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Development of a novel therapy for chronic GVHD targeting a macrophage-myofibroblast axis in fibrotic process

Research Project

Project/Area Number 17K09945
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Hematology
Research InstitutionHokkaido University

Principal Investigator

Hashimoto Daigo  北海道大学, 医学研究院, 准教授 (20419576)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords慢性移植片対宿主病 / 線維化 / マクロファージ / ドライアイ / 筋線維芽細胞 / HSP47 / GVHD / 同種造血幹細胞移植 / ドライアイ症候群 / 線維芽細胞 / リポソーム / 慢性GVHD / 移植片対宿主病
Outline of Final Research Achievements

In the current study, we developed a novel anti-fibrotic therapy for chronic GVHD using murine model of allogeneic bone marrow transplantation. We found that macrophage depletion using anti-CSF1R antibody ameliorated skin fibrosis in chronic GVHD. We also found that systemic administration of vitamin A coupled liposomes containing siRNA against HSP47 (VA-lip HSP47) could ameliorate fibrosis in the skin, lacrimal gland, and salivary gland in chronic GVHD. Finally, we found that ocular instillation of VA-lip HSP47 ameliorate lacrimal grand fibrosis and dry eye syndrome in chronic GVHD.

Academic Significance and Societal Importance of the Research Achievements

同種造血幹細胞移植の技術の進歩により, より多く移植が行われるようになり, より多くの移植患者の長期生存が可能となっている。そのため慢性GVHDによる生活の質の低下を防ぐことはより重要になっている。本研究では, 免疫抑制剤を使用せず線維化のメカニズムを標的にした新しい慢性GVHD治療法を開発した。これにより, 感染症や腫瘍の再発を増加させずに, 慢性GVHDの治療を行える可能性がある。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (31 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (2 results) Journal Article (15 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 14 results,  Open Access: 5 results) Presentation (13 results) (of which Int'l Joint Research: 4 results,  Invited: 4 results) Remarks (1 results)

  • [Int'l Joint Research] Memorial Sloan Kettering Cancer Center/Duke University(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] University Hospital Regensburg(ドイツ)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Short-term KRP203 and posttransplant cyclophosphamide for graft-versus-host disease prophylaxis.2020

    • Author(s)
      Yokoyama E, Hashimoto D, Hayase E, Ara T, Ogasawara R, Takahashi S, Ohigashi H, Tateno T, Hasegawa Y, Chen X, Teshima T.
    • Journal Title

      Bone Marrow Transplant.

      Volume: 55 Issue: 4 Pages: 787-795

    • DOI

      10.1038/s41409-019-0733-8

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation2020

    • Author(s)
      Peled Jonathan U.、Gomes Antonio L.C.、Devlin Sean M.、Littmann Eric R.、Taur Ying、Sung Anthony D.、Teshima Takanori、…van den Brink Marcel R.M.
    • Journal Title

      New England Journal of Medicine

      Volume: 382 Issue: 9 Pages: 822-834

    • DOI

      10.1056/nejmoa1900623

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Histological and magnified endoscopic evaluation of villous atrophy in gastrointestinal graft-versus-host disease.2020

    • Author(s)
      Matsuda K, Ono S, Tanaka I, Inoue M, Kinowaki S, Ishikawa M, Tsuda M, Yamamoto K, Shimizu Y, Takahashi S, Hayase E, Hashimoto D, Teshima T, Sakamoto N.
    • Journal Title

      Ann Hematol.

      Volume: ー Issue: 5 Pages: 1121-1128

    • DOI

      10.1007/s00277-020-03966-y

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ocular instillation of vitamin A-coupled liposomes containing HSP47 siRNA ameliorates dry eye syndrome in chronic GVHD.2019

    • Author(s)
      Ohigashi, H., Hashimoto, D., Hayase, E., Takahashi, S., Ara, T., Yamakawa, T., Sugita, J., Onozawa, M., Nakagawa, M., Teshima, T.
    • Journal Title

      Blood Adv.

      Volume: 3 Issue: 7 Pages: 1003-1010

    • DOI

      10.1182/bloodadvances.2018028431

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Myeloid differentiation factor 88 signaling in donor T cells accelerates graft-versus-host disease2019

    • Author(s)
      Matsuoka Satomi、Hashimoto Daigo、Kadowaki Masanori、Ohigashi Hiroyuki、Hayase Eiko、Yokoyama Emi、Hasegawa Yuta、Tateno Takahiro、Chen Xuanzhong、Aoyama Kazutoshi、Oka Hideyo、Onozawa Masahiro、Takeda Kiyoshi、Akashi Koichi、Teshima Takanori
    • Journal Title

