Mechanisms of disruption of homeostasis in GVHD

• Project/Area Number: 25293217
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Hokkaido University
• Principal Investigator: Teshima Takanori 北海道大学, 医学(系)研究科(研究院), 教授 (40284096)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2015: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2013: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 造血幹細胞移植 / ＧＶＨＤ / 腸幹細胞 / パネート細胞 / R-Spondin1 / defensin / GVHD / Defensin / Paneth cells / Intestinal stem cells / Reg3 / 腸管

Outline of Final Research Achievements

We studied on target tissue injury in graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation and found that intestinal stem cells and their niche are targeted by alloreactive donor T cells. Intestinal ecology system is also distiubed and such a disruption of tissue homeostasis of intestinal microbial ecology is associated with clinical manifestation of GVHD. We found that Intestinal stem cell growth factor R-spondin1 promotes growth of both intestinal stem cells and Paneth cells. Brief administration of R-spondin1 to hosts protects the intestinal stem-niche system, ameliorates GVHD, prevents infection, and improves transplant outcome. Our study suggests that such novel strategies to maintain host homeostasis could improve transplant outcome.

Research Products

• [Int'l Joint Research] Queensland Institute of Medical Research(Ａｕｓｔｒａｌｉａ)
• [Journal Article] Acute Graft-versus-Host Disease: Novel Biological Insights (2016)
  • Author(s): Teshima T, Reddy P, Zeiser R
  • Journal Title: Biol Blood Marrow Transplant Volume: 22 Pages: 11-16
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] α-Mannan induces Th17-mediated pulmonary graft-versus-host disease in mice (2015)
  • Author(s): Uryu H, Hashimoto D, Kato K, Hayase E, Matsuoka S, Ogasawara R, Takahashi S, Maeda Y, Iwasaki H, Miyamoto T, Saijo S, Iwakura Y, Hill GR, Akashi K, Teshima T
  • Journal Title: Blood Volume: 125 Pages: 3014-3023
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Decreased secretion of Paneth cell α-defensin in graft-versus-host disease (2015)
  • Author(s): Eriguchi Y, Nakamura K, Hashimoto D, Shimoda S, Shimono N, Akashi K, Ayabe T, Teshima T
  • Journal Title: Transpl Infect Dis Volume: 17 Pages: 702-706
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The primacy of IL-6 in IPS? (2015)
  • Author(s): Teshima T
  • Journal Title: Blood Volume: 125 Pages: 2320-2322
  • Peer Reviewed
• [Journal Article] Expansion of donor-reactive host T cells in primary graft failure after allogeneic hematopoietic SCT following reduced-intensity conditioning. (2014)
  • Author(s): Koyama M, Hashimoto D, Nagafuji K, Eto T, Ohno Y, Aoyama K, Iwasaki H, Miyamoto T, Hill GR, Akashi K, Teshima T.
  • Journal Title: Bone Marrow Transplant. Volume: 2014 Issue: 1 Pages: 110-115
  • DOI: 10.1038/bmt.2013.134
  • NAID: 120005460247
  • Peer Reviewed / Open Access
• [Journal Article] Mammalian target of rapamycin inhibitors permit regulatory T cell reconstitution and inhibit experimental chronic graft-versus-host disease. (2014)
  • Author(s): Sugiyama H, Maeda Y, Nishimori H, Yamasuji Y, Matsuoka K, Fjii N, Kondo E, Shinagawa K, Takeuchi K, Teshima T, and Tanimoto M
  • Journal Title: Biol Blood Marrow Transplant. Volume: 20 Issue: 2 Pages: 183-91
  • DOI: 10.1016/j.bbmt.2013.11.018
  • NAID: 120005469526
  • Peer Reviewed / Open Access
• [Journal Article] Bone Marrow Graft-versus-Host Disease: Evaluation of Its Clinical Impact on Disrupted Hematopoiesis after Allogeneic Hematopoietic Stem Cell Transplantation (2014)
  • Author(s): Souichi Shiratori, Mizuha Kosugi-Kanaya, Satoshi Ueha, Junichi Sugita1, Akio Shigematsu, Takeshi Kondo, Daigo Hashimoto, Katsuya Fujimoto, Tomoyuki Endo, Mitsufumi Nishio, Satoshi Hashino, Yoshihiro Matsuno, Kouji Matsushima, Junji Tanaka, Masahiro Imamura, Takanori Teshima
  • Journal Title: Biol Blood Marrow Transplant Volume: 20 Issue: 4 Pages: 495-500
  • DOI: 10.1016/j.bbmt.2013.12.568
  • NAID: 120005427744
  • Peer Reviewed / Open Access
• [Journal Article] Stenotrophomonas maltophilia infection during allogeneic hematopoietic stem cell transplantation: a single-center experience (2014)
  • Author(s): Shiratori S, Wakasa K, Okada K, Sugita J, Akizawa K, Shigematsu A, Hashimoto D, Fujimoto K, Endo T, Kondo T, Shimizu C, Hashino S, Teshima T
  • Journal Title: Clin Transplant Volume: 28(6) Issue: 6 Pages: 656-661
  • DOI: 10.1111/ctr.12356
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] High Level of Serum Soluble Interleukin-2 Receptor at Transplantation Predicts Poor Outcome of Allogeneic Stem Cell Transplantation for Adult T Cell Leukemia. (2014)
  • Author(s): Shigematsu A, Kobayashi N, Yasui H, Shindo M, Kakinoki Y, Koda K, Iyama S, Kuroda H, Tsutsumi Y, Imamura M, Teshima T.
