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全身性強皮症における組織中B細胞と組織微小環境の検討

Research Project

Project/Area Number 22K16259
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53050:Dermatology-related
Research InstitutionThe University of Tokyo

Principal Investigator

久住 藍  東京大学, 医学部附属病院, 助教 (80907759)

Project Period (FY) 2022-04-01 – 2025-03-31
Project Status Granted (Fiscal Year 2023)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2024: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords全身性強皮症 / 自己免疫疾患 / B細胞 / 組織微小環境
Outline of Research at the Start

抗CD20抗体によるB細胞除去療法は全身性強皮症(SSc)の新規治療として注目されているが、しばしば治療効果に乏しい。申請者はSScモデルマウスの組織中B細胞の一部が抗CD20抗体による除去に抵抗性であることを見出し、これが治療抵抗性に寄与しているのではないかと着想した。本研究では、自己抗原反応性B細胞をもつ独自のモデルマウスを用いて、除去抵抗性の組織中B細胞の病原性を明らかにする。また、SScの組織微小環境が組織中B細胞の除去抵抗性に関与する可能性について、B細胞の生存と局在に重要なCXCL12-CXCR4軸に着目して検討し、組織中B細胞の除去率の高い、より効果的なB細胞除去療法を探求する。

Outline of Annual Research Achievements

全身性強皮症(systemic sclerosis; SSc)は皮膚と内臓諸臓器に線維化をきたす予後不良な自己免疫疾患である。近年、SScの病態形成にB細胞が重要であることが見出され、抗ヒトCD20ヒト・マウスキメラ抗体であるリツキシマブによるB細胞除去療法が新規治療として注目されている。しかし、リツキシマブにより末梢血中のB細胞がほぼ完全に除去されるのにも関わらず治療効果に乏しいSSc患者もしばしば見られ、組織中のB細胞がリツキシマブに除去抵抗性である可能性が示唆された。しかし、SScの組織中B細胞について検討した研究はなく、除去抵抗性の組織中B細胞の病原性や、抵抗性の機序、治療ターゲットとしての可能性は不明である。
本研究では、自己抗原反応性B細胞をもつ独自のモデルマウスを用いて、抗CD20抗体による除去に抵抗性の組織中B細胞を解析している。また、SScの組織微小環境が組織中B細胞の除去抵抗性に関与する可能性について、B細胞の生存と局在に重要なCXCL12-CXCR4軸について検討中である。さらに、CXCL12-CXCR4軸を阻害することで組織中B細胞の除去率を向上させた、より有効なB細胞除去療法が実現できないか、臨床応用の可能性を模索している。
これまでの検討により、抗CD20抗体による除去に抵抗性の組織中B細胞の病原性および組織中B細胞におけるCXCL12-CXCR4軸の重要性が明らかになってきており、組織中B細胞をより効率良く除去する具体的なアプローチのひとつとして、CXCL12-CXCR4軸のシグナルを阻害する薬剤を抗CD20抗体と併用する新たなSScの治療法について検討している。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

本研究では、topo I誘導SScモデルマウスを用いて、抗CD20抗体による除去に抵抗性の組織中B細胞に関して、その病原性、CXCL12-CXCR4軸の関与、および、治療ターゲットとしての可能性を明らかにすることを目的とする。今年度の進捗を以下に記載した。
1) 抗CD20抗体による除去に抵抗性の組織中B細胞の病原性の解析
野生型マウスにtopo I抗原を免疫し、topo I誘導SScモデルを作成し、抗CD20抗体を腹腔内投与し、皮膚・肺の線維化に対する効果を病理組織学的に評価した。
2) 組織中B細胞におけるCXCL12-CXCR4軸の解析
topo I誘導SScモデルに抗CD20抗体とCXCR4のアンタゴニストAMD3100を投与し、抗線維化効果を調べ、抗CD20抗体単独投与の場合と比べた。

