R-spondin1の腸管保護による造血幹細胞移植の成績向上の試み

2010 Fiscal Year Annual Research Report

• Project/Area Number: 20659153
• Research Institution: Kyushu University
• Principal Investigator: 豊嶋 崇徳 九州大学, 大学病院, 准教授 (40284096)
• Keywords: GVHD / R-spondinl / 腸管

Research Abstract

R-spondinl(R-Spol)の作用機序についてさらなる検討を加えた。WntシグナルはT細胞の機能分化に関連していることが報告されており、Wntシグナル活性化作用を有するR-SpolのT細胞機能分化に及ぼす影響を検討した。まずin vitroでT細胞をCD3/CD28で刺激培養する際に各種濃度のR-Spolを添加し、T細胞増殖とCD62L,CD44発現に対する影響を検討したが、変化を認めなかった。次にin vivoで同種骨髄移植後のアロ応答性T細胞のeffector/memory T細胞分化へのR-Spolの影響を検討したが変化を認めなかった。Foxp3陽性制御性T細胞数にも変化は見られなかった。これらの結果からR-Spolの全身性GVHD抑制効果はT細胞に対する直接的な影響ではなく、前年度までに明らかになった腸管傷害を軽減することにより間接的にもたらされたと考えられた。これを証明するために、移植前処置を実施せずに、MHC不適合のB6ドナーからB6D2F1レシピエントへの骨髄移植モデルにおいて移植day-3からday-1.day1からday3までR-spondinl 200μgを静脈内投与した.移植後のGVHDの重症度と生存率を観察したところ,R-spol投与によるGVHD抑制効果はみられなかった。以上の結果から,R-spolは移植前処置から腸管を保護し,その後のGVHDを軽減する可能性が示唆された.

