Development of a novel interferon with mild adverse effects

• Project/Area Number: 19390264
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Osaka University
• Principal Investigator: ORITANI Kenji Osaka University, 医学系研究科, 講師 (70324762)
• Co-Investigator(Kenkyū-buntansha): KANAKURA Yuzuru 大阪大学, 医学系・研究科, 教授 (20177489) ; MATSUMURA Itaru 大阪大学, 医学系・研究科, 准教授 (00294083) ; YOKOTA Takahumi 大阪大学, 医学系・研究科, 助教 (60403200)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2008: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2007: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: インターフェロン / サイトカイン / Limitin / ウイルス感染 / IFN-ζ / アミノ酸置換 / 骨髄抑制 / 骨髓抑制

Research Abstract

新規インターフェロン(IFN-zeta/Limitin)はIFN-alphaと同等の免疫調節作用・抗腫瘍作用・抗ウイルス作用を持つものの骨髄抑制作用が軽微である。我々は、受容体結合部位でIFN-alphaやIFN-betaと一致しIFN-zeta/Limitinとは異なるアミノ酸に変異を加え、骨髄抑制作用減弱(m3変異)・抗ウイルス活性増強(m1変異)に関わる責任アミノ酸を決定した。さらに、変異ヒトIFN-alpha1を作製し、それらの生理活性を野生型IFN-alpha1と比較した。ヒトIFN-alphaにおいてもm1、m3各変異部位が生理活性に影響を及ぼすことが判明した。

Research Products

• [Journal Article] The endothelial antigen ESAM marks hematopoietic stem cells throughout life. (2009)
  • Author(s): Yokota T
  • Journal Title: Blood (In press)
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus-derived EBXA2 regulates STAT3 activation. (2009)
  • Author(s): Moromoto R
  • Journal Title: Biochem Biophys Res Commun (In press)
  • Peer Reviewed
• [Journal Article] Regulation of human B lymphopoiesis by the transforming growth factor-beta superfamily in a newly established coculture system using human mesenchymal stem cells as a supportive microenvironment (2008)
  • Author(s): Ichii M, Oritani K, Yokota T, Nishida M, Takahashi I, Shirogane T, Ezoe S, Saitoh N, Tanigawa R, Kincade PW, Kanakura Y
  • Journal Title: Exp Hematol 36 Pages: 587-597
  • Peer Reviewed
• [Journal Article] Soluble Frizzled-related protein 1 is estrogen inducible in bone marrow stromal cells and suppresses the earliest events in lymphopoiesis (2008)
  • Author(s): Yokota T, Oritani K, Garrett KP, Kouro T, Nishida M, Takahashi I, Ichii M, Satoh Y, Kincade PW, Kanakura Y
  • Journal Title: J Immunol 181 Pages: 6061-6072
  • Peer Reviewed
• [Journal Article] STAP-2 negatively regulates both canonical and noncanonical NF-kappaB activation induced by Epstein-Barr virus-derived latent membrane protein 1 (2008)
  • Author(s): Ikeda O, Sekine Y, Yasui T, Oritani K, Sugiyma K, Muromoto R, Ohbayashi N, Yoshimura A, Matsuda T
  • Journal Title: Mol Cel Biol 28 Pages: 5527-5542
  • Peer Reviewed
• [Journal Article] Physical and functional interactions between STAT3 and KAP1 (2008)
  • Author(s): Tsuruma R, Ohbayashi N, Kamitani S, Ikeda O, Sato N, Muromoto R, Sekine Y, Oritani K, Matsuda T
  • Journal Title: Oncogene 27 Pages: 3054-3059
  • NAID: 120000947432
  • Peer Reviewed
• [Journal Article] The tetraspanin CD9 modulates epidermal growth factor receptor signaling in cancer cells (2008)
  • Author(s): Murayama Y, Shinomura Y, Oritani K, Miyagawa J, Yoshida H, Nishida M, Katsube F, Shiraga M, Miyazaki T, Nakamoto T, Tsutsui S, Tamura S, Higashiyama S, Shimomura I, Hayashi N
  • Journal Title: J Cell Physiol 36 Pages: 135-143
  • Peer Reviewed
• [Journal Article] AML1/RUNX1 works as a negative regulator of c-Mpl in hematopoietic stem cells (2008)
  • Author(s): Satoh Y, Matsumura I, Tanaka H, Ezoe S, Fukushima K, Tokunaga M, Yasumi M, Shibayama H, Mizuki M, Era T, Okuda T, Kanakura Y
