GVHD・GVLに関わる新たなドナーT細胞活性化のメカニズム

2010 Fiscal Year Annual Research Report

• Project/Area Number: 21390295
• Research Institution: Kyushu University
• Principal Investigator: 豊嶋 崇徳 九州大学, 病院, 准教授 (40284096)
• Keywords: GVHD / GVL / T細胞 / 樹状細胞 / 形質細胞様樹状細胞 / Toll like receptor

Research Abstract

前年度に引き続き、ドナーT細胞の活性化に関わるToll like receptor (TLR)を介するシグナルの関与について検討した。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、野生型、MyD88-/-,TRIF-/-,MyD88/TRIF-/-の4種類のB6マウス由来のT細胞のGVHD誘導能を比較検討した。移植前処置には骨髄破壊的全身放射線照射を用いた。T細胞除去骨髄は一貫して野生型-マウスからのものを用いた。移植後にGVHDの重症度を観察したところ、野生型T細胞、TRIF-/-T細胞の移植では同等に重症なGVHDが発症したのに対し、MyD88-/-,MyD88/TRIF-/-T細胞の移植ではGVHDが有意に軽症であった。この結果はT細胞におけるMyD88シグナルがT細胞活性化に重要な役割をしている可能性を示唆している。次に、移植前処置によって惹起される炎症環境によってもたらされるTLRシグナルがこのT細胞活性化に関与する可能性を検討するために、移植前処置なしに移植可能なSCIDマウスをレシピエントとして各種マウスからのT細胞の移植実験を行った。4種類のドナーT細胞はほぼ同等な重症度のGVHDを発症した。以上の結果から、移植前処置によってもたらされる炎症環境下でのT細胞上のMyD88を介する刺激によってドナーT細胞の活性化が増幅され、GVHDの重症化がもたらされるものと考えられた。

Research Products

• [Journal Article] The Wnt agonist R-spondinl 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, Inone Y, To K, Miyamoto T, Iwasaki H, Teshima T, Harada M, Akashi K
  • Journal Title: Rheumatology Volume: (online)
  • Peer Reviewed
• [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 (2011)
  • 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
  • Year and Date: 20110219-20110220
• [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 (2011)
  • 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
  • Year and Date: 20110219-20110220
• [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 (2011)
  • 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
  • Year and Date: 20110219-20110220
• [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 (55years 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