Identification of transcription factors responsible for suppression of dendritic cells by regulatory T cells and development of immunotherapy

• Project/Area Number: 23791067
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Tohoku University
• Principal Investigator: ONISHI Yasushi 東北大学, 大学病院, 助教 (10509574)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2012: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2011: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 樹状細胞 / 免疫寛容 / 制御性T細胞 / ＦｏｘＯ３ａ / ＣＤ８６ / 免疫療法 / 移植再生医療 / FoxO3a / ＣＤ86 / TIM-3 / CD86 / 免疫学 / 移植・再生医療 / CTLA-4

Research Abstract

Suppression of FoxO3a in human monocyte-derived dendritic cells (DC) increased the expression of CD80/86 and HLA-DR. T-cell proliferation and production of inflammatory cytokines, IL-6 and TNFa, were enhanced in co-culture of FoxO3a-knockdown DC and T cells. The activation of DC by FoxO3a suppression was dependent on NF-kB. When DC was stimulated with LPS, FoxO3a was promptly phosphorylated and moved to cytoplasm from nucleus. Levels of FoxO3a mRNA increased later than elevation of CD86 mRNA levels after the addition of LPS. Inactivation of FoxO3a induced the activation of DC in an early phase of the LPS stimulation. These results suggest that FoxO3a has a central role in the regulation of DC functions.