  • Journal Title: Biol Blood Marrow Transplant Volume: － Issue: 6 Pages: 801-805
  • DOI: 10.1016/j.bbmt.2014.02.014
  • NAID: 120005455889
  • Peer Reviewed / Open Access
• [Journal Article] The Use of Oral Beclomethasone Dipropionate in the Treatment of Gastrointestinal Graft-versus-host Disease: The Experience of the Fukuoka Blood and Marrow Transplantation (BMT) Group (2014)
  • Author(s): Takashima S, Eto T, Shiratsuchi M, Hidaka M, Mori Y, Kato K, Kamezaki K, Oku S, Henzan H, Takase K, Matsushima T, Takenaka K, Iwasaki H, Miyamoto T, Akashi K, Teshima T
  • Journal Title: Internal Medicine Volume: 53 Issue: 12 Pages: 1315-1320
  • DOI: 10.2169/internalmedicine.53.1858
  • NAID: 130004466355
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Essential requirements for setting up a stem cell processing laboratory (2014)
  • Author(s): Leemhuis T, Padley D, Keever-Taylor C, Niederwieser D, Teshima T, Lanza F, Chabannon C, Szabolcs P, Bazarbachi A, Koh MB
  • Journal Title: Bone Marrow Transplant Volume: 49(8) Issue: 8 Pages: 1098-1105
  • DOI: 10.1038/bmt.2014.104
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning for mycosis fungoides and Sezary syndrome. (2014)
  • Author(s): Shiratori S, Fujimoto K, Nishimura M, Hatanaka KC, Kosugi-Kanaya M, Okada K, Sugita J, Shigematsu A, Hashimoto D, Endo T, Kondo T, Abe R, Hashino S, Matsuno Y, Shimizu H, Teshima T.
  • Journal Title: Hematol Oncol Volume: Epub Ahead of Print Issue: 1 Pages: 9-16
  • DOI: 10.1002/hon.2162
  • NAID: 120005981361
  • Peer Reviewed / Open Access
• [Journal Article] Hepatitis B virus (HBV) reverse seroconversion (RS) can be prevented even in non-responders to hepatitis B vaccine after allogeneic stem cell transplantation: long-term analysis of intervention in RS with vaccine for patients with previous HBV infection (2014)
  • Author(s): Takahata M, Hashino S, Onozawa M, Shigematsu A, Sugita J, Fujimoto K, Endo T, Kondo T, Tanaka J, Imamura M, Teshima T
  • Journal Title: Transpl Infect Dis Volume: 16(5) Issue: 5 Pages: 797-801
  • DOI: 10.1111/tid.12283
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] JAK inhibitors: a home run for GVHD patients? (2014)
  • Author(s): Teshima T
  • Journal Title: Blood Volume: 123(24) Issue: 24 Pages: 3691-3693
  • DOI: 10.1182/blood-2014-04-570325
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Quantification of hematogones at the time of engraftment is a useful prognostic indicator in allogeneic stem cell transplantation. (2013)
  • Author(s): Shima T
  • Journal Title: Blood Volume: 121 Issue: 5 Pages: 840-848
  • DOI: 10.1182/blood-2012-02-409607
  • Peer Reviewed
• [Journal Article] A novel filtration method for cord blood processing using a polyester fabric filter (2013)
  • Author(s): Shima T, Forraz N, Sato N, Yamauchi T, Iwasaki H, Takenaka K, Akashi K, McGuckin C, Teshima T
  • Journal Title: Int J Lab Hematol Volume: 35 Issue: 4 Pages: 436-446
  • DOI: 10.1111/ijlh.12039
  • Peer Reviewed
• [Journal Article] Evaluation of the feasibility and efficacy of autologous stem cell transplantation in elderly patients with multiple myeloma. (2013)
  • Author(s): Muta T, Miyamoto T, Fujisaki T, Ohno Y, Kamimura T, Kato K, Takenaka K, Iwasaki H, Eto T, Takamatsu Y, Teshima T, Akashi K