Research Products

• [Journal Article] The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells. (2011)
  • Author(s): Takashima S, Kadowaki M, Aoyama K, Koyama M, Oshima T, Tomizuka K, Akashi K, Teshima T
  • Journal Title: J Exp Med Volume: 208 Pages: 285-294
  • Peer Reviewed
• [Journal Article] Long-term outcomes of autologous PBSCT for peripheral T-cell lymphoma : retrospective analysis of the experience of the Fukuoka BMT group (2010)
  • Author(s): Numata A, Miyamoto T, Ohno Y, Kamimura T, Kamezaki K, Tanimoto T, Takase K, Henzan H, Kato K, Takenaka K, Fukuda T, Harada N, Nagafuji K, Teshima T, Akashi K, Harada M, Eto T
  • Journal Title: Bone Marrow Transplant Volume: 45 Pages: 311-316
  • Peer Reviewed
• [Journal Article] High incidence of false-positive Aspergillus galactomannan test in multiple myeloma (2010)
  • Author(s): Mori Y, Nagasaki Y, Kamezaki K, Takenaka K, Iwasaki H, Harada N, Miyamoto T, Abe Y, Shimono N, Akashi K, Teshima T
  • Journal Title: Am J Hematol Volume: 85 Pages: 449-451
  • Peer Reviewed
• [Journal Article] Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice (2010)
  • Author(s): Asakura S, Hashimoto D, Takashima S, Sugiyama H, Maeda Y, Akashi K, Tanimoto M, Teshima T
  • Journal Title: J Clin Invest Volume: 120 Pages: 2370-2378
  • Peer Reviewed
• [Journal Article] Peripheral blood stem cell versus bone marrow transplantation from HLA-identical sibling donors in patients with leukemia : a propensity score-based comparison from the Japan Society for Hematopoietic Stem Cell Transplantation registry (2010)
  • Author(s): Nagafuji K, Matsuo K, Teshima T, Mori S, Sakamaki H, Hidaka M, Ogawa H,, Kodera Y, Kanda Y, Maruta A, Mori T, Yoshiba F, Ichinohe T, Kasai M, Takatsuka Y, Kubo K, Sao H, Atsuta Y, Suzuki R, Yoshida T, Tsuchida M, Harada M
  • Journal Title: Int J Hematol Volume: 91 Pages: 855-864
  • Peer Reviewed
• [Journal Article] Altered effector CD4^+ T cell function in IL-21R^<-/-> CD4^+ T cell-mediated graft-versus-host disease (2010)
  • Author(s): Oh I, Ozaki K, Meguro A, Hatanaka K, Kadowaki M, Matsu H, Tatara R, Sato K, Iwakura Y, Nakae S, Sudo K, Teshima T, Leonard WJ, Ozawa K
  • Journal Title: J Immunol Volume: 185 Pages: 1441-1444
  • Peer Reviewed
• [Journal Article] High incidence of human herpes virus 6-associated encephalitis/myelitis following a second unrelated cord blood transplantation. (2010)
  • Author(s): Mori Y, Miyamoto T, Nagafuji K, Kamezaki K, Yamamoto A, Saito N, Kato K, Takenaka K, Iwasaki H, Harada N, Abe Y, Teshima T, Akashi K
  • Journal Title: Biol Blood Marrow Transplant Volume: 16 Pages: 1596-1602
  • Peer Reviewed
• [Journal Article] TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells (2010)
  • Author(s): Kikushige Y, Shima T, Takayanagi S, Urata S, Miyamoto T, Iwasaki H, Teshima T, Harada M, Akashi K
  • Journal Title: Cell Stem Cell Volume: 7 Pages: 708-717
  • Peer Reviewed
• [Journal Article] Role of autotransplantation in the treatment of acute promyelocytic leukemia patients in remission : fukuoka BMT group observations and a literature review (2010)
  • Author(s): Kamimura T, Miyamoto T, Nagafuji K, Numata A, Henzan H, Takase K, Ito Y, Ohno Y, Fujisaki T, eto T, Takamatsu Y, Teshima T, Gondo H, Akashi K, Taniguchi S, Harada M
  • Journal Title: Bone Marrow Transplant Volume: (online)
  • Peer Reviewed
• [Journal Article] Analysis of immune reconstitution after autologous CD34+ stem/progenitor cell transplantation for systemic sclerosis : predominant reconstitution of Th1 CD4+ T cells (2010)
  • Author(s): Tsukamoto H, Nagafuji K, Horiuchi T, Mitoma H, Niiro H, Arinobu Y, Inoue Y, To K, Miyamoto T, Iwasaki H, Teshima T, Harada M, Akashi K
  • Journal Title: Rheumatology Volume: (online)
  • Peer Reviewed
• [Presentation] Pre-Transplant CSF-1 Therapy Expands the Recipient Macrophage Pool and Modulates Graft Versus Host Disease After Allogeneic Hematopoietic Cell Transplantation (2010)