  • Journal Title: J Biol Chem 283 Pages: 30045-30056
  • Peer Reviewed
• [Journal Article] Roles for deregulated receptor tyrosine kinases and their downstream signaling molecules in hematologic malignancies (2008)
  • Author(s): Matsumura I, Mizuki M, Kanakura Y
  • Journal Title: Cancer Sci 99 Pages: 479-485
  • NAID: 10024003430
  • Peer Reviewed
• [Journal Article] Regulation of human B lymphopoiesis by the transforming growthfactor-beta superfaimily in a newly established coculture system using human mesenchymal stem cells as a supportive microenvironment. (2008)
  • Author(s): Ichii M
  • Journal Title: Exp Hematol 36 (5) Pages: 587-597
  • Peer Reviewed
• [Journal Article] Soluble Frizzled-related protein 1 is estrogen inducible in bone mar row stromal cells and suppresses the earliest events inlymphopoiesis. (2008)
  • Author(s): Yokota T
  • Journal Title: J Immunol 181(9) Pages: 6061-6072
  • Peer Reviewed
• [Journal Article] STAP-2 negatively regulates both canonical and noncanonical XF-kappaB activation induced by Edstein-Barr virus-derived latent membrane protein 1. (2008)
  • Author(s): Ikeda o
  • Journal Title: Mol Cell Biol 28 (16) Pages: 5527-5542
  • Peer Reviewed
• [Journal Article] Physical and functional interactions between STAT3 and KAPl. (2008)
  • Author(s): Tsuruma R
  • Journal Title: Oncogene 27(21) Pages: 3054-3059
  • Peer Reviewed
• [Journal Article] The tetraspanin CD9 modulates epidermal growth factor receptorsignaling in cancer cells. (2008)
  • Author(s): Murayama Y
  • Journal Title: J Cell Physiol 36(5) Pages: 135-143
  • Peer Reviewed
• [Journal Article] Physical and functional interactions between STAT3 and KAP1. (2008)
  • Author(s): Tsuruma R, et. al.
  • Journal Title: Oncogene (In press)
  • Peer Reviewed
• [Journal Article] Adiponectin binds to chemokines via the globular head and modulates interactions between chemokines and heparan sulfates (2007)
  • Author(s): Masaie H, Oritani K, Yokota T, Takahashi I, Shirogane T, Ujiie H, Ichii M, Saitoh N, Maeda T, Tanigawa R, Oka K, Hoshida Y, Tomiyama Y, Kanakura Y
  • Journal Title: Exp Hematol 35 Pages: 947-956
  • Peer Reviewed
• [Journal Article] Signal-transducing adaptor protein-2 regulates integrin-mediated T cell adhesion through protein degradation of focal adhesion kinase (2007)
  • Author(s): Sekine Y, Tsuji S, Ikeda O, Sugiyma K, Oritani K, Shimoda K, Muromoto R, Ohbayashi N, Yoshimura A, Matsuda T
  • Journal Title: J Immunol 179 Pages: 2397-2407
  • Peer Reviewed
• [Journal Article] STAP-2 regulates c-Fms/M-CSF receptor signaling in murine macrophage Raw 264.7 cells (2007)
  • Author(s): Ikeda O, Sekine Y, Kakisaka M, Tsuji S, Muromoto R, Ohbayashi N, Oritani K, Yoshimura A, Matsuda T
  • Journal Title: Biochem Biophys Res Commun 358 Pages: 931-937
  • NAID: 120000969065
  • Peer Reviewed
• [Journal Article] Adiponectin binds to chemokines via the globular head and modulates in teractions between chemokines and heparan sulfates. (2007)
  • Author(s): Masaie H, et. al.
  • Journal Title: Exp Hematol 35(6) Pages: 947-956
  • Peer Reviewed
• [Journal Article] Signal-transducing adaptor protein-2 regulates integrin-mediated T cell adhesion through protein degradation of focal adhesion kinase. (2007)
  • Author(s): Sekine Y, et. al.
