Basic research of new treatment strategy for graft-versus-host disease via tissue stem cell protection

• Project/Area Number: 24790977
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Kyushu University
• Principal Investigator: TAKASHIMA Shuichiro 九州大学, 大学病院, 助教 (70622116)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 組織幹細胞 / 腸幹細胞 / 移植片対宿主病 / パネート細胞 / 脂肪前駆細胞 / 脱毛 / GVHD / 造血幹細胞移植 / REGIIIα / 皮膚幹細胞

Research Abstract

The efficacy of allogeneic stem cell transplantation (allo-SCT) is limited by the devastating complication, graft-versus-host disease (GVHD). We evaluated a link between GVHD induced tissue damage and tissue stem cells.
We discovered that Paneth cells, which are identified as niche for intestinal stem cells, are targeted by GVHD, resulting in marked reduction in the expression of alfa-defensins. GVHD associated changes in production of antimicrobial peptides including alfa-defensins delivered loss of physiological diversity among the intestinal microflora. We also found the possibilities that pretransplant conditioning regimen damaged adipose precursor cells, which function as skin stem cell niche to drive hair cycling, and the process of adipose precursor cell recovery was inhibited by chronic GVHD development, resulting in alopecia.
Therefore, protection of tissue stem cells as well as their niche from GVHD may ameliorate tissue damage and promote tissue regeneration after allo-SCT.

Research Products

• [Journal Article] Comparison of bortezomib, cyclophosphamide, and dexamethasone (VCD) induction with bortezomib and dexamethasone (BD) induction for the newly diagnosed symptomatic multiple myeloma (2014)
  • Author(s): Takashima S, Miyamoto T, Kamimura T, Yoshimoto G, Kato K, Ito Y, Muta T, Matsushima T, Shiratsuchi M, Tanimoto K, Takenaka K, Iwasaki H, Teshima T, Akashi K
  • Journal Title: Int J Myeloma Volume: 4(1) Pages: 7-12
  • URL: http://www.jsm.gr.jp/files/journalpdf/2014_4_1_final2.pdf
  • Peer Reviewed
• [Journal Article] Comparison of bortezomib, cyclophosphamide, and dexamethasone (VCD) induction with bortezomib and dexamethasone (BD) induction for the newly diagnosed symptomatic multiple myeloma (2014)
  • Author(s): Takashima S, Miyamoto T, Kamimura T, Yoshimoto G, Kato K, Ito Y, Muta T, Matsushima T, Shiratsuchi M, Tanimoto K, Takenaka K, Iwasaki H, Teshima T, Akashi K.
  • Journal Title: Int J Myeloma. Volume: 4-1 Pages: 7-12
  • Peer Reviewed
• [Journal Article] The Use of Oral Beclomethasone Dipropionate in the Treatment of Gastrointestinal Graft-versus-host Disease: The Experience of the Fukuoka 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: in press
  • 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] 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] Higher incidence of injection site reactions after subcutaneous bortezomib administration on the thigh compared with the abdomen. (2013)
  • Author(s): Kamimura T, et al
  • Journal Title: Eur J Haematol Volume: 90 Issue: 2 Pages: 157-161
  • DOI: 10.1111/ejh.12055
  • Peer Reviewed
• [Journal Article] Higher incidence of injection site reactions after subcutaneous bortezomib administration on the thigh compared with the abdomen (2013)
  • Author(s): Kamimura T, Miyamoto T, Yokota N, Takashima S, Chong Y, Ito Y, Akashi K.
  • Journal Title: Eur J Haematol. Volume: 90-2 Pages: 157-61
  • Peer Reviewed
• [Journal Article] Injection site reaction after subcutaneous administration of bortezomib in Japanese patients with multiple myeloma (2012)
  • Author(s): Kamimura T, Miyamoto T, Takashima S, Yokota N, Chong Y, Ito Y, Akashi K
  • Journal Title: Int J Hematol Volume: 96(4) Issue: 4 Pages: 525-7
  • DOI: 10.1007/s12185-012-1167-x
  • NAID: 10031126747
  • Peer Reviewed
• [Journal Article] Low incidence of adenovirus hemorrhagic cystitis following autologous hematopoietic stem cell transplantation in the rituximab era. (2012)
  • Author(s): Mori Y, Miyamoto T, Kamezaki K, Kato K, Kikushige Y, Takashima S, Urata S, Shimoda S, Shimono N, Takenaka K, Iwasaki H, Nagafuji K, Teshima T, Akashi K.
  • Journal Title: Am J Hematol. Volume: 87 Issue: 8 Pages: 828-30
  • DOI: 10.1002/ajh.23247
  • Peer Reviewed
• [Journal Article] Graft-versus-host disease disrup ts intestinal microbial ecology by i nhibiting Paneth cell production of α-defensins (2012)
  • Author(s): Eriguchi Y, Takashima S 他10名
  • Journal Title: Blood Volume: 120巻 Issue: 1 Pages: 223-231
  • DOI: 10.1182/blood-2011-12-401166
  • Peer Reviewed
• [Journal Article] The Use of Oral Beclomethasone Dipropionate in the Treatment of Gastrointestinal Graft-versus-host Disease : The Experience of the Fukuoka BMT Group
  • 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: (In press)
  • Peer Reviewed
• [Presentation] 同種移植後再発に対してAzacitidine 併用ドナーリンパ球輸注を行い, 非血縁者間同種骨髄移植を実施した急性骨髄性白血病 (2014)
  • Author(s): 高嶋 秀一郎, 加藤 光次, 林 正康, 浦田 真吾, 菊繁 吉謙, 牟田 毅, 竹中 克斗, 岩崎 浩己, 宮本 敏浩, 豊嶋 崇徳, 赤司 浩一
  • Organizer: 第35回日本造血細胞移植学会
  • Place of Presentation: 金沢
  • Year and Date: 2014-03-09
• [Presentation] 多発性骨髄腫に対する自家末梢血幹細胞移植後の地固め療法としてのVTD 療法の安全性と有効性の検討 (2014)
  • Author(s): 高嶋 秀一郎, 門脇 賢典, 上村 智彦, 宮本 敏浩, 吉本 五一, 高瀬 謙, 赤司 浩一
  • Organizer: 第36回日本造血細胞移植学会
  • Place of Presentation: 那覇
  • Year and Date: 2014-03-08
• [Presentation] Fungal cell wall component induces Th17 response and accelerates acute GVHD in lung (2013)
  • Author(s): Uryu H, Shimoji S, Eriguchi Y, Takasihma S, Kato K, Akashi K, Teshima T
  • Organizer: 第75回日本血液学会 学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2013-10-12
• [Presentation] Oral beclomethasone dipropionate for treatment of gastrointestinal graft-versus-host disease : Experience of the Fukuoka BMT group (2013)
  • Author(s): Shuichiro Takashima, Tetsuya Eto, Motoaki Shiratsuchi, Michihiro Hidaka, Yasuo Mori, Koji Kato, Kenjiro Kamezaki, Seido Oku, Hideho Henzan, Ken Takase, Takamitsu Matsushima, Katsuto Takenaka, Hiromi Iwasaki, Toshihiro Miyamoto, Koichi Akashi, and Takanori Teshima
  • Organizer: 第75回日本血液学会 学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2013-10-12
• [Presentation] Grsft-Versus-Host Disease Targets Ovary and Causes Infertility After Allogeneic Hematopoietic Stem Cell Transplantation (2013)
  • Author(s): Shimoji S, Kato K, Tsujigiwa H, Eriguchi Y, Lee L, Uryu H, Takasihma S, Hashimoto D, Akashi K, Teshima T
  • Organizer: The 55th American Society of Hamatology Annual Meeting and Exposition
  • Place of Presentation: New Orleans
• [Presentation] Graft-Versus-Host Disease Targets Ovary and Causes Infertility After Allogeneic Hematopoietic Stem Cell Transplantation (2013)
  • Author(s): Shimoji S, Kato K, Tsujigiwa H, Eruguchi Y, Lee L, Uryu H, Takashima S, Hashimoto D, Akashi K, Teshima T
  • Organizer: The 55th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: New Orleans
• [Presentation] Bortezomib, cyclophosphamide and dexamethasone (VCD) induction for symptomatic multiple myeloma (2012)
  • Author(s): Shuichiro Takashima, Toshihiro Miyamoto, Tomohiko Kamimura, Shingo Urata, Yoshikane Kikushuge, Yong Chong, Yoshikiyo Ito, Koji Kato, Kazuki Tanimoto, Katsuto Takenaka, Hiromi Iwasaki, Takanori Teshima, and Koichi Akashi
  • Organizer: 第74回日本血液学会 学術集会
  • Place of Presentation: 京都
  • Year and Date: 2012-10-21
• [Presentation] Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of -defensins (2012)
  • Author(s): Shuichiro Takashima, Yoshihiro Eriguchi, Nobuyuki Shimono, Tokiyoshi Ayabe, Koichi Akashi, and Takanori Teshima
  • Organizer: The ISSCR 10^t^h Annual Meeting
  • Place of Presentation: Yokohama
  • Year and Date: 2012-06-15
• [Presentation] 多発性骨髄腫に対する自家末梢血幹細胞移植後の地固め療法としてのVTD療法の安全性と有効性の検討
  • Author(s): 高嶋秀一郎,門脇賢典,上村智彦,宮本敏浩,吉本五一,高瀬謙,赤司浩一
  • Organizer: 第36回日本造血細胞移植学会総会
  • Place of Presentation: 那覇
• [Presentation] Fungal cell wall component induces Th17 response and accelerates acute GVHD in lung
  • Author(s): Uryu H, Shimoji S, Eriguchi Y, Takashima S, Kato K, Akashi K, Teshima T
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Sapporo
• [Presentation] Oral beclomethasone dipropionate for treatment of gastrointestinal graft-versus-host disease: Experience of the Fukuoka BMT group
  • 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
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Sapporo
• [Presentation] Allogeneic stem cell transplantation for t-MDS/AML following chemotherapy for solid cancer
  • Author(s): Jinnouchi F, Muta T, Yurino A, Tochigi T, Semba Y, Kusumoto H, Shima T, Takashima S, Kohno K, Yoshimoto G, Yamasaki S, Kato K, Takenaka K, Iwasaki H, Miyamoto T, Ohno Y, Henzan H, Eto T, Akashi K
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Sapporo
• [Presentation] HHV-6-associated encephalitis and / or myelitis: Retrospective analysis of 374 cases
  • Author(s): Yoshimoto G, Miyamoto T, Shima T, Takashima S, Kamezaki K, Kato K, Muta T, Takenaka K, Iwasaki H, Akashi K
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Sapporo
• [Presentation] Successful treatment of refractory primary C-ALCL with hematopoietic stem cell transplantation
  • Author(s): Yurino A, Yoshimoto G, Takenaka K, Shima T, Takashima T, Kamezaki K, Kato K, Muta T, Iwasaki H, Miyamoto T, Akashi K
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Sapporo
• [Presentation] Severe cholecystitis induced remission for relapsed AML after allogeneic PBSCT
  • Author(s): Semba Y, Yamasaki S, Miyamoto T, Jinnnouchi F, Kikushige Y, Takashima S, Yoshimoto G, Kato K, Muta T, Takenaka K, Iwasaki H, Akashi K
  • Organizer: The 75th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Sapporo
• [Presentation] BKV サブタイプ3 型が同種造血幹細胞移植後出血性膀胱炎の発症リスクである：福岡骨髄移植グループ(FBMTG) の検討
  • Author(s): 加藤光次,宮本 敏浩,江藤義隆,米本孝二,吉田周郎,斉藤統之,平安山英穂,伊藤能清,高嶋秀一郎,菊繁吉謙,牟田毅,竹中克斗,岩崎浩己,上村智彦,衛藤徹也,豊嶋崇徳,下野信行,林純,赤司浩一
  • Organizer: 第35回日本造血細胞移植学会総会
  • Place of Presentation: 金沢
• [Presentation] 新規薬剤が濾胞性リンパ腫の同種造血幹細胞移植に与える影響
