Reconstitution of mononuclear phagocyte system following allogeneic hematopoietic stem cell transplantation

• Project/Area Number: 26461438
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Hokkaido University
• Principal Investigator: Hashimoto Daigo 北海道大学, 大学病院, 講師 (20419576)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 同種造血幹細胞移植 / マクロファージ / 移植片対宿主病 / GVHD / 貪食細胞 / 造血幹細胞移植 / ステロイド / JAK1/2阻害剤 / 組織幹細胞 / 皮膚 / JAK阻害剤 / 腸管 / 腸内細菌叢

Outline of Final Research Achievements

Reconstitution of tissue resident macrophages and inflammatory macrophages after allogeneic hematopoietic stem cell transplantation (SCT) were assessed using murine model of allogeneic bone marrow transplantation (BMT). We found that severe GVHD promoted replacement of tissue resident macrophages in the target organs by donor-derived macrophages on day +14 after allogeneic BMT. Contrary, it took at least a few months for reconstitution of donor macrophages after syngeneic BMT, suggesting that allogeneic response accelerated donor reconstitution of tissue resident macrophages. Next, we addressed turnover of inflammatory macrophages after SCT. Massive infiltration of inflammatory macrophages was found in the lung and skin, and depletion of these cells using monoclonal antibodies ameliorated graft versus host disease (GVHD) after allogeneic SCT. Our findings have important clinical implications with respect to establishment of tolerance and pathophysiology of GVHD after allogeneic SCT.