Strategy for Future Research Activity

引き続き、抗CD20抗体による除去に抵抗性の組織中B細胞の病原性の解析と組織中B細胞におけるCXCL12-CXCR4軸の解析を進め、topo I誘導SScモデルマウスを用いて、抗CD20抗体による除去に抵抗性の組織中B細胞に関して、その病原性、CXCL12-CXCR4軸の関与、および、治療ターゲットとしての可能性を明らかにしていく予定である。
本研究は、SScに対するB細胞除去療法を考える上で組織中B細胞の除去が重要であることを見出し、CXCL12-CXCR4軸が組織中B細胞の除去抵抗性に関与することを明らかにしうる。さらに、組織中B細胞をより効率良く除去する具体的なアプローチのひとつとして、CXCL12-CXCR4軸のシグナルを阻害するAMD3100を抗CD20抗体と併用する、新たなSScの治療法を提示できる可能性がある。

Report

(2 results)
  • 2023 Research-status Report
  • 2022 Research-status Report
  • Research Products

    (23 results)

All 2024 2023 2022

All Journal Article (13 results) (of which Int'l Joint Research: 11 results,  Peer Reviewed: 13 results,  Open Access: 11 results) Presentation (10 results) (of which Int'l Joint Research: 8 results,  Invited: 2 results)

  • [Journal Article] Autoantibodies to nuclear valosin-containing protein-like protein: systemic sclerosis-specific antibodies revealed by in vitro human proteome2024

    • Author(s)
      Matsuda Kazuki M, Fukasawa Takemichi et al.
    • Journal Title

      Rheumatology

      Volume: - Issue: 10 Pages: 2865-2873

    • DOI

      10.1093/rheumatology/keae063

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cannabinoids for the treatment of autoimmune and inflammatory skin diseases: A systematic review2024

    • Author(s)
      Kuzumi Ai、Yamashita Takashi、Fukasawa Takemichi、Yoshizaki‐Ogawa Asako、Sato Shinichi、Yoshizaki Ayumi
    • Journal Title

      Experimental Dermatology

      Volume: 33 Issue: 3

    • DOI

      10.1111/exd.15064

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Reliability, validity, and sensitivity of the Japanese version of the University of California Los Angeles scleroderma clinical trial consortium gastrointestinal tract instrument: Application to efficacy assessment of intravenous immunoglobulin administration2024

    • Author(s)
      Matsuda Kazuki M.、Sugimoto Eiki、Ako Yoshiaki、Kitamura Marie、Miyahara Mai、Kotani Hirohito、Norimatsu Yuta、Hisamoto Teruyoshi、Kuzumi Ai、Fukasawa Takemichi、Sato Shinichi、Yoshizaki Ayumi
    • Journal Title

      The Journal of Dermatology

      Volume: - Issue: 6 Pages: 741-751

    • DOI

      10.1111/1346-8138.17202

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Dual blockade of interleukin-17A and interleukin-17F as a therapeutic strategy for liver fibrosis: Investigating the potential effect and mechanism of brodalumab2024

    • Author(s)
      Matsuda Kazuki M.、Kotani Hirohito、Hisamoto Teruyoshi、Kuzumi Ai、Fukasawa Takemichi、Yoshizaki-Ogawa Asako、Sato Shinichi、Yoshizaki Ayumi
    • Journal Title

      Cytokine

      Volume: 178 Pages: 156587-156587

    • DOI

      10.1016/j.cyto.2024.156587

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Comprehensive autoantibody profiling in systemic autoimmunity by a highly-sensitive multiplex protein array2023

    • Author(s)
      Kuzumi Ai、Norimatsu Yuta、Matsuda Kazuki M.、Ono Chihiro、Okumura Taishi、Kogo Emi、Goshima Naoki、Fukasawa Takemichi、Fushida Natsumi、Horii Motoki、Yamashita Takashi、Yoshizaki-Ogawa Asako、Yamaguchi Kei、Matsushita Takashi、Sato Shinichi、Yoshizaki Ayumi
    • Journal Title

      Frontiers in Immunology

      Volume: 14 Pages: 1255540-1255540

    • DOI

      10.3389/fimmu.2023.1255540

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Long-term outcomes after rituximab treatment for patients with systemic sclerosis: follow-up of the DESIRES trial with a focus on serum immunoglobulin levels2023

    • Author(s)
      Kuzumi A, Ebata S, Fukasawa T, Matsuda KM, Kotani H, Yoshizaki-Ogawa A, Sato S, Yoshizaki A
    • Journal Title