      Haematologica

      Volume: 105 Issue: 1 Pages: 226-234

    • DOI

      10.3324/haematol.2018.203380

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lactose drives Enterococcus expansion to promote graft-versus-host disease2019

    • Author(s)
      Stein-Thoeringer C. K.、Nichols K. B.、Lazrak A.、Docampo M. D.、Slingerland A. E.、Slingerland J. B.、Teshima T.、…van den Brink M. R. M.
    • Journal Title

      Science

      Volume: 366 Issue: 6469 Pages: 1143-1149

    • DOI

      10.1126/science.aax3760

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Intestinal Lymphatic Endothelial Cells Produce R-Spondin32018

    • Author(s)
      Ogasawara Reiki、Hashimoto Daigo、Kimura Shunsuke、Hayase Eiko、Ara Takahide、Takahashi Shuichiro、Ohigashi Hiroyuki、Yoshioka Kosuke、Tateno Takahiro、Yokoyama Emi、Ebata Ko、Kondo Takeshi、Sugita Junichi、Onozawa Masahiro、Iwanaga Toshihiko、Teshima Takanori
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 1-9

    • DOI

      10.1038/s41598-018-29100-7

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The association between the incidence of intestinal graft-vs-host disease and antibiotic use after allogeneic hematopoietic stem cell transplantation2018

    • Author(s)
      Hidaka Daisuke、Hayase Eiko、Shiratori Souichi、Hasegawa Yuta、Ishio Takashi、Tateno Takahiro、Okada Kohei、Goto Hideki、Sugita Junichi、Onozawa Masahiro、Nakagawa Masao、Kahata Kaoru、Endo Tomoyuki、Hashimoto Daigo、Teshima Takanori
    • Journal Title

      Clinical Transplantation

      Volume: 32 Issue: 9

    • DOI

      10.1111/ctr.13361

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Essential role of IFN-γ in T cell?associated intestinal inflammation2018

    • Author(s)
      Eriguchi Yoshihiro、Nakamura Kiminori、Yokoi Yuki、Sugimoto Rina、Takahashi Shuichiro、Hashimoto Daigo、Teshima Takanori、Ayabe Tokiyoshi、Selsted Michael E.、Ouellette Andre J.
    • Journal Title

      JCI Insight

      Volume: 3 Issue: 18 Pages: 1-18

    • DOI

      10.1172/jci.insight.121886

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Ruxolitinib protects skin stem cells and maintains skin homeostasis in murine graft-versus-host disease2018

    • Author(s)
      Takahashi Shuichiro、Hashimoto Daigo、Hayase Eiko、Ogasawara Reiki、Ohigashi Hiroyuki、Ara Takahide、Yokoyama Emi、Ebata Ko、Matsuoka Satomi、Hill Geoffrey R.、Sugita Junichi、Onozawa Masahiro、Teshima Takanori
    • Journal Title

      Blood

      Volume: 131 Issue: 18 Pages: 2074-2085

    • DOI

      10.1182/blood-2017-06-792614

    • NAID

      120006626559

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Cecum ulcer is a reliable endoscopic finding in cytomegalovirus colitis concomitant with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation2018

    • Author(s)
      Matsuda Kana、Ono Shoko、Ishikawa Marin、Miyamoto Shuichi、Abiko Satoshi、Tsuda Momoko、Yamamoto Keiko、Kudo Takahiko、Shimizu Yuichi、Hayase Eiko、Hashimoto Daigo、Teshima Takanori、Matsuno Yoshihiro、Sakamoto Naoya
    • Journal Title

      Annals of Hematology

      Volume: 97 Issue: 5 Pages: 877-883

    • DOI

      10.1007/s00277-018-3241-9

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Niche signals regulate differentiation and functions of tissue resident macrophages2018

    • Author(s)
      橋本 大吾
    • Journal Title

      Rinsho Ketsueki

      Volume: 59 Issue: 10 Pages: 1886-1894

    • DOI

      10.11406/rinketsu.59.1886

    • NAID

      130007496929

    • ISSN
      0485-1439, 1882-0824
    • Related Report
      2018 Research-status Report
  • [Journal Article] Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease2018

    • Author(s)
      Yamakawa T*, Ohigashi H*, Hashimoto D*, Hayase E, Takahashi S, Miyazaki M, Minomi K, Onozawa M, Niitsu Y, Teshima T (*: equally contributed)
    • Journal Title

      Blood

      Volume: 131 Issue: 13 Pages: 1476-1485

    • DOI

      10.1182/blood-2017-04-779934

    • NAID

      120006595502

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease2017

    • Author(s)
      Hayase E, Hashimoto D, Nakamura K, Noizat C, Ogasawara R, Takahashi S, Ohigashi H, Yokoi Y, Sugimoto R, Matsuoka S, Ara T, Yokoyama E, Yamakawa T, Ebata K, Kondo T, Hiramine R, Aizawa T, Ogura Y, Hayashi T, Mori H, Kurokawa K, Tomizuka K, Ayabe T, Teshima T
    • Journal Title