  • Author(s): Hashimoto D, Andrew C, Melanie G, Marylene L, Florent G, Teshima T, Miriam M
  • Organizer: 52^<nd> ASH Annual Meeting
  • Place of Presentation: Orland, USA
  • Year and Date: 20101204-20101207
• [Presentation] Graft-Versus-Host Disease Alters Intestinal Microbial Ecology by Inhibiting Production of Enteric Defensins (2010)
  • Author(s): Eriguchi Y, Takashima S, Miyake N, Nagasaki Y, Shimono N, Akashi K, Teahima T
  • Organizer: 52^<nd> ASH Annual Meeting
  • Place of Presentation: Orland, USA
  • Year and Date: 20101204-20101207
• [Presentation] Prospective Multicenter Phase II Study of Myeloablative Conditioning Consisted of Intravenous Busulfan and Fludarabine +/- Total Body Irradiation for Older Patients (55 years and older) : Results of JSCT FB09 Study (2010)
  • Author(s): Uchida N, Hidaka M, Sakura T, Miyamoto T, Fujisaki T, Eto T, Maeda Y, Fukuno K, Matsumoto K, Morita K, Kishimoto J, Fukuda T, Teshima T, Taniguchi S, Mori S, Harada M
  • Organizer: 52^<nd> ASH Annual Meeting
  • Place of Presentation: Orland, USA
  • Year and Date: 20101204-20101207
• [Presentation] Crosstalk between graft-versus-host disease and intestinal ecology (2010)
  • Author(s): Teshima T
  • Organizer: Shanghai Workshop for Hematopoietic Stem Cell Transplantation
  • Place of Presentation: Shanghai, China
  • Year and Date: 20101015-20101017
• [Presentation] A possible role of recombinant thrombomodulin for a treatment of sinusoidal obstruction syndrome (2010)
  • Author(s): Kato K, Mori Y, Saito N, Miyawaki K, Tokuyama T, Oka H, Takenaka K, Harada N, Iwasaki H, Miyamoto T, Teshima T, Akashi K
  • Organizer: 第72回日本血液学会学総会
  • Place of Presentation: 横浜
  • Year and Date: 20100924-20100926
• [Presentation] High incidence of false-positive Aspergillus galactomannan test in multiple myeloma (2010)
  • Author(s): Mori Y, Kato K, Takenaka K, Iwasaki H, Harada N, Miyamoto T, Akashi K, Teshima T
  • Organizer: 第72回日本血液学会学総会
  • Place of Presentation: 横浜
  • Year and Date: 20100924-20100926
• [Presentation] Drug interactions between calcineurin inhibitors and voriconazole or itraconazole in Allo-HSCT (2010)
  • Author(s): Takashima S, Nagafuji K, Teshima T, Takenaka K, Iwasaki H, Harada N, Miyamoto T, Akashi K
  • Organizer: 第72回日本血液学会学総会
  • Place of Presentation: 横浜
  • Year and Date: 20100924-20100926
• [Presentation] A novel fusion partner of PDGFRA identified in chronic eosinophilic leukemia (2010)
  • Author(s): Kohno K, Mori Y, Iwasaki H, Haro T, Kato K, Takenaka K, Harada N, Miyamoto T, Teshima T, Akashi K
  • Organizer: 第72回日本血液学会学総会
  • Place of Presentation: 横浜
  • Year and Date: 20100924-20100926
• [Presentation] 臓器・細胞移植と輸血の現状 (2010)
  • Author(s): 豊嶋崇徳
  • Organizer: 第34回日本血液事業学会総会
  • Place of Presentation: 福岡
  • Year and Date: 20100921-20100923
• [Presentation] T細胞疲弊による移植片対白血病効果減弱のメカニズム (2010)
  • Author(s): 朝倉昇司, 橋本大吾, 高嶋秀一郎, 杉山暖子, 前田嘉信, 赤司浩一, 谷本光音, 豊嶋崇徳
  • Organizer: 第2回 造血器腫瘍免疫療法研究会学術集会
  • Place of Presentation: 松山
  • Year and Date: 20100828-20100829
• [Presentation] Stimulation of Intestinal stem cells with R-spondin1 improves outcome of allogeneic stem cell transplantation by regulating systemic graft-versus-host desease (2010)
  • Author(s): Takashima S, Kadowaki M, Aoyama K, Koyama M, Oshima T, Tomizuka K, Akashi K, Teshima T
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-20100827
• [Presentation] Current status and future prospects of hematopoietic stem cell transplantation in Japan (2010)
  • Author(s): Teshima T
  • Organizer: Chinese Marrow Donor Program Transplant Hospital Technical Conference
  • Place of Presentation: Wuhan, China
  • Year and Date: 20100520-20100521
• [Presentation] 非血縁者間同種末梢血幹細胞移植の実施に向けて (2010)
  • Author(s): 豊嶋崇徳
  • Organizer: 第17回日本輸血・細胞治療学会秋季シンポジウム
  • Place of Presentation: 福岡
  • Year and Date: 2010-09-22