculitis treated with biological disease-modifying anti-rheumatic drugs and Janus kinase inhibitors (2023)
  • Author(s): Matsumoto K, Suzuki K, Takeshita M, Takeuchi T, Kaneko Y
  • Journal Title: Frontiers in Immunology Volume: 14
  • DOI: 10.3389/fimmu.2023.1197342
  • Peer Reviewed / Open Access
• [Journal Article] Longitudinal monitoring of circulating immune cell phenotypes in large vessel vasculitis (2022)
  • Author(s): Matsumoto Kotaro、Suzuki Katsuya、Yoshida Hiroto、Magi Mayu、Kaneko Yuko、Takeuchi Tsutomu
  • Journal Title: Autoimmunity Reviews Volume: 21 Issue: 10 Pages: 103160-103160
  • DOI: 10.1016/j.autrev.2022.103160
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin‐1 pathway in active large vessel vasculitis patients with a poor prognosis: a longitudinal transcriptome analysis (2021)
  • Author(s): Matsumoto Kotaro、Suzuki Katsuya、Yoshimoto Keiko、Ishigaki Sho、Yoshida Hiroto、Magi Mayu、Matsumoto Yoshihiro、Kaneko Yuko、Takeuchi Tsutomu
  • Journal Title: Clinical and Translational Immunology Volume: 10 Issue: 7
  • DOI: 10.1002/cti2.1307
  • Peer Reviewed / Open Access
• [Patent(Industrial Property Rights)] MMP12を指標とした免疫介在性炎症性疾患の診断、及びMMP12阻害による免疫介在性炎症性疾患の治療用医薬 (2023)
  • Inventor(s): 松本紘太郎、金子祐子、鈴木勝也、花岡健二郎、佐々木栄太
  • Industrial Property Rights Holder: 松本紘太郎、金子祐子、鈴木勝也、花岡健二郎、佐々木栄太
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2022-173336
  • Filing Date: 2023
  • Overseas