造血幹細胞移植後不妊の新たなメカニズム

2014 Fiscal Year Annual Research Report

• Project/Area Number: 25670443
• Research Institution: Hokkaido University
• Principal Investigator: 豊嶋 崇徳 北海道大学, 医学(系)研究科(研究院), 教授 (40284096)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: GVHD / 卵巣 / 不妊 / 免疫抑制剤 / 造血幹細胞移植

Outline of Annual Research Achievements

前年度に、マウス骨髄移植モデルB6 → B6D2F1(♀)において、GVHD群では、卵巣にドナーＴ細胞の浸潤がみられ、卵巣細胞、とくに顆粒膜細胞にアポトーシスがみられ、両者のsatellitosis もみられ、卵巣GVHDの発症を病理学的に確認できた。今年度は、妊孕性についての機能的な検討を行った。顆粒膜細胞からの抗ミューラー管ホルモン（AMH)の産生を免疫組織検査で検討したところ、GVHD群でその発現低下が認められた。これを反映して、血清AMHの低下も確認できた。次いでゴナドトロピン投与による強制排卵実験を行った。GVHD群で排卵数の低下が認められた。また移植後の雌マウスを健康なオスマウスと交配実験を行った。その結果、GVHD群で有意な出産数の低下が観察された。さらにこれら一連の研究をbusulfanとcyclophosphamideによる移植前処置法を用いた移植実験においても繰り返し実施した。その結果、病理学的な卵巣GVHDの発症、顆粒膜細胞からのAMHの産生低下、排卵数の低下、交配実験での出産数の低下が確認でいた。さらに免疫抑制剤投与によって、卵巣GVHDの発症を抑制可能か検討し、Methylprednisolone 10mg/kgを投与することにより全身GVHDとともに卵巣GVHDの発症が抑制された。その結果、顆粒膜細胞からのAMHの産生と排卵数の回復が認められ、妊孕性が回復した。以上の結果から、GVHD予防が卵巣機能と妊孕性の維持に重要であることが示唆された。

Research Products

• [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: 49(1) Pages: 110-115
  • DOI: 10.1038/bmt.2013.134
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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 KI, Fujii N, Kondo E, Shinagawa K, Tanaka T, Takeuchi K, Teshima T, Tanimoto M
  • Journal Title: Biol Blood Marrow Transplant Volume: 20(2) Pages: 183-191
  • DOI: 10.1016/j.bbmt.2013.11.018
  • 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): Shono Y, Shiratori S, Kosugi-Kanaya M, Ueha S, Sugita J, Shigematsu A, Kondo T, Hashimoto D, Fujimoto K, Endo T, Nishio M, Hashino S, Matsuno Y, Matsushima K, Tanaka J, Imamura M, Teshima T
  • Journal Title: Biol Blood Marrow Transplant Volume: 20(4) Pages: 495-500
  • DOI: 10.1016/j.bbmt.2013.12.568
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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) 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: 20(6) Pages: 801-805
  • DOI: 10.1016/j.bbmt.2014.02.014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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: Intern Med Volume: 53(12) Pages: 1315-1320
  • DOI: 10.2169/internalmedicine.53.1858
  • 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) 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: - Pages: -
  • DOI: 10.1002/hon.2162
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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) 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) Pages: 3691-3693
  • DOI: 10.1182/blood-2014-04-570325
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 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