Research Products

• [Journal Article] Risk factors of human herpesvirus 6 encephalitis/myelitis after allogeneic hematopoietic stem cell transplantation. (2017)
  • Author(s): Miyashita N, Endo T, Onozawa M, Hashimoto D, Kondo T, Fujimoto K, Kahata K, Sugita J, Goto H, Matsukawa T, Hashino S, Teshima T.
  • Journal Title: Transpl Infect Dis. Volume: 印刷中 Issue: 3
  • DOI: 10.1111/tid.12682
  • NAID: 120006470980
  • Peer Reviewed
• [Journal Article] A leukemogenic kinase, FIP1L1-PDGFRA, and a SUMO E3 ligase, PIAS1, form a positive crosstalk via their enzymatic activities. (2017)
  • Author(s): M. Ibata, J. Iwasaki, Y. Fujioka, K. Nakagawa, S. Darmanin, M. Onozawa, D. Hashimoto, Y. Ohba, S. Hatakeyama, T. Teshima and T. Kondo.
  • Journal Title: Cancer Sci. Volume: 108 Issue: 2 Pages: 200-207
  • DOI: 10.1111/cas.13129
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Graft-versus-host disease targets ovary and causes female infertility in mice. (2017)
  • Author(s): S. Shimoji, D. Hashimoto, H. Tsujigiwa, K. Miyawaki, K. Kato, S. Takahashi, R. Ogasawara, T. Jiromaru, H. Iwasaki, T. Miyamoto, K. Akashi, *T. Teshima
  • Journal Title: Blood Volume: 129 Issue: 9 Pages: 1216-1225
  • DOI: 10.1182/blood-2016-07-728337
  • Peer Reviewed
• [Journal Article] MALDI-TOF MS in post-transplant bloodstream infections: reliable identification of causative bacteria in the neutropenic phase. (2017)
  • Author(s): Kanaya M, Hayashi Y, Hashimoto D, Endo T, Sugita J, Ohigashi H, Hashiguchi J, Matsukawa T, Matsuoka S, Kosugi-Kanaya M, Goto H, Onozawa M, Kahata K, Fujimoto K, Kondo T, Akizawa K, Shibuya H, Shimizu C, Teshima T.
  • Journal Title: Bone Marrow Transplant. Volume: 印刷中 Issue: 5 Pages: 778-780
  • DOI: 10.1038/bmt.2016.365
  • Peer Reviewed
• [Journal Article] Reduced-dose methotrexate in combination with tacrolimus was associated with rapid engraftment and recovery from oral mucositis without affecting the incidence of GVHD. (2016)
  • Author(s): Matsukawa T, Hashimoto D, Sugita J, Nakazawa S, Matsushita T, Kashiwazaki H, Goto H, Onozawa M, Kahata K, Fujimoto K, Endo T, Kondo T, Hashino S, Yamazaki Y, Teshima T.
  • Journal Title: Int J Hematol. Volume: 104 Issue: 1 Pages: 117-124
  • DOI: 10.1007/s12185-016-1996-0
  • NAID: 120006313418
  • Peer Reviewed
• [Journal Article] Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition. (2016)
  • Author(s): Salmon H, Idoyaga J, Rahman A, Leboeuf M, Remark R, Jordan S, Casanova-Acebes M, Khudoynazarova M, Agudo J, Tung N, Chakarov S, Rivera C, Hogstad B, Bosenberg M, Hashimoto D, Gnjatic S, Bhardwaj N, Palucka AK, Brown BD, Brody J, Ginhoux F, Merad M.
  • Journal Title: Immunity. Volume: 44 Issue: 4 Pages: 924-938
  • DOI: 10.1016/j.immuni.2016.03.012
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The Mononuclear Phagocyte System in Organ Transplantation. (2016)
  • Author(s): Ochando J, Kwan WH, Ginhoux F, Hutchinson JA, Hashimoto D, Collin M
  • Journal Title: American Journal of Transplantation Volume: 16(4) Issue: 4 Pages: 1053-1069
  • DOI: 10.1111/ajt.13627
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cytogenetically Unrelated Clones in Acute Myeloid Leukemia Showing Different Responses to Chemotherapy. (2016)
  • Author(s): Kasahara K, Onozawa M, Miyashita N, Yokohata E, Yoshida M, Kanaya M, Kosugi-Kanaya M, Takemura R, Takahashi S, Sugita J, Shigematsu A, Takahata M, Fujisawa S, Hashimoto D, Fujimoto K, Endo T, Kondo T, Teshima T
  • Journal Title: Case Rep Hematol. Volume: 2016 Pages: 1-5
  • DOI: 10.1155/2016/2373902
  • NAID: 120005822530
  • Peer Reviewed / Open Access
• [Journal Article] Key players in intestinal GVHD (2015)
  • Author(s): 橋本 大吾, 豊嶋 崇徳
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 7 Pages: 807-814
  • DOI: 10.11406/rinketsu.56.807
  • NAID: 130005093106
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Decreased secretion of Paneth cell α-defensins 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: Transplant Infectious Disease Volume: 17 Issue: 5 Pages: 702-706
  • DOI: 10.1111/tid.12423
  • Peer Reviewed / 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 Issue: 19 Pages: 3014-23
  • DOI: 10.1182/blood-2014-12-615781
  • Peer Reviewed / Open Access
• [Journal Article] Requirement for Innate Immunity and CD90+ NK1.1- Lymphocytes to Treat Established Melanoma with Chemo-Immunotherapy. (2015)
  • Author(s): Moskalenko M, Pan M, Fu Y, de Moll EH, Hashimoto D, Mortha A, Leboeuf M, Jayaraman P, Bernardo S, Sikora AG, Wolchok J, Bhardwaj N, Merad M, Saenger Y
  • Journal Title: Cancer Immunology Research Volume: 3 Issue: 3 Pages: 296-304
  • DOI: 10.1158/2326-6066.cir-14-0120
  • Peer Reviewed
• [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] 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] 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] FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia (2014)