      JAMA Dermatol

      Volume: - Issue: 4 Pages: 374-374

    • DOI

      10.1001/jamadermatol.2022.6340

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Significance of anti-transcobalamin receptor antibodies in cutaneous arteritis revealed by proteome-wide autoantibody screening2023

    • Author(s)
      Matsuda K, Kotani H, Yoshizaki A, et al.
    • Journal Title

      Journal of Autoimmunity

      Volume: 135 Pages: 102995-102995

    • DOI

      10.1016/j.jaut.2023.102995

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Rapid improvement of systemic sclerosis-associated intestinal pseudo-obstruction with intravenous immunoglobulin administration.2023

    • Author(s)
      Matsuda KM, Yoshizaki A, Kuzumi A, Toyama S, Awaji K, Miyake T, Sato S.
    • Journal Title

      Rheumatology (Oxford)

      Volume: - Issue: 9 Pages: 3139-3145

    • DOI

      10.1093/rheumatology/kead093

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Interleukin-17 pathway inhibition with brodalumab in early systemic sclerosis: analysis of a single-arm, open-label, phase 1 trial2023

    • Author(s)
      Fukasawa Takemichi、Yoshizaki Ayumi、Ebata Satoshi、Fukayama Maiko、Kuzumi Ai、Norimatsu Yuta、Matsuda Kazuki M、Kotani Hirohito、Sumida Hayakazu、Yoshizaki-Ogawa Asako、Kagebayashi Hisashi、Sato Shinichi
    • Journal Title

      Journal of the American Academy of Dermatology

      Volume: - Issue: 2 Pages: 366-369

    • DOI

      10.1016/j.jaad.2023.02.061

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genital necrosis with cutaneous thrombosis after COVID-19 mRNA vaccination.2022

    • Author(s)
      Kuzumi A, Yoshizaki A, Chiba K, Mitsuo S, Matsuda KM, Norimatsu Y, Nagai K, Omatsu J, Miyake T, Sato S.
    • Journal Title

      J Eur Acad Dermatol Venereol.

      Volume: 36 Issue: 3

    • DOI

      10.1111/jdv.17837

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Autoantibody Landscape Revealed by Wet Protein Array: Sum of Autoantibody Levels Reflects Disease Status2022

    • Author(s)
      Matsuda Kazuki M.、Yoshizaki Ayumi、Yamaguchi Kei、Fukuda Eriko、Okumura Taishi、Ogawa Koji、Ono Chihiro、Norimatsu Yuta、Kotani Hirohito、Hisamoto Teruyoshi、Kawanabe Ruriko、Kuzumi Ai、Fukasawa Takemichi、Ebata Satoshi、Miyagawa Takuya、Yoshizaki-Ogawa Asako、Goshima Naoki、Sato Shinichi
    • Journal Title

      Frontiers in Immunology

      Volume: 13 Pages: 893086-893086

    • DOI

      10.3389/fimmu.2022.893086

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Serum C-X-C Chemokine Ligand 1 Levels in Patients with Systemic Sclerosis: Relationship of Clinical and Laboratory Observations to Anti-CD20 Monoclonal Antibody Administration2022

    • Author(s)
      Kawanabe R, Yoshizaki A, et al
    • Journal Title

      Life

      Volume: 12 Issue: 5 Pages: 646-646

    • DOI

      10.3390/life12050646

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Tocilizumab-induced organizing pneumonia in a patient with systemic sclerosis-associated interstitial lung disease2022

    • Author(s)
      Kuzumi A, Yoshizaki A, Mitsuo S, Miyake T, Sato S.
    • Journal Title

      Rheumatology (Oxford)

      Volume: 62 Issue: SI Pages: SI143-SI144

    • DOI

      10.1093/rheumatology/keac435

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Presentation] Highly sensitive multiplex protein array reveals diverse autoantibody landscape in systemic sclerosis and polymyositis/dermatomyositis2024

    • Author(s)
      Ai Kuzumi, Yuta Norimatsu, Ayumi Yoshizaki, Shinichi Sato
    • Organizer
      2024 31th KSID Annual Meeting
    • Related Report
      2023 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Long-term efficacy of rituximab in patients with systemic sclerosis: follow-up of the DESIRES trial with a focus on serum immunoglobulin levels2023