  • Journal Title: Intern Med Volume: 52(1) Pages: 63-70
  • NAID: 130003365558
  • Peer Reviewed
• [Journal Article] Decrease in Venous Irritation by Adjusting the Concentration of Injected Bendamustine (2013)
  • Author(s): Watanabe H, Ikesue H, Tsujikawa T, Nagata K, Uchida M, Suetsugu K, Egashira N, Muta T, Kato K, Takenaka K, Ohga S, Matsushima T, Shiratsuchi M, Miyamoto T, Teshima T, Akashi K, Oishi R
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 36 Issue: 4 Pages: 574-578
  • DOI: 10.1248/bpb.b12-00901
  • NAID: 130003361397
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed
• [Journal Article] Diagnosis and evaluation of intestinal graft-versus-host disease after allogeneic hematopoietic stem cell transplantation following reduced-intensity and myeloablative conditioning regimens (2013)
  • Author(s): Yamasaki S, Miyagi-Maeshima A, Kakugawa Y, Matsuno Y, Ohara-Waki F, Fuji S, Morita-Hoshi Y, Mori M, Kim S, Mori S, Fukuda T, Tanosaki R, Shimono T, Tobinai K, Saito D, Takaue Y, Teshima T, Heike Y
  • Journal Title: Int J Hematol Volume: 97(3) Issue: 3 Pages: 421-426
  • DOI: 10.1007/s12185-013-1297-9
  • NAID: 10031162908
  • Peer Reviewed
• [Journal Article] Protective roles of epithelial cells in the survival of adult T-cell leukemia/lymphoma cells. (2013)
  • Author(s): Miyatake Yukiko
  • Journal Title: The American Journal of Pathology Volume: 182 Issue: 5 Pages: 1832-1842
  • DOI: 10.1016/j.ajpath.2013.01.015
  • Peer Reviewed
• [Journal Article] Evaluating the association between histological manifestations of cord colitis syndrome with GVHD. (2013)
  • Author(s): Shimoji S, Kato K, Eriguchi Y, Takenaka K, Iwasaki H, Miyamoto T, Oda Y, Akashi K, Teshima T
  • Journal Title: Bone Marrow Transplant Volume: 48 Issue: 9 Pages: 1249-1252
  • DOI: 10.1038/bmt.2013.44
  • Peer Reviewed
• [Journal Article] Autologous peripheral blood stem cell transplantation with granulocyte colony-stimulating factor combined conditioning regimen as a postremission therapy for acute myelogenous leukemia in first complete remission (2013)
  • Author(s): Eto T, Takase K, Miyamoto T, Ohno Y, Kamimura T, Nagafuji K, Takamatsu Y, Teshima T, Gondo H, Taniguchi S, Akashi K, Harada M
  • Journal Title: Int J Hematol Volume: 98 Issue: 2 Pages: 186-196
  • DOI: 10.1007/s12185-013-1378-9
  • NAID: 10031194734
  • Peer Reviewed
• [Journal Article] Unrelated allogeneic bone marrow-derived mesenchymal stem cells for steroid-refractory acute graft-versus-host disease: a phase I/II study. (2013)
  • Author(s): Muroi K, Miyamura K, Ohashi K, Murata M, Eto T, Kobayashi N, Taniguchi S, Imamura M, Ando K, Kato S, Mori T, Teshima T, Mori M, Ozawa K.
  • Journal Title: Int J Hematol. Volume: 98 Issue: 2 Pages: 206-213
  • DOI: 10.1007/s12185-013-1399-4
  • NAID: 10031194736
  • Peer Reviewed
• [Journal Article] Combination of high-dose melphalan and bortezomib as conditioning regimen for autologous peripheral blood stem cell transplantation in multiple myeloma. (2013)
  • Author(s): Miyamoto T, Yoshimoto G, Kamimura T, Muta T, Takashima S, Ito Y, Shiratsuchi M, Choi I, Kato K, Takenaka K, Iwasaki H, Takamatsu Y, Teshima T, Akashi K.
