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

• Project/Area Number: 20659153
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Kyushu University
• Principal Investigator: 豊嶋 崇徳 九州大学, 大学病院, 准教授 (40284096)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2010: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2009: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2008: ¥1,100,000 (Direct Cost: ¥1,100,000)
• Keywords: GVHD / R-spondinl / 腸管 / 腸幹細胞 / Wntシグナル

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
  • NAID: 130004505744
  • 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
  • NAID: 10026511359
  • 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
• [Journal Article] Improved outcome of allogeneic bone marrow transplantation due to breast-feeding-induced tolerance to maternal antigens (2009)
  • Author(s): Aoyama K, Koyama M, Matsuoka KI, Hashimoto D, Ichinohe T, Harada M, Akashi K, Tanimoto M, Teshima T
  • Journal Title: Blood 113 Pages: 1829-1833
  • Peer Reviewed
• [Journal Article] Plasmacytoid dendritic cells prime alloreactive T cells to mediate graft-versus-host disease as antigen-presenting cells (2009)
  • Author(s): Koyama M, Hashimoto D, Aoyama K, Matsuoka KI, Karube K, Niiro H, Harada M, Tanimoto M, Akashi K, Teshima T
  • Journal Title: Blood 113 Pages: 2088-2095
  • Peer Reviewed
• [Journal Article] Oral valganciclovir as preemptive therapy is effective for cytomegalovirus infection in allogeneic hematopoietic stem cell transplantation (2009)
  • Author(s): Takenaka K, Eto T, Nagafuji K, Kamezaki K, Matsuo Y, Yoshimoto G, Harada N, Yoshida M, Henzan H, Takase K, Miyamoto T, Akashi K, Harada M, Teshima T
  • Journal Title: Int J Hematol 89 Pages: 318-323
  • Peer Reviewed
• [Journal Article] Rituximab for the treatment of corticosteroid-refractory chronic graft-versus-host disease (2009)
  • Author(s): Teshima T, Nagafuji K, Henzan H, Miyamura K, Takase K, Hidaka M, Miyamoto T, Takenaka K, Akashi K, Harada M
  • Journal Title: Int J Hematol 90 Pages: 253-260
  • NAID: 10026108612
  • Peer Reviewed
• [Journal Article] Infectious complications in patients receiving autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune disease (2009)
  • Author(s): Kohno K, Nagafuji K, Tsukamoto H, Horiuchi T, Takase K, Aoki K, Henzan H, Kamezaki K, Takenaka K, Miyamoto T, Teshima T, Harada M, Akashi K
  • Journal Title: Transpl Infect Dis 11 Pages: 318-323
  • Peer Reviewed
• [Journal Article] Nonmyeloablative allogeneic hematopoietic stem cell transplantation as immunotherapy for pancreatic cancer (2009)
  • Author(s): Abe Y, Ito T, Baba E, Nagafuji K, Kawabe K, Choi I, Arita Y, Miyamoto T, Teshima T, Nakano S, Harada M
  • Journal Title: Pancreas 38 Pages: 815-819
  • NAID: 10027055213
  • Peer Reviewed
• [Journal Article] Second unrelated cord blood transplantation using a reduced conditioning regimen combined with gemtuzumab ozogamicin in patients with relapsed acute myelogenous leukemia (2009)
  • Author(s): Yamauchi T, Mori Y, Miyamoto T, Kamezaki K, Aoki T, Yamamoto A, Takenaka K, Iwasaki H, Harada N, Nagafuji K, Teshima T, Akashi K
  • Journal Title: Int J Hematol 90 Pages: 416-420
  • Peer Reviewed
• [Journal Article] Infectious complications in chronic graft-versus-host disease : a retrospective study of 145 recipients of allogeneic hematopoietic stem cell transplantation with reduced- and conventional-intensity conditioning regimens (2008)
  • Author(s): Yamasaki S, Heike Y, Mori S, Fukuda T, Maruyama D, Kato R, Usui E, Koido K, Kim S, Tanosaki R, Tobinai K, Teshima T, Takaue Y
  • Journal Title: Transplant Infect Dis 10 Pages: 252-259
  • Peer Reviewed
• [Journal Article] Posttransplant administration of cyclophosphamide and donor lymphocyte infusion induces potent antitumor immunity to solid tumor (2008)
  • Author(s): Eto M, Kamiryo Y, Takeuchi A, Hirano M, Tatsugami K, Harada M, Kiyoshima K, Hamaguchi M, TeshimaT, Tsuneyoshi M, Yoshikai Y
  • Journal Title: Clin Cancer Res 14 Pages: 2833-40
  • Peer Reviewed
• [Journal Article] Reduced-intensity unrelated donor Bone Marrow Transplant for hematologic malignancies (2008)
