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Comprehensive analysis and interventional approach for intestinal dysbisosi in GVHD

Research Project

Project/Area Number 17H04206
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionHokkaido University

Principal Investigator

Teshima Takanori  北海道大学, 医学研究院, 教授 (40284096)

Project Period (FY) 2017-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000)
Fiscal Year 2020: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2019: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2017: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Keywords腸内細菌 / 造血幹細胞移植 / GVHD / Goblet細胞 / 腸内細菌叢 / IL-25 / Lypd8 / Microbiota / R-Spondin / Goblet cell / Paneth cell / 腸球菌 / Dysbiosis / Defensin / 腸内フローラ / defensin / R-Spondin1
Outline of Final Research Achievements

We compared association of intestinal microbial ecology and outcomes of allogeneic hematpoietic stem cell transplantation. In mouse models, changes in microflora posttransplat were associated with GVHD severity and survival. Administration of wnt agonist R-spondin1 restored intestinal microflora and ameliorated GVHD. An international cooperative study showed that changes in intestinal microflora were associated with GVHD severity and mortality, irrespective of ethnicity. Overgrowth of Enterococcus was assocaited with poor transplant outcomes. These largest studies ever demosntrate that composition of the posttransplant microbiota could be associated with transplant outcomes.

Academic Significance and Societal Importance of the Research Achievements

骨髄移植をはじめとする造血幹細胞移植は難治性の白血病など、血液がんや再生不良性貧血などに対する根治的治療法として普及している。しかし、その最重要の合併症である移植片対宿主病(GVHD)のより有効な治療法の開発によって、さらに移植の成績を向上させることができる。本研究では移植後の腸内細菌叢と移植成績の関連を検討した。その結果、移植後には腸内細菌叢の多様性が喪失し、特定の細菌種の増加がみられた。この変化は欧米人と日本人で同等であった。腸内細菌叢の変化が高度な例ではGVHDの重症化、死亡率の増加がみられた。腸内細菌叢を回復させることで移植成績の向上が期待できる。

Report

(5 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (44 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (7 results) Journal Article (17 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 17 results,  Open Access: 12 results) Presentation (20 results) (of which Int'l Joint Research: 15 results,  Invited: 7 results)

  • [Int'l Joint Research] Regensburg大学(ドイツ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Sloan Kettering Cancer Center/Duke University/University of Chicago(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Universitatario Puerta de Hierro(スペイン)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Memorial Sloan Kettering Cancer Center/Duke Univ./Univ. of South California(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Regensburg Univ.(ドイツ)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] QIMR Berghofer Medical Research Inst.(オーストラリア)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center(米国)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Intestinal goblet cells protect against GVHD after allogeneic stem cell transplantation via Lypd82020

    • Author(s)
      Ara Takahide、Hashimoto Daigo、Hayase Eiko、Noizat Clara、Kikuchi Ryo、Hasegawa Yuta、Matsuda Kana、Ono Shoko、Matsuno Yoshihiro、Ebata Ko、Ogasawara Reiki、Takahashi Shuichiro、Ohigashi Hiroyuki、Yokoyama Emi、Matsuo Keitaro、Sugita Junichi、Onozawa Masahiro、Okumura Ryu、Takeda Kiyoshi、Teshima Takanori
    • Journal Title

      Science Translational Medicine

      Volume: 12 Issue: 550

    • DOI

      10.1126/scitranslmed.aaw0720

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] High lymphocyte counts before antithymocyte globulin administration predict acute graft-versus-host disease2020

    • Author(s)
      Shiratori Souichi、Ohigashi Hiroyuki、Ara Takahide、Yasumoto Atsushi、Goto Hideki、Nakagawa Masao、Sugita Junichi、Onozawa Masahiro、Kahata Kaoru、Endo Tomoyuki、Hashimoto Daigo、Teshima Takanori
    • Journal Title

      Annals of Hematology

      Volume: - Issue: 5 Pages: 1321-1328

    • DOI

      10.1007/s00277-020-04347-1

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [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
      2020 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] 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] Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation2019

    • Author(s)
      Toffalori Cristina、Zito Laura、Gambacorta Valentina、Riba Michela、Oliveira Giacomo、Bucci Gabriele、Teshima Takanori、…Vago Luca
    • Journal Title

