Comprehensive analysis and interventional approach for intestinal dysbisosi in GVHD

• Project/Area Number: 17H04206
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Hokkaido 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: ¥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。

Research Products

• [Int'l Joint Research] Regensburg大学(ドイツ)
• [Int'l Joint Research] Sloan Kettering Cancer Center/Duke University/University of Chicago(米国)
• [Int'l Joint Research] Universitatario Puerta de Hierro(スペイン)
• [Int'l Joint Research] Memorial Sloan Kettering Cancer Center/Duke Univ./Univ. of South California(米国)
• [Int'l Joint Research] Regensburg Univ.(ドイツ)
• [Int'l Joint Research] QIMR Berghofer Medical Research Inst.(オーストラリア)
• [Int'l Joint Research] Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center(米国)
• [Journal Article] Intestinal goblet cells protect against GVHD after allogeneic stem cell transplantation via Lypd8 (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] High lymphocyte counts before antithymocyte globulin administration predict acute graft-versus-host disease (2020)
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation (2020)
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation (2019)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Myeloid differentiation factor 88 signaling in donor T cells accelerates graft-versus-host disease (2019)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Lactose drives Enterococcus expansion to promote graft-versus-host disease (2019)
  • 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
  • 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 transplantation (2018)
  • 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
  • Peer Reviewed
• [Journal Article] Intestinal Lymphatic Endothelial Cells Produce R-Spondin3 (2018)
  • 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
  • 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 transplantation (2018)
  • 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
  • Peer Reviewed
• [Journal Article] Essential role of IFN-γ in T cell?associated intestinal inflammation (2018)
  • 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
  • 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
  • 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
  • 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]
  • 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
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Gut microbiome and its relevance to immunology of transplantation (2020)
  • Author(s): Takanori Teshima
  • Organizer: The 25th Annual Congress of APBMT-2020
  • 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
• [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
  • Invited
• [Presentation] Intestinal microbioata are associated with outcome of hematopoietc stem cell transplantation (2019)
  • Author(s): Takanori Teshima
  • Organizer: The 10th Asian Cellular Therapy Organization
  • Int'l Joint Research / Invited
• [Presentation] Restoration of gut microbial ecology (2019)
  • Author(s): Takanori Teshima
  • Organizer: 1st EBMT GVHD Summit
  • Int'l Joint Research / Invited
• [Presentation] Multicenter Microbiota Analysis Indicates That Pre-HCT Microbiota Injury Is Prevalent across Geography and Predicts Poor Overall Survival (2019)
  • 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
  • Int'l Joint Research
• [Presentation] Ocular Instillation of Vitamin A-Coupled Liposomes Containing HSP47 siRNA Ameliorates Dry Eye Syndrome in Chronic Graft-Versus-Host Disease (2019)
  • Author(s): Hiroyuki Ohigashi、Daigo Hashimoto、Shuichiro Takahashi、Tomohiro Yamakawa、Eiko Hayase、Takanori Teshima
  • Organizer: 2019 TCT Meetings of ASBMT & CIBMTR
  • 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
• [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
• [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
• [Presentation] Intestinal Goblet Cells Play a Protective Role Against Gvhd Via a Lypd8-Dependent Manner after Allogeneic Hematopoietic Stem Cell Transplantation (2018)
  • Author(s): Takahide Ara、Daigo Hashimoto、Eiko Hayase、Noizat Clara、Ryu Okumura、Kiyoshi Takeda、Takanori Teshima
  • Organizer: 60th ASH Annual Meeting & Exposition
  • Int'l Joint Research
• [Presentation] Intestinal Enterococcus Is a Major Risk Factor for the Development of Acute Gvhd (2018)
  • 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
  • Int'l Joint Research
• [Presentation] Multicenter Microbiota Analysis Indicates That Pre-HCT Microbiota Injury Is Prevalent across Geography and Predicts Poor Overall Survival (2018)
  • 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
  • Int'l Joint Research
• [Presentation] Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate fibrosis in chronic GVHD (2018)
  • Author(s): Ohigashi H、Hashimoto D、Yamakawa T、Teshima T
  • Organizer: The international congress of BMT
  • Int'l Joint Research
• [Presentation] Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate fibrosis in chronic GVHD (2018)
  • Author(s): Hiroyuki Ohigashi、Daigo Hashimoto、Tomohiro Yamakawa、Takanori Teshima
  • Organizer: ICBMT 2018
  • Int'l Joint Research
• [Presentation] Novel insights in target tissue injury in graft-versus-host disease (2018)
  • Author(s): Takanori Teshima
  • Organizer: Hematology/Oncology Seminar, Icahn School of Medicine at Mount Sinai
  • Int'l Joint Research / Invited
• [Presentation] Current issue in chronic GVHD (2017)
  • Author(s): Teshima T
  • Organizer: International Conference with Korean Society of Experimental Hematology
  • 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
  • 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
  • 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
  • Int'l Joint Research