Decoy receptor for IL-21 ameliorates GVHD

• Project/Area Number: 19591131
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Jichi Medical University
• Principal Investigator: OZAKI Katsutoshi Jichi Medical University, 医学部, 講師 (10286453)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 血液免疫学 / 免疫制御 / IL-21 / GVHD / GVL

Research Abstract

これまでの研究成果(平成17-18 年若手研究B)からIL-21R を欠損した脾細胞を用いると誘導されるGVHD が減弱することが示されている。つまりIL-21 シグナルのない状態ではGVHD は引き起こされにくいと考えられたため、GVHD を予防、治療するためにIL-21 のデコイ受容体を作成し、骨髄細胞に強制発現させ移植を行った。デコイ受容体は細胞内ドメインの大部分を欠損させたため、リガンドであるIL-21 と結合はするものの、シグナルを伝達しない。生理的なIL-21 と結合し、その機能を競合的に抑制することが期待された。実際、in vitroの実験ではデコイ受容体は上清中のIL-21 の濃度低下をもたらした。マウスを用いた移植実験では、コントロールベクターを感染させた場合と比較するとデコイ受容体は有意に生存率を上昇させることが明らかとなった。デコイ受容体はIL-21 のシグナルを抑制することで、GVHDを抑制し、生存率を高めたと推察された。このことはIL-21 のシグナルの阻害がGVHD の予防、治療に応用できる可能性を示している。

Research Products

• [Journal Article] Prediction of response t o imatinib in patients with chronic mye logenous leukemia by flow cytometric an alysis of bone marrow blastic cell phen otypes (2009)
  • Author(s): Oka S, Muroi K, Mori M, Matsuyama T, Fujiwara S, Oh I, Sato K, Kikuchi S, Ue da M, Toshima M, Suzuki T, Ozaki K, Nagai T, Ozawa K
  • Journal Title: Leuk Lymphoma. 50(2) Pages: 290-29
  • Peer Reviewed
• [Journal Article] Bortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma (2009)
  • Author(s): Noborio-Hatano K, Kikuchi J, Takatoku M, Shimizu R, Wada T, Ueda M, Nobuyoshi M, Oh I, Sato K, Suzuki T, Ozaki K, Mori M, Nagai T, Muroi K, Kano Y, Furukawa Y, Ozawa K
  • Journal Title: Oncogene 28(2) Pages: 231-242
  • Peer Reviewed
• [Journal Article] Prediction of response to imatinib in patients with chronic myelogenous leukemia by flow cytometric analysis of bone marrow blastic cell phenotypes. (2009)
  • Author(s): Oka S, Muroi K, Mori M, Matsuyama T, Fujiwara S, Oh I, Sato K, Kikuchi S, Ueda M, Toshima M, Suzuki T, Ozaki K, Nagai T, Ozawa K
  • Journal Title: Leuk Lymphoma 50(2) Pages: 290-293
  • Peer Reviewed
• [Journal Article] Bortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma. (2008)
  • Author(s): Noborio-Hatano K, Kikuchi J, Takatoku M, Shimizu R, Wada T, Ueda M, Nobuyoshi M, Oh I, Sato K, Suzuki T, Ozaki K, Mori M, Nagai T, Muroi K, Kano Y, Furukawa Y, Ozawa K
  • Journal Title: Oncogene. 28(2) Pages: 231-242
  • Peer Reviewed
• [Journal Article] Cell and gene therapy using mesenchymal stem cells (MSCs). (2008)
  • Author(s): Ozawa K, Sato K, Oh I, Ozaki K, Uchibori R, Obara Y, Kikuchi Y, Ito T, Okada T, Urabe M, Mizukami H, Kume A
  • Journal Title: J Autoimmun. 30(3) Pages: 121-127
  • Peer Reviewed
• [Journal Article] Screening of genes responsible for differentiation of mouse mesenchymal stromal cells by DNA micro-array analysis of C3H10T1/2 and C3H10T1/2-derived cell lines. (2007)
  • Author(s): Oh I, Ozaki K, Miyazato A, Sato K, Meguro A, Muroi K, Nagai T, Mano H, Ozawa K
  • Journal Title: Cytotherapy 9 Pages: 80-90
  • Peer Reviewed
• [Journal Article] Nitric oxide plays a critical role in suppression of T cell proliferation by mesenchy mal stem cells. (2007)
  • Author(s): Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, Nagai T, Muroi K, Ozawa K
  • Journal Title: Blood 109 Pages: 228-234
  • Peer Reviewed
• [Journal Article] Interferon-gamma and NF-kappaB mediate nitric oxide production by mesenchymal stromal cells. (2007)
  • Author(s): Oh I, Ozaki K, Sato K, Meguro A, Tatara R, Hatanaka K, Nagai T, Muroi K, Ozawa K
  • Journal Title: Biochem Biophys Res Commun 355 Pages: 956-962
  • Peer Reviewed
• [Presentation] Blocking of IL-21 signal attenuates graft-versus-host disease but not graft-versus-leukemia effect in a mouse model. (2008)
  • Author(s): Meguro A, Ozaki K, Oh I, Matsu H, Hatanaka K, Tatara R, Leonard WJ, Sato K, Ozawa K
  • Organizer: 2008 Annual Meeting of ASH(Blood 2008;112(11): 453a)
  • Place of Presentation: San Francisco, CA,
  • Year and Date: 2008-12-07
• [Presentation] Blocking of IL-21 signal attenuates graft-versus-host disease but not graft-versus-leukemia effect in a mouse model. (2008)
  • Author(s): Meguro A, Ozaki K, Oh I, Matsu H, Hatanaka K, Tatara R, Leonard WJ, Sato K, Ozawa K
  • Organizer: 2008 Annual Meeting of ASH at San Francisco, CA
  • Place of Presentation: Moscone Center
  • Year and Date: 2008-12-06
• [Presentation] Blocking of IL-21 signal attenuates graft-versus-host disease but not graft-versus-leukemia effect in a mouse model. (2008)
  • Author(s): Meguro A, Ozaki K, Oh I, Matsu H, Hatanaka K, Sato K, Tatara R, Suzuki T, Mori M, Nagai T, Muroi K, Ozawa K
  • Organizer: 第67 回日本癌学会学術総会(O-181, Program p87)
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-28
• [Presentation] Blocking of IL-21 signal attenuates graft-versus-host disease but not graft-versus-leukemia effect in a mouse model. (2008)
  • Author(s): Meguro A, Ozaki K, Oh I, Matsu H, Hatanaka K, Sato K, Tatara R, Suzuki T, Mori M, Nagai T, Muroi K, Ozawa K
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2008-10-28
• [Presentation] GVHDにおけるIL-21の役割 (2007)
  • Author(s): 目黒 明子, 尾崎 勝俊, 翁 家国, 佐藤 一也, 多々良 礼音, 松 春子, 畑中 恵子, 鈴木 隆浩, 森 政樹, 永井 正, 室井 一男, 小澤 敬也
  • Organizer: 日本血液学会日本臨床血液学会合同総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-11