  • Journal Title: J Immunol 179(4) Pages: 2397-2407
  • Peer Reviewed
• [Journal Article] The endothelial antigen ESAM marks hematopoietic stem cells throughout life
  • Author(s): Yokota T, Oritani K, Butz S, Kokame K, Kincade PW, Miyata T, Vestweber D, Kanakura Y
  • Journal Title: Blood (in press)
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus-derived EBNA2 regulates STAT3 activation
  • Author(s): Muromoto R, Ikeda O, Okabe K, Togi S, Kamitani S, Fujimuro M, Harada S, Oritani K, Matsuda T
  • Journal Title: Biochem Biophys Res Commun (in press)
  • NAID: 120001024527
  • Peer Reviewed
• [Presentation] Effects of iron overload on hematopoiesis (2008)
  • Author(s): Matsumura I
  • Organizer: The 8th International Porphyrin-Heme Symposium
  • Place of Presentation: Shimane, Japan
• [Presentation] The endothelial antigen ESAM marks hematopoietic stem cells throughout life in mice (2008)
  • Author(s): Yokota T, Oritani K, Butz S, Kokame K, Kincade PW, Miyata T, Vestweber D, Kanakura Y
  • Organizer: The American Society of Hematology 50th Annual meeting
  • Place of Presentation: San Francisco, USA
• [Presentation] NAD-dependent histone deacetylase, SIRT1, plays essential roles in the maintenance of hematopoietic stem cells (2008)
  • Author(s): Ezoe S, Matsumura I, Tanaka H, Satoh Y, Yokota T, Oritani K, Kanakura Y
  • Organizer: The American Society of Hematology 50th Annual meeting
  • Place of Presentation: San Francisco, USA
• [Presentation] Roles for the AML1/RUNX1 point mutation in the pathogenesis of MDS/AML (2008)
  • Author(s): Satoh Y, Tanaka H, Yokota T, Ezoe S, Oritani K, Kanakura Y
  • Organizer: The American Society of Hematology 50th Annual meeting
  • Place of Presentation: San Francisco, USA
• [Presentation] 新規造血幹細胞表面マーカーESAM1の同定 (2008)
  • Author(s): 横田貴史, 織谷健司, 小亀浩市, 宮田敏行, 金倉譲
  • Organizer: 第6回幹細胞シンポジウム
  • Place of Presentation: 東京
• [Presentation] NUP98-HOXA10 およびMeis1 の共発現によるマウスES 由来血液細胞の白血病化モデル (2008)
  • Author(s): 川本晋一郎, 織谷健司, 横田貴史, 高橋功, 金倉譲
  • Organizer: 第70 回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] The endothelial antigen ESAM marks hematopoietic stem cells throughout life in mice. (2008)
  • Author(s): Yokota T
  • Organizer: The Amerual meetcan Society of Hematology 50th Annng
  • Place of Presentation: San Francisco, USA
• [Presentation] NAD-dependent histone deacetylase, SIRTl, plays essential roles in the maintenance of hematopoietic stem cells. (2008)
  • Author(s): Ezoe S
  • Organizer: The Amerual meetcan Society of Hematology 5Oth Annng
  • Place of Presentation: San Francisco, USA
• [Presentation] Roles for the AMLI/RUXXI point mutation in the pathogenesis of MDS/AML. (2008)
  • Author(s): Satoh Y
  • Organizer: The American Society of Hematology 50th Annual meeting
  • Place of Presentation: San Francisco, USA
• [Presentation] NUP98-HOXA10およびMeislの共発現によるマウスES由来血液細胞の白血病化モデル (2008)
  • Author(s): 川本晋一郎
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] Regulation by the TGFβ superfamily of human B lymphopoiesis by in a newly established lymphocyte culture system using human mesenchymal stem cells as a supportive microenvironment (2007)