  • Author(s): Kim S-W, Matsuo K, Fukuda T, Hara M, Matsue K, Taniguchi S, Eto T, Tanimoto M, Wake A, Hatanaka K, Nakao S, Ishid a Y, Harada M, Utsunomiya A, Imamura M, Kanda Y, Sunami K, Kawano F, Takaue Y, Teshima T
  • Journal Title: Int J Hematol 88 Pages: 324-330
  • NAID: 10023970450
  • Peer Reviewed
• [Journal Article] Preparation of functionally preserved CD4+CD25high regulatory T cells from leukapheresis products from ulcerative colitis patients, which are applicable to regulatory T cell-transfer therapy. (2008)
  • Author(s): Sumida Y, Nakamura K, Kanayama K, Akiho H, Teshima T, Takayanagi R
  • Journal Title: Cytotherapy 10 Pages: 698-710
  • Peer Reviewed
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [Presentation] R-spondin1は移植前処置から腸管を保護し、移植片対宿主病(GVHD)を改善する (2010)
  • Author(s): 高嶋秀一郎, 門脇賢典, 青山一利, 小山幹子, 大島毅, 富塚一磨, 赤司浩一, 原田実根, 豊嶋崇徳
  • Organizer: 第32回日本造血細胞移植学会総会
  • Place of Presentation: 浜松
• [Presentation] 同種造血幹細胞移植後の Hematogones は良好な移植経過を反映する (2010)
  • Author(s): 島隆弘, 宮本敏浩, 菊繁吉謙, 亀崎健次郎, 竹中克斗, 豊嶋崇徳, 赤司浩一
  • Organizer: 第32回日本造血細胞移植学会総会
  • Place of Presentation: 浜松
• [Presentation] マウスGVHDモデルにおける移植後長期の制御性T細胞再構築の検討 (2010)
  • Author(s): 杉山暖子, 前田嘉信, 西森久和, 小林孝一郎, 山筋好子, 竹内賢吾, 豊嶋崇徳, 谷本光音
  • Organizer: 第32回日本造血細胞移植学会総会
  • Place of Presentation: 浜松
• [Presentation] Cyclosporine, but not mTOR inhibitors, hampers the reconstitution of bone marrow-derived Tregs (2009)
  • Author(s): 杉山暖子, 前田嘉信, 西森久和, 小林孝一郎, 竹内賢吾, 豊嶋崇徳, 谷本光音
  • Organizer: 第71回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] Depletion of regulatory T cells causes chronic GVHD in experimental bone marrow transplantation (2009)
  • Author(s): Kadowaki M, Sakoda Y, Takashima S, Aoyama K, Koyama M, Hashimoto D, Akashi K, Teshima T
  • Organizer: 第71回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] Successful treatment of 8p11 myeloproliferative syndrome with allogeneic stem cell transplantation (2009)
  • Author(s): Yamauchi T, Kouno K, Yamamoto A, Shima T, Yoshida S, Mori Y, Kamezaki K, Takenaka K, Harada N, Nagafuji K, Miyamoto T, Teshima T, Iwasaki H, Akashi K
  • Organizer: 第71回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] Rituximab improves the outcome of newly diagnosed diffuse-large B-cell lymphoma following auto-PBSCT (2009)
  • Author(s): Kamezaki K, Takenaka K, Mori Y, Numata A, Harada N, Miyamoto T, Nagafuji K, Teshima T, Harada M, Akashi K
  • Organizer: 第71回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] Additional acquisition of t(1;21) in a patient relapsing with AML with NUP98-HOXA9 (2009)
  • Author(s): Aoki T, Miyamoto T, Yoshida S, Yamamoto A, Kamezaki K, Iwasaki H, Takenaka K, Harada N, Teshima T, Akashi K
  • Organizer: 第71回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] Reduced intensity cord blood transplantation with GO for relapsed AML patients (2009)
  • Author(s): Mori Y, Yamauchi T, Miyamoto T, Aoki T, Yamamoto A, Kamezaki K, Takenaka K, Iwasaki H, Harada N, Nagafuji K, Teshima T, Akashi K
  • Organizer: 第71回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] Activation of PD-1/PD-L1 interaction by graft-versus-host disease paradoxically impairs GVL effects (2009)
  • Author(s): Takashima S, Asakura S, Hashimoto D, Tanimoto M, Akashi K, Teshima T
  • Organizer: 第71回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] ドナーT細胞のToll-like receptor (TLR)シグナルはGVHDの重症化に関与する. (2008)
  • Author(s): 青山一利, 小山幹子, 橋本大吾, 佐古田幸美, 竹田潔, 赤司浩一, 原田実根, 谷本光音, 豊嶋崇徳
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] T cell Toll-like receptors play a critical role in graft-versus-host disease and graft-versus-leukemia (2008)
  • Author(s): Kadowaki M, Aoyama K, Koyama M, Sakoda Y, Takeda K, Liu C, Akashi K, Tanimoto M, Teshima T
  • Organizer: 50^<th> Annual Meeting of The American Society of Hematology
  • Place of Presentation: 米国
• [Presentation] Protection of the intestinal epithelium from conditioning with R-spondinl ameliorates graft-versus-host disease (2008)
  • Author(s): Takashima S, Aoyama K, Koyama M, Hashimoto D, Oshima T, Tomizuka K, Akashi K, Teshima T
  • Organizer: 50^<th> Annual Meeting of The American Society of Hematology
  • Place of Presentation: 米国
• [Book] ガイドラインパースペクティブ造血幹細胞移植 (2009)
  • Author(s): 豊嶋崇徳編
  • Total Pages: 323
  • Publisher: 医薬ジャーナル社