      J Exp Med

      Volume: 214 Issue: 12 Pages: 3507-3518

    • DOI

      10.1084/jem.20170418

    • NAID

      120006394569

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Graft-versus-host disease in the ovary potentially causes female infertility after allogeneic hematopoietic stem cell transplantation2017

    • Author(s)
      Shimoji S, Hashimoto D, Teshima T
    • Journal Title

      Rinsho Ketsueki

      Volume: 58 Issue: 7 Pages: 827-834

    • DOI

      10.11406/rinketsu.58.827

    • NAID

      130005907633

    • ISSN
      0485-1439, 1882-0824
    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] IRAK4 阻害薬はドナー T 細胞の MyD88 シグナルを阻害して同種造血幹細胞移植後の GvHD を軽減する2020

    • Author(s)
      松岡里湖、橋本大吾、門脇賢典、長谷川裕太、大東寛幸、早瀬英子、 横山絵美、立野貴大、青山一利、岡 英世、小野澤真弘、竹田 潔、 赤司浩一、豊嶋崇徳
    • Organizer
      第42回日本造血細胞移植学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Post-transplant enterococcus mono-domination is a risk of acute Graft-versus- Host disease2020

    • Author(s)
      Shuichiro Takahashi、Daigo Hashimoto、Souichi Shiratori、Junichi Sugita、Tomoyuki Endo、 Takanori Teshima
    • Organizer
      第42回日本造血細胞移植学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] A novel graft-versus-host disease prophylaxis with selective S1P1 agonist, KRP203 with posttransplant cyclophosphamide2020

    • Author(s)
      Emi Yokoyama、Daigo Hashimoto、Eiko Hayase、Takahide Ara、Reiki Ogasawara、 Tomohiro Yamakawa、Shuichiro Takahashi、Hiroyuki Ohigashi、Takahiro Tateno、 Yuta Hasegawa、Xuanzhong Chen、Takanori Teshima
    • Organizer
      第42回日本造血細胞移植学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] HSP47 siRNA 含有ビタミン A 結合リポソーム点眼は慢性GVHD による涙腺線維化とドライアイを改善する2020

    • Author(s)
      大東 寛幸、橋本 大吾、高橋秀一郎、荒 隆英、山川 知宏、早瀬 英子、杉田 純一、 小野澤真弘、中川 雅夫、豊嶋 崇徳
    • Organizer
      第42回日本造血細胞移植学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] GVHD new insight of pathogenesis2019

    • Author(s)
      Daigo Hashimoto
    • Organizer
      第81回日本血液学会学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 小腸リンパ管内皮細胞はR-Sondin3産生細胞でありGVHDの標的となる2018

    • Author(s)
      Ogasawara Reiki
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 腸管杯細胞は移植片対宿主病のバイオマーカーであり、その増殖因子IL-25は移植片対宿主病を軽減する2018

    • Author(s)
      Ara Takahide
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Crosstalk between microbiota and host immune system affects the outcomes of hematopoietic stem cell transplantation2018

    • Author(s)
      Hashimoto Daigo
    • Organizer
      The 7th Global Network Forum on Infection and Immunity
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] ニッチ機能による組織常在マクロファージの分化・維持・多様化の制御,2018

    • Author(s)
      Hashimoto Daigo
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate fibrosis in chronic GVHD.2018

    • Author(s)
      Ohigashi Hiroyuki
    • Organizer
      The international congress of BMT
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] HSP47 siRNA含有ビタミンA結合リポソームは慢性移植片対宿主病の皮膚線維化を改善する2018

    • Author(s)
      山川知宏, 橋本大吾, 早瀬英子, 高橋秀一郎, 大東寛幸, 新津洋司郎, 豊嶋 崇徳
    • Organizer
      第40回日本造血細胞移植学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] Intestinal microbiota play a critical role in neutrophil engraftment posttransplant and recovery after chemotherapy by stimulating T cell production of IL-17A.2017

    • Author(s)
      Ebata K, Hashimoto D, Takahashi S, Hayase E, Ogasawara R, Teshima T.
    • Organizer
      59th ASH Annual Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Gastric stem cells are targeted in upper gastrointestinal GVHD.2017

    • Author(s)
      Hayase E, Hashimoto D, Takahashi S, Ohigashi H, Takahiro T, Ara T, Yokoyama E, Teshima T.
    • Organizer
      59th ASH Annual Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Remarks] 造血幹細胞移植後の慢性 GVHD による線維化の新治療法を開発

    • URL

      https://www.hokudai.ac.jp/news/180404_pr2.pdf

    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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