  • Author(s): Ichii M, Oritani K, Yokota T, Takahashi I, Shirogane T, Saitoh N, Tanigawa R, Kanakura Y
  • Organizer: The 12th Congress of the European Hematology Association
  • Place of Presentation: Vienna, Austria
• [Presentation] Wnt/beta-catenin pathway modulates multipotency of hematopoietic stem/progenitor cells regulating the activity of various essential transcription factors (2007)
  • Author(s): Tanaka H, Matsumura I, Itoh K, Nakahata T, Kanakura Y
  • Organizer: The 12th Congress of the European Hematology Association
  • Place of Presentation: Vienna, Austria
• [Presentation] SFRP1 is estrogen inducible in bone marrow stromal cells and suppresses the earliest events in lymphopoiesis (2007)
  • Author(s): Yokota T, Oritani K, Garrett KP, Kouro T, Nishida M, Takahashi I, Ichii M, Matsumura I, Kincade PW, Kanakura Y
  • Organizer: American Society of Hematology 49th Annual meeting
  • Place of Presentation: Atlanta, USA
• [Presentation] Establishment of stroma-free cultures for human B lymphopoiesis : Roles of high cell density condition and mesenchymal stem cell-secreted factors (2007)
  • Author(s): Ichii M, Oritani K, Yokota T, Takahashi I, Shirogane T, Saitoh N, Tanigawa R, Kasai S, Kanakura Y
  • Organizer: American Society of Hematology 49th Annual meeting
  • Place of Presentation: Atlanta, USA
• [Presentation] 骨髄異形成症候群におけるE2F1の役割 (2007)
  • Author(s): 佐藤友亮, 松村到, 江副幸子, 織谷健司, 金倉譲
  • Organizer: 第104回日本内科学会総会
  • Place of Presentation: 大阪
• [Presentation] Estrogen が誘導する骨髄間質細胞分泌蛋白sFRP1はリンパ球初期分化を負に制御する (2007)
  • Author(s): 横田貴史, 織谷健司, Paul W. Kincade, 高橋功, 一井倫子, 松村到, 金倉譲
  • Organizer: 第69回日本血液学会・第49回日本臨床血液学会合同総会
  • Place of Presentation: 横浜
• [Presentation] ヒトCD34 陽性細胞からのB リンパ球産生 : ストローマ細胞非存在下での培養系の確立と支持因子の性状解析 (2007)
  • Author(s): 一井倫子, 織谷健司, 横田貴史, 高橋功, 白銀隆宏, 齋藤則充, 松村到, 金倉譲
  • Organizer: 69回日本血液学会・第49回日本臨床血液学会合同総会
  • Place of Presentation: 横浜
• [Presentation] 造血幹細胞の増殖・分化におけるエネルギー代謝制御 (2007)
  • Author(s): 江副幸子, 松村到, 徳永正浩, 安見正人, 田中宏和, 織谷健司, 金倉譲
  • Organizer: 第69回日本血液学会・第49 回日本臨床血液学会合同総会
  • Place of Presentation: 横浜
• [Presentation] 骨髄異形成症候群におけるE2F1 の役割 (2007)
  • Author(s): 佐藤友亮, 松村到, 江副幸子, 織谷健司, 金倉譲
  • Organizer: 第69回日本血液学会・第49 回日本臨床血液学会合同総会
  • Place of Presentation: 横浜
• [Presentation] 腫瘍性チロシンキナーゼによる病型決定機構 : FIP1L1/PDGFRαによる好酸球系細胞への選択的誘導 (2007)
  • Author(s): 福島健太郎, 松村到, 江副幸子, 佐藤友亮, 水木満佐央, 田中宏和, 織谷健司,金倉譲
  • Organizer: 第69回日本血液学会・第49回日本臨床血液学会合同総会
  • Place of Presentation: 横浜
• [Presentation] SFRP1 is estrogen inducible in bone marrow stromal cells and suppresses the earliest events in lymphopoiesis (2007)
  • Author(s): Yokota T, Oritani K, Kouro T, Ichii M,Kincade PW, Kanakura Y
  • Organizer: 第37回日本免疫学会総会
  • Place of Presentation: 東京
• [Presentation] ストローマ非依存性ヒトBリンパ球培養には細胞密度が重要である (2007)
  • Author(s): 一井倫子, 織谷健司, 横田貴史, 金倉譲
  • Organizer: 第37回日本免疫学会総会
  • Place of Presentation: 東京
• [Presentation] Establishment of stroma-free cultures fot human B lymphopoiesis: Roles of high cell density condition and mesenchymal stem cell-secreted factors. (2007)
  • Author(s): Ichii M, et. al.
  • Organizer: American Society of Hematology 49th Annual meeting
  • Place of Presentation: Atlanta, USA
• [Book] Bリンパ球初期分化と制御機構 (2009)
  • Author(s): 織谷健司
  • Publisher: 科学評論社(印刷中)