Research Products

• [Journal Article] 3-Deazaneplanocin A (DZNep), an inhibitor of S-adenosylmethionine-dependent methyltransferase, promotes erythroid differentiation (2014)
  • Author(s): Fujiwara T, Saitoh H, Inoue A, Kobayashi M, Okitsu Y, Katsuoka Y, Fukuhara N, Onishi Y, Ishizawa K, Ichinohasama R, Harigae H
  • Journal Title: The Journal of Biological Chemistry Volume: 289 Issue: 12 Pages: 8121-8134
  • DOI: 10.1074/jbc.m114.548651
  • Peer Reviewed
• [Journal Article] Induction of thymic stromal lymphopoietin in mesenchymal stem cells by interaction with myeloma cells (2014)
  • Author(s): Nakajima S, Ohguchi H, Fujiwara T, Onishi Y, Kamata M, Okitsu Y, Fukuhara N, Ishizawa K, Harigae H
  • Journal Title: Leuk Lymphoma Volume: (Epub ahead of print) Issue: 11 Pages: 2605-2613
  • DOI: 10.3109/10428194.2014.881478
  • Peer Reviewed
• [Journal Article] Significant improvement of Takayasu arteritis after cord blood transplantation in a patient with myelodysplastic syndrome (2014)
  • Author(s): Kato H, Onishi Y, Nakajima S, Okitsu Y, Fukuhara N, Fujiwara T, Yamada-Fujiwara M, Kameoka J, Ishizawa K, Harigae H
  • Journal Title: Bone Marrow Transplantation Volume: 49 Issue: 3 Pages: 458-459
  • DOI: 10.1038/bmt.2013.198
  • Peer Reviewed
• [Journal Article] Effects of kir ligand incompatibility on clinical outcomes of umbilical cord blood transplantation without atg for acute leukemia in complete remission (2013)
  • Author(s): Tanaka J, Morishima Y, Takahashi Y, Yabe T, Oba K, Takahashi S, Taniguchi S, Ogawa H, Onishi Y, Miyamura K, Kanamori H, Aotsuka N, Kato K, Kato S, Atsuta Y, Kanda Y
  • Journal Title: Blood Cancer J Volume: 3 Issue: 11 Pages: 1-10
  • DOI: 10.1038/bcj.2013.62
  • Peer Reviewed
• [Journal Article] Clinical and genetic characteristics of congenital sideroblastic anemia: comparison with myelodysplastic syndrome with ring sideroblast (MDS-RS) (2013)
  • Author(s): 大場理恵、吉田健一
  • Journal Title: Ann Hematol Volume: 92 Issue: 1 Pages: 1-9
  • DOI: 10.1007/s00277-012-1564-5
  • Peer Reviewed
• [Journal Article] Addition of clarithromycin to lenalidomide/low-dose dexamethasone was effective in a case of relapsed myeloma after long-term use of lenalidomide (2013)
  • Author(s): Kato H, Onishi Y, Okitsu Y, Katsuoka Y, Fujiwara T, Fukuhara N, Ishizawa K, Takagawa M, Harigae H
  • Journal Title: Ann Hematol Volume: 92 Issue: 12 Pages: 1711-1712
  • DOI: 10.1007/s00277-013-1761-x
  • Peer Reviewed
• [Journal Article] Impact of the direction of HLA mismatch on transplantation outcomes in single unrelated cord blood transplantation (2013)
  • Author(s): Kanda J, Atsuta Y, Wake A, Ichinohe T, Takanashi M, Morishima Y, et al.
  • Journal Title: Biol Blood Marrow Transplant Volume: 19 Issue: 2 Pages: 247-254
  • DOI: 10.1016/j.bbmt.2012.09.017
  • Peer Reviewed
• [Journal Article] Elucidation of the role of LMO2 in human erythroid cells (2013)
  • Author(s): Inoue A, Fujiwara T, Okitsu Y, Katsuoka Y, Fukuhara N, Onishi Y, Ishizawa K, Harigae H
  • Journal Title: Experimantal Hematology Volume: 41 Issue: 12 Pages: 1062-1076
  • DOI: 10.1016/j.exphem.2013.09.003
  • Peer Reviewed
• [Journal Article] Clinicopathological analysis of primary adrenal diffuse large b-cell lymphoma : Effectiveness of rituximab-containing chemotherapy including central nervous system prophylaxis (2013)
  • Author(s): Ichikawa S, Fukuhara N, Inoue A, Katsushima H, Ohba R, Katsuoka Y, Onishi Y, Yamamoto J, Sasaki O, Nomura J, Fukuhara O, Ishizawa K, Ichinohasama R, Harigae H
  • Journal Title: Exp Hematol Oncol Volume: 2 Issue: 1 Pages: 19-19
  • DOI: 10.1186/2162-3619-2-19
  • Peer Reviewed
• [Journal Article] Expression profiling of eto2-regulated mirnas in erythroid cells : Possible influence on mirna abundance (2013)
  • Author(s): Fujiwara T, Okitsu Y, Katsuoka Y, Fukuhara N, Onishi Y, Ishizawa K, Harigae H
  • Journal Title: FEBS Open Bio Volume: 3 Issue: 1 Pages: 428-432
  • DOI: 10.1016/j.fob.2013.10.004
  • Peer Reviewed
• [Journal Article] Role of transcriptional corepressor ETO2 in erythroid cells (2013)
  • Author(s): Fujiwara T, Alqadi YW, Okitsu Y, Fukuhara N, Onishi Y, Ishizawa K, Harigae H
  • Journal Title: Experimental Hematology Volume: 41 Issue: 3 Pages: 303-315
  • DOI: 10.1016/j.exphem.2012.10.015
  • Peer Reviewed
• [Journal Article] Different effects of hla disparity on transplant outcomes after single-unit cord blood transplantation between pediatric and adult patients with leukemia (2013)
  • Author(s): Atsuta Y, Kanda J, Takanashi M, Morishima Y, Taniguchi S, Takahashi S, Ogawa H, Ohashi K, Ohno Y, Onishi Y, Aotsuka N, Nagamura-Inoue T, Kato K, Kanda Y
  • Journal Title: Haematologica Volume: 98 Issue: 5 Pages: 814-822
  • DOI: 10.3324/haematol.2012.076042
  • Peer Reviewed
• [Journal Article] 妊娠時の貧血 (2013)
  • Author(s): 大西康
  • Journal Title: Medical Practice Volume: vol.30 (9) Pages: 1569-1572
• [Journal Article] 造血器腫瘍に対する分子標的薬(白血病・悪性リンパ腫) (2013)
  • Author(s): 大西康
  • Journal Title: プロフェッショナルがんナーシング(メディカ出版) Volume: vol.3(5) Pages: 42-44
• [Journal Article] 造血器腫瘍に対する分子標的薬 (2013)
  • Author(s): 大西 康
  • Journal Title: MCメディカ出版 プロフェッショナルがんナーシング Volume: 3 Pages: 42-44
• [Journal Article] 妊娠時の貧血 (2013)
  • Author(s): 大西 康
  • Journal Title: 文光堂 Medical Practice Volume: 30 Pages: 1569-1572
• [Journal Article] Diagnosis of Intestinal Graft-versus-Host Disease and