    • Author(s)
      Ai Kuzumi, Satoshi Ebata, Takemichi Fukasawa, Shinichi Sato, Ayumi Yoshizaki
    • Organizer
      ICCLE2023
    • Related Report
      2023 Research-status Report
    • Int'l Joint Research
  • [Presentation] Effect of previous rituximab administration on immune response after SARS-CoV-2 vaccination in Japanese patients with systemic sclerosis (SSc)2023

    • Author(s)
      Ruriko Kawanabe, Ayumi Yoshizaki, Kazuki M. Matsuda, Hirohito Kotani, Teruyoshi Hisamoto, Yuta Norimatsu, Ai Kuzumi, Takemichi Fukasawa, Satoshi Ebata, Asako Yoshizaki-Ogawa, Shinichi Sato
    • Organizer
      ICCLE2023
    • Related Report
      2023 Research-status Report
    • Int'l Joint Research
  • [Presentation] 全身性強皮症に対するリツキシマブの長期投与における有効性と血清免疫グロブリンの臨床的意義2023

    • Author(s)
      久住藍、江畑慧、深澤毅倫、佐藤伸一、吉崎歩
    • Organizer
      第122回日本皮膚科学会総会
    • Related Report
      2023 Research-status Report
  • [Presentation] 炎症性筋疾患における自己抗体~新たな網羅的自己抗体検出法A-Cubeについて~2023

    • Author(s)
      久住藍、吉崎歩
    • Organizer
      第35回日本神経免疫学会学術集会
    • Related Report
      2023 Research-status Report
    • Invited
  • [Presentation] Genital necrosis with platelet thrombosis after COVID-19 mRNA vaccination2022

    • Author(s)
      Ai Kuzumi, Ayumi Yoshizaki, Kazue Chiba, Shunki Mitsuo, Kazuki M Matsuda, Yuta Norimatsu, Kojiro Nagai, Jun Omatsu, Tomomi Miyake, Shinichi Sato
    • Organizer
      The 12th Asian Dermatological Congress
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Interleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis.2022

    • Author(s)
      Ai Kuzumi, Ayumi Yoshizaki, Kazuki M Matsuda, Hirohito Kotani, Yuta Norimatsu, Maiko Fukayama, Satoshi Ebata, Takemichi Fukasawa, Asako Yoshizaki-Ogawa, Yoshihide Asano, Kojiro Morikawa, Yutaka Kazoe, Kazuma Mawatari, Takehiko Kitamori, Shinichi Sato
    • Organizer
      The 47th Annual Meeting of the Japanese Society for Investigative Dermatology
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Impact of anti-interleukin-4 receptor alpha antibodies on cutaneous T-cell lymphoma via regulatory T cell induction2022

    • Author(s)
      Teruyoshi Hisamoto, Ruriko Kawanabe, Yurika Osuji, Hirohito Kotani, Kazuki M Matsuda, Ai Kuzumi, Takemichi Fukasawa, Satoshi Ebata, Asako Yoshizaki-Ogawa, Shinichi Sato, Ayumi Yoshizaki
    • Organizer
      The 47th Annual Meeting of the Japanese Society for Investigative Dermatology
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Impact of anti-transcobalamin receptor antibodies on cutaneous arteritis2022

    • Author(s)
      Matsuda KM, Kotani H, Yamaguchi K, Okumura T, Fukuda E, Kono M, Hisamoto T, Kawanabe R, Norimatsu Y, Kuzumi A, Fukayama M, Fukasawa T, Ebata S, Yoshizaki-Ogawa A, Okamura T, Shoda H, Fujio K, Goshima N, Sato S, Yoshizaki A
    • Organizer
      The 47th Annual Meeting of the Japanese Society for Investigative Dermatology
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] Adipose derived regenerative cells improve fibrosis in systemic sclerosis model mice by stimulating IL-10 production in B lymphocytes2022

    • Author(s)
      Hirohito Kotani, Kazuki M. Matsuda, Teruyoshi Hisamoto, Ruriko Kawanabe, Yurika Osuji, Ai Kuzumi, Takemichi Fukasawa, Satoshi Ebata, Asako Yoshizaki-Ogawa, Shinichi Sato, Ayumi Yoshizaki
    • Organizer
      The 47th Annual Meeting of the Japanese Society for Investigative Dermatology
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research

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Published: 2022-04-19   Modified: 2024-12-25  

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