      Nature Medicine

      Volume: 25 Issue: 4 Pages: 603-611

    • DOI

      10.1038/s41591-019-0400-z

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [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] 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 Annual Research Report
    • Peer Reviewed
  • [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 Annual Research 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 Annual Research 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 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease.2018

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

      Blood

      Volume: 131(13) Pages: 1476-1485

    • NAID

      120006595502

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ruxolitinib protects skin stem cells and maintains skin homeostasis in murine graft-versus-host disease.2018

    • Author(s)
      Takahashi S, Hashimoto D, Hayase E, Ogasawara R, Ohigashi H, Ara T, Yokoyama E, Ebata K, Matsuoka S, Hill G, Sugita J, Onozawa M, Teshima T
    • Journal Title

      Blood

      Volume: [Epub ahead of print]

    • NAID

      120006626559

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Microbiome-Host Interactions in Hematopoietic Stem-Cell Transplant Recipients.2018

    • Author(s)
      Andermann T, Peled J, Ho C, Reddy P, Riches M, Storb R,Teshima T, van den Brink M, Alousi A, Balderman S, Chiusolo P, Clark W, Holler E, Howard A, Kean L, Koh A, McCarthy P, McCarty J, Mohty M, Nakamura R, Rezvani K, Segal B, Shaw B, Shpall E, Sung A, Weber D, Whangbo J, Wingard J, Wood W, Perales MA, Jenq R, Bhatt A
    • Journal Title

      Biol Blood Marrow Transplant

      Volume: [Epub ahead of print]

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease.2017

    • 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 (12) Pages: 3507-3518

    • NAID

      120006394569

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long-Lasting Graft-Derived Donor T Cells Contribute to the Pathogenesis of Chronic Graft-versus-Host Disease in Mice.2017

    • Author(s)
      Kosugi-Kanaya M, Ueha S, Abe J, Shichino S, Shand FHW, Morikawa T, Kurachi M, Shono Y, Sudo N, Yamashita A, Suenaga F, Yokoyama A, Yong W, Imamura M, Teshima T, Matsushima K.
    • Journal Title

      Front Immunol

      Volume: 8 Pages: 1842-1842

    • DOI

      10.3389/fimmu.2017.01842

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Gut microbiome and its relevance to immunology of transplantation2020

    • Author(s)
      Takanori Teshima
    • Organizer
      The 25th Annual Congress of APBMT-2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 大腸杯細胞は抗菌分子Lypd8依存性に同種造血幹細胞移植後の移植片対宿主病を予防する2020

    • Author(s)
      荒隆英、橋本大吾、早瀬英子、Clara Noizat、菊池遼、長谷川祐太、奥村龍、竹田潔、豊嶋崇徳
    • Organizer
      第24回腸内細菌学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 造血幹細胞移植後の腸内フローラの解析2020

    • Author(s)
      豊嶋崇徳
    • Organizer
      第53回日本無菌生物ノートバイオロジー学会総会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Intestinal microbioata are associated with outcome of hematopoietc stem cell transplantation2019

    • Author(s)
      Takanori Teshima
    • Organizer
      The 10th Asian Cellular Therapy Organization
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Restoration of gut microbial ecology2019

    • Author(s)
      Takanori Teshima
    • Organizer
      1st EBMT GVHD Summit
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Multicenter Microbiota Analysis Indicates That Pre-HCT Microbiota Injury Is Prevalent across Geography and Predicts Poor Overall Survival2019

    • Author(s)
      Jonathan U. Peled、Antonio Gomes、Christoph Stein-Thoeringer、John Slingerland、 Ann E. Slingerland、Daniela Weber、Kate Ann Markey、Melody Smith、Doris M. Ponce、 Annelie Clurman、Anthony D. Sung、Daigo Hashimoto、Molly A. Maloy、Niloufer Khan、Boglarka Gyurkocza、Sergio A. Giralt、Takanori Teshima、et.al
    • Organizer
      2019 TCT Meetings of ASBMT & CIBMTR
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Ocular Instillation of Vitamin A-Coupled Liposomes Containing HSP47 siRNA Ameliorates Dry Eye Syndrome in Chronic Graft-Versus-Host Disease2019