  • Author(s): Junko Iwasaki, Takeshi Kondo, Stephanie Darmanin, Makoto Ibata, Masahiro Onozawa, Daigo Hashimoto, Naoya Sakamoto and Takanori Teshima
  • Journal Title: Annals of Hematology Volume: 未定 Issue: 9 Pages: 1473-1482
  • DOI: 10.1007/s00277-014-2085-1
  • NAID: 120005656326
  • Peer Reviewed
• [Journal Article] Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. (2014)
  • Author(s): Muller PA, Koscso B, Rajani GM, Stevanovic K, Berres ML, Hashimoto D, Mortha A, Leboeuf M, Li XM, Mucida D, Stanley ER, Dahan S, Margolis KG, Gershon MD, Merad M, Bogunovic M
  • Journal Title: Cell Volume: 158 Issue: 2 Pages: 300-313
  • DOI: 10.1016/j.cell.2014.04.050
  • Peer Reviewed
• [Journal Article] マクロファージは末梢組織でも自己増殖する！？ (2014)
  • Author(s): 橋本大吾
  • Journal Title: 炎症と免疫 Volume: 22 Pages: 411-415
• [Presentation] Vitamin A-Coupled Liposomes Carrying siRNA Against HSP47 Ameliorate Skin Fibrosis in Chronic Graft-Versus-Host Disease (2016)
  • Author(s): Yamakawa T, Hashimoto D, Hayase E, Takahashi S, Teshima T
  • Organizer: 58th ASH Annual Meeting
  • Place of Presentation: San Diego, USA, San Diego Convention Center
  • Year and Date: 2016-12-05
  • Int'l Joint Research
• [Presentation] LGR5+ skin stem cells are targeted in GVHD and topical ruxolitinib protects them against GVHD (2016)
  • Author(s): 高橋秀一郎, 橋本大吾, 早瀬英子, 豊嶋崇徳
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜 (神奈川県横浜市)
  • Year and Date: 2016-10-14
• [Presentation] マクロファージ研究の最前線 (マクロファージの分化・維 持・可塑性に関して) (2016)
  • Author(s): 橋本大吾
  • Organizer: 第26回日本樹状細胞研究会
  • Place of Presentation: ホテル日航熊本 (熊本県熊本市)
  • Year and Date: 2016-09-02
  • Invited
• [Presentation] R-spondin1 promotes Panted cell growth, maintains intestinal microbial ecology, and ameliorates GVHD. (2016)
  • Author(s): Hayase E, Hashimoto D, Nakamura K, Ogura Y, Hayashi T, Kurokawa K, Ayabe T, Teshima T.
  • Organizer: The 7th JSH International Symposium
  • Place of Presentation: 淡路夢舞台国際会議場 (兵庫県淡路市)
  • Year and Date: 2016-05-13
  • Int'l Joint Research
• [Presentation] 急性 GVHD 予防における短期メトトレキセート投与量の検討 (2016)
  • Author(s): 松川 敏大, 杉田 純一, 中澤誠多朗, 阿部 貴恵, 柏崎 晴彦, 大東 寛幸, 金谷 穣, 後藤 秀樹, 小野澤真弘, 橋本大吾, 加畑馨, 藤本勝也, 遠藤知之, 近藤健, 山崎裕, 豊嶋崇徳
  • Organizer: 第38回日本造血細胞移植学会総会
  • Place of Presentation: 名古屋国際会議場 (名古屋市)
  • Year and Date: 2016-03-03
• [Presentation] Topical ruxolitinib protects LGR5+ stem cells in the hair follicle and ameliorates skin graft- versus-host disease. (2016)
  • Author(s): Takahashi S, Hashimoto D, Hayase E, Teshima T
  • Organizer: 2016 BMT Tandem Meetings
  • Place of Presentation: Hawaii Convention Center (Honolulu, USA)
  • Year and Date: 2016-02-18
  • Int'l Joint Research
• [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: 57th ASH Annual Meeting
  • Place of Presentation: Orange County Convention Center (Orlando, USA)
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] Graft-Versus-Host Disease Targets Granulosa Cell of Ovarian Follicle and Causes Infertility after Allogeneic Hematopoietic Stem Cell Transplantation. (2015)
  • Author(s): Shimoji S, Hashimoto D, Kato K, Tujigiwa H, Akashi K, Teshima T
  • Organizer: 2015 BMT Tandem Meetings
  • Place of Presentation: Manchester Grand Hyatt (San Diego, USA)
  • Year and Date: 2015-02-11 – 2015-02-15
• [Presentation] Graft-Versus-Host Disease targets ovary and causes infertility after allo-HSCT (2014)
  • Author(s): Shimoji S, Kato K, Tujigiwa H, Eriguchi Y, Uryu H, Takashima S, Hashimoto D, Miyamoto T, Iwasaki H, Akashi K, Teshima T
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場 (大阪市)
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Key players in intestinal GVHD. (2014)
  • Author(s): Hashimoto D, Teshima T
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場 (大阪市)
  • Year and Date: 2014-10-31 – 2014-11-02
  • Invited
• [Presentation] CSF-1/CSF-2による炎症性疾患制御 (2014)
  • Author(s): 橋本大吾, Arthur Mortha, 豊嶋崇徳, Miriam Merad
  • Organizer: 第79回日本インターフェロンサイトカイン学会学術集会
  • Place of Presentation: 北海道大学医学部学友会館フラテホール (札幌市)
  • Year and Date: 2014-06-19 – 2014-06-20
• [Presentation] Tissue Resident Macrophages Self-maintain Locally Throughout Adult Life with Minimal Contribution from Circulating Monocytes. (2014)
  • Author(s): Hashimoto D
  • Organizer: The 22nd International Symposium on Molecular Cell Biology of Macrophages
  • Place of Presentation: 神戸商工会議所 (神戸市)
  • Year and Date: 2014-06-02 – 2014-06-03
  • Invited
• [Remarks] 橋本大吾オフィシャルウェブ
  • URL: http://tenure-track.cris.hokudai.ac.jp/lab/hashimoto/
• [Remarks] 北海道大学大学院医学研究科医学専攻内科学講座血液内科学分野
  • URL: http://www.hokudai-hematology.jp/medical/results/
• [Remarks] 北海道大学大学院 医学研究科医学専攻 内科学講座 血液内科学分野
  • URL: http://www.hokudai-hematology.jp/medical/results/
• [Patent(Industrial Property Rights)] 皮膚線維症治療剤 (2015)
  • Inventor(s): 2015年5月29日
  • Industrial Property Rights Holder: 豊嶋崇徳, 橋本大吾, 新津洋司郎, 味呑憲二郎
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-05-29