  • Journal Title: Int J Hematol Volume: 98 Issue: 3 Pages: 337-345
  • DOI: 10.1007/s12185-013-1402-0
  • Peer Reviewed
• [Journal Article] Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration (2013)
  • Author(s): Aoyama K, Saha A, Tolar J, Riddle MJ, Veenstra RG, Taylor PA, Blomhoff R, Panoskaltsis-Mortari A, Klebanoff CA, Socie G, Munn DH, Murphy WJ, Serody JS, Fulton L, Teshima T, Chandraratna RA, Dmitrovsky E, Guo Y, Noelle RJ, Blazar BR
  • Journal Title: Blood Volume: 122(12) Issue: 12 Pages: 2125-2134
  • DOI: 10.1182/blood-2012-11-470252
  • Peer Reviewed
• [Journal Article] Reciprocal expression of enteric antimicrobial proteins in intestinal graft-versus-host disease. (2013)
  • Author(s): Eriguchi Y, Uryu H, Nakamura K, Shimoji S, Takashima S, Iwasaki H, Miyamoto T, Shimono N, Hashimoto D, Akashi K, Ayabe T, Teshima T.
  • Journal Title: Biol Blood Marrow Transplant Volume: 19 Issue: 10 Pages: 1525-1529
  • DOI: 10.1016/j.bbmt.2013.07.027
  • NAID: 120005347004
  • Peer Reviewed
• [Journal Article] Clinical outcomes of allogeneic stem cell transplantation for relapsed or refractory follicular lymphoma: a retrospective analysis by the Fukuoka Blood and Marrow Transplantation Group. (2013)
  • Author(s): 107 Ito Y, Miyamoto T, Kamimura T, Takase K, Henzan H, Sugio Y, Kato K, Ohno Y, Eto T, Teshima T, Akashi K
  • Journal Title: Int J Hematol Volume: 98 Issue: 4 Pages: 463-471
  • DOI: 10.1007/s12185-013-1430-9
  • Peer Reviewed
• [Presentation] 造血幹細胞移植の新たな展開 (2016)
  • Author(s): 豊嶋崇徳
  • Organizer: 日本血液学会関東甲信越地方会
  • Place of Presentation: 東京都文京区、ホテルガーデンパレス
  • Year and Date: 2016-03-19
  • Invited
• [Presentation] GVHD組織障害の新たな概念 (2016)
  • Author(s): 豊嶋崇徳
  • Organizer: 第38回 日本造血幹細胞移植学会総会
  • Place of Presentation: 愛知県、名古屋市、名古屋国際会議場
  • Year and Date: 2016-03-03
  • Invited
• [Presentation] Emerging concepts on tissue injury in GVHD (2016)
  • Author(s): Teshima T
  • Organizer: BMT Tandem Meetings 2016
  • Place of Presentation: Honolulu, （USA）
  • Year and Date: 2016-02-17
  • Int'l Joint Research / Invited
• [Presentation] R-spondin1 promotes Paneth cell growth, maintains intestinal microbial ecology, and ameliorates GVHD (2015)
  • Author(s): Hayase E, Hashimoto D, Nakamura K, Ogura Y, Hayashi T, Kurokawa K, Ayabe T, Teshima T
  • Organizer: American Society of Hematology
  • Place of Presentation: Orlando, （USA）
  • Year and Date: 2015-12-04
  • Int'l Joint Research
• [Presentation] 同種造血幹細胞移植後の不妊 (2014)
  • Author(s): 下地 園子, 加藤 光次, 辻極 秀次, 江里口 芳裕, 瓜生 英尚, 髙嶋 秀一郎, 橋本 大吾, 宮本 敏浩, 岩崎 浩己, 赤司 浩一, 豊嶋 崇徳
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪府・大阪市)
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Key players in intestinal GVHD (2014)
  • Author(s): 橋本 大吾, 豊嶋 崇徳
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪府・大阪市)
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Mechanisms of intestinal and pulmonary GVHD after allogeneic stem cell transplantation (2014)
  • Author(s): Teshima T
  • Organizer: Kolloquium 2014 Hematology and Oncology
  • Place of Presentation: Freiburg University(Freiburg, Germany)
  • Year and Date: 2014-06-30
  • Invited
• [Presentation] Role of the intestinal tract for acute GVHD (2014)
  • Author(s): Teshima T
  • Organizer: Kolloquium 2014 Immunity and Infection
  • Place of Presentation: Freiburg University(Freiburg, Germany)
  • Year and Date: 2014-06-30
  • Invited
• [Presentation] Reciprocal expression of antimicrobial peptides in GVHD (2014)
  • Author(s): Teshima T
  • Organizer: GvHGvL 2014
  • Place of Presentation: Thon-Dittmer Palais Regensburg(Germany)
  • Invited