    • Author(s)
      Hiroyuki Ohigashi、Daigo Hashimoto、Shuichiro Takahashi、Tomohiro Yamakawa、Eiko Hayase、Takanori Teshima
    • Organizer
      2019 TCT Meetings of ASBMT & CIBMTR
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 発症時における感染の合併は消化管急性GVHDにおけるステロイド抵抗性のリスク因子である2018

    • Author(s)
      白鳥 聡一、後藤 秀樹、杉田 純一、小野澤 真弘、中川 雅夫、加畑 馨、早瀬 英子、遠藤 知之、橋本 大吾、豊嶋 崇徳
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research Report
  • [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)
      小笠原 励起、橋本 大吾、早瀬 英子、高橋 秀一郎、荒 隆英、大東 寛幸、吉岡 康介、立野 貴大、豊嶋 崇徳
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research 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)
      荒 隆英、橋本 大吾、早瀬 英子、Noizat Calara、松田 可奈、小野 尚子、松野 吉宏、白鳥 聡一、後藤 秀樹、中川 雅夫、遠藤 知之、豊嶋 崇徳
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Intestinal Goblet Cells Play a Protective Role Against Gvhd Via a Lypd8-Dependent Manner after Allogeneic Hematopoietic Stem Cell Transplantation2018

    • Author(s)
      Takahide Ara、Daigo Hashimoto、Eiko Hayase、Noizat Clara、Ryu Okumura、Kiyoshi Takeda、Takanori Teshima
    • Organizer
      60th ASH Annual Meeting & Exposition
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Intestinal Enterococcus Is a Major Risk Factor for the Development of Acute Gvhd2018

    • Author(s)
      Christoph K. Stein-Thoeringer、Jonathan U. Peled、Antonio LC Gomes、Amina Lazrak、Melissa D Docampo、 Ann E. Slingerland、Katherine Nichols、Yusuke Shono、Daniela Weber、Anthony D. Sung、Daigo Hashimoto、Justin Cross、Takanori Teshima、Ernst Holler、Nelson J. Chao、Eric G. Pamer、Marcel R.M. van den Brink
    • Organizer
      60th ASH Annual Meeting & Exposition
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Multicenter Microbiota Analysis Indicates That Pre-HCT Microbiota Injury Is Prevalent across Geography and Predicts Poor Overall Survival2018

    • Author(s)
      Jonathan U. Peled、Antonio LC Gomes、Christoph K. Stein-Thoeringer、John B. Slingerland、Ann E. Slingerland、Daniela Weber、Kate A Markey、Melody Smith、Doris Ponce、Annelie Clurman、Anthony D. Sung、Daigo Hashimoto、Molly Maloy、Niloufer Khan、Boglarka Gyurkocza、Sergio Giralt、Takanori Teshima、et.al
    • Organizer
      60th ASH Annual Meeting & Exposition
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate fibrosis in chronic GVHD2018

    • Author(s)
      Ohigashi H、Hashimoto D、Yamakawa T、Teshima T
    • Organizer
      The international congress of BMT
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate fibrosis in chronic GVHD2018

    • Author(s)
      Hiroyuki Ohigashi、Daigo Hashimoto、Tomohiro Yamakawa、Takanori Teshima
    • Organizer
      ICBMT 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Novel insights in target tissue injury in graft-versus-host disease2018

    • Author(s)
      Takanori Teshima
    • Organizer
      Hematology/Oncology Seminar, Icahn School of Medicine at Mount Sinai
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Current issue in chronic GVHD2017

    • Author(s)
      Teshima T
    • Organizer
      International Conference with Korean Society of Experimental Hematology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Did we improve in treatment of steroid-resistant GVHD?2017

    • Author(s)
      Teshima T
    • Organizer
      4th International Congress on Stem Cel Transplantation and Cellular Therapies
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [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 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Gastric stem cells are targeted in upper gastrointestinal GVHD. 59th ASH Annual Meeting, Dec 9-12, 2017, Atlanta, GA, USA.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 Annual Research Report
    • Int'l Joint Research

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Published: 2017-04-28   Modified: 2022-05-23  

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