  • Author(s): 湯田 淳一朗、加藤 光次、高嶋 秀一郎、河野 健太郎、菊繁 吉謙、山崎 聡、牟田 毅、竹中 克斗、岩崎 浩己、宮本 敏浩、豊嶋 崇徳、赤司 浩一
  • Organizer: 第35回日本造血細胞移植学会総会
  • Place of Presentation: 金沢
• [Presentation] 移植後早期再発ATLL に対する通常量抗CCR4 抗体の使用経験
  • Author(s): 陳之内 文昭、河野 健太郎、加藤 光次、瓜生 英尚、高嶋 秀一郎、山崎 聡、牟田 毅、竹中 克斗、岩崎 浩己、宮本 敏浩、豊嶋 崇徳、赤司 浩一
  • Organizer: 第35回日本造血細胞移植学会総会
  • Place of Presentation: 金沢
• [Presentation] 同種移植後再発に対してAzacitidine 併用ドナーリンパ球輸注を行い、非血縁者間同種骨髄移植を実施した急性骨髄性白血病
  • Author(s): 高嶋 秀一郎、加藤 光次、林 正康、浦田 真吾、菊繁 吉謙、牟田 毅、竹中 克斗、岩崎 浩己、宮本 敏浩、豊嶋 崇徳、赤司 浩一
  • Organizer: 第35回日本造血細胞移植学会総会
  • Place of Presentation: 金沢
• [Presentation] BK Virus Subtype III Is Associated with Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation
  • Author(s): Kato K,Miyamoto T,ETO Y,Yonemoto K,Yoshida S,Saito N,Henzan H,Ito Y,Yuda J,Hayashi M,Takashima S, et. al
  • Organizer: 2013 BMT Tandem Meetings
  • Place of Presentation: Salt Lake City, USA
• [Presentation] Lenalidomide Could Minimize an Engraftment Syndrome After Autologous Hematopoietic Stem Cell Transplantation in Patients with POEMS Syndrome
  • Author(s): Yuda J, Kato K, Takenaka K, Hayashi J, Urata S, Takashima S, Kikushige Y, Tanimoto K, Iwasaki H, Miyamoto T, Teshima T, Akashi K
  • Organizer: 2013 BMT Tandem Meetings
  • Place of Presentation: Salt Lake City, USA
• [Presentation] α-Mannan Can Induce Acute Pulmonary Gvhd Dependent On Th17 Subsets
  • Author(s): Uryu H, Oka H, Shimoji S, Eriguchi Y, Takashima S, Kato K, Akashi K, Teshima T
  • Organizer: 2013 BMT Tandem Meetings
  • Place of Presentation: Salt Lake City, USA
• [Presentation] 当院における造血幹細胞移植後の血流感染症の検討
  • Author(s): 湯田淳一朗、竹中克斗、林正康、浦田真吾、高嶋秀一郎、菊繁吉謙、加藤光次、谷本一樹、牟田毅、岩崎浩己、宮本敏浩、豊嶋崇徳、赤司浩一
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] BKV subtype is associated with haemorrhagic cystitis after allo-HSCT: Analysis of data from FBMTG
  • Author(s): Kato K, Miyamoto T, Eto Y, Yoshida S, Saito N, Henzan H, Ito Y, Oku S, Kuriyama T, Mori Y, Urata S, Takashima S, et al.
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Bortezomib, cyclophosphamide and dexamethasone (VCD) induction for symptomatic multiple myeloma
  • Author(s): Takashima S, Miyamoto T, Kamimura T, Urata S, Kikushige Y, Chong Y, Ito Y, Kato K, Tanimoto K, Takenaka K, Iwasaki H, Teshima T, Akashi K
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] GRAFT VERSUS HOST DISEASE DISRUPTS INTESTINAL MICROBIAL ECOLOGY BY INHIBITING PANETH CELL PRODUCTION OF DEFENSINS
  • Author(s): Takashima S, Eriguchi Y, Ayabe T, Akashi K, Teshima T
  • Organizer: The ISSCR 10th Annual Meeting
  • Place of Presentation: 横浜
• [Book] New 専門医を目指すケース・メソッド・アプローチ血液疾患 (2012)
  • Author(s): 安部 達生, 谷脇 雅史, 横田 昇平
  • Publisher: 日本医事新報社
• [Book] New専門医を目指すケース・メソッド・アプローチ血液疾患 (2012)
  • Author(s): 安部 達生、谷脇 雅史、横田 昇平
  • Total Pages: 417
  • Publisher: 日本医事新報社
• [Remarks] 九州大学大学院 病態修復内科
  • URL: http://www.1nai.med.kyushu-u.ac.jp/
• [Remarks] 九州大学 医学部 第一内科（病態修復内科）
  • URL: http://www.1nai.med.kyushu-u.ac.jp/