GVHDによるホメオスタシス破綻のメカニズム

2013 Fiscal Year Annual Research Report

• Project/Area Number: 25293217
• Research Category: Grant-in-Aid for Scientific Research (B)
• 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 – 2016-03-31
• Keywords: GVHD / 造血幹細胞移植 / 腸管 / パネート細胞 / defensin

Research Abstract

初年度はR-Spondin1のパネート細胞に対する効果とdefensin産生に対する効果を検討した。ナイーブマウスにR-Spondin1を投与し、パネート細胞の増殖・分化をdefensin, MMP7による蛍光免疫染色によって可視化し検討した。その結果、R-Spondin1の3-6回投与によって、陰窩に存在するパネート細胞が有意に増加し、絨毛方向へと移動もみられたことから分化の可能性も示唆された。次に、パネート細胞機能に対する影響を検討するため、われわれの開発した糞便中抗菌ペプチドdefensinのELISA測定系を用いて検討した。その結果、腸管内容物中のdefensinの含有量が増加しており、R-Spondin1は機能的なパネート細胞の増殖作用があることが明らかになった。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

初年度の目標であった、R-Spondin1のパネート細胞に対する効果とdefensin産生に対する効果はほぼ確実に証明された。したがって、初年度は想定通りの成果が達成されたと判断した。

Strategy for Future Research Activity

得られたデータをリピートし、統計学的有意差を検討し、データの確実性を検証する。次いで、R-Spondin1投与による腸内細菌叢などのホメオスタシスに及ぼす影響について詳細に検討を行う予定である。さらに、腸管GVHDや感染症などの疾患モデルにおいて、R-Spondin1のin vivoでの効果を検討するための予備実験に入り、治療応用の観点からの研究を展開する準備を行う予定である。

Expenditure Plans for the Next FY Research Funding

動物実験施設の改修に伴い、十分な研究スペースが確保できなかった。
今年度は十分な実験スペースを確保することと、その他の実験スペースを有効利用することで対応する。

Research Products

• [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, Miyamoto T, Kikushige Y, Mori Y, Kamezaki K, Takase K, Henzan N, Numata A, Ito A, Takenaka K, Iwasaki H, Kamimura T, Eto T, Nagafuji K, Teshima T, Kato K, Akashi K
  • Journal Title: Blood Volume: 121(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 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
  • 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: Biol Pharm Bull Volume: 36(4) Pages: 574-578
  • DOI: 10.1248/bpb.b12-00901
  • 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) Pages: 421-426
  • DOI: 10.1007/s12185-013-1297-9
  • Peer Reviewed
• [Journal Article] Protective roles of epithelial cells in the survival of adult T-cell leukemia/lymphoma cells (2013)
  • Author(s): Miyatake Y, Oliveira AL, Jarboui MA, Ota S, Tomaru U, Teshima T, Hall WW, Kasahara M
  • Journal Title: Am J Pathol Volume: 182(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(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(2) Pages: 186-196
  • DOI: 10.1007/s12185-013-1378-9
  • 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(2) Pages: 206-213
  • DOI: 10.1007/s12185-013-1399-4
  • 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, Nagafuji K, Takamatsu Y, Teshima T, Akashi K
  • Journal Title: Int J Hematol Volume: 98(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) 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(10) Pages: 1525-1529
  • DOI: 10.1016/j.bbmt.2013.07.027
  • 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): 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(4) Pages: 463-471
  • DOI: 10.1007/s12185-013-1430-9
  • Peer Reviewed
• [Presentation] Reciprocal expression of antimicrobial peptides in GVHD (2014)
  • Author(s): Teshima T
  • Organizer: GvHGvL 2014
  • Place of Presentation: Thon-Dittmer Palais Regensburg(Germany)
  • Year and Date: 20140326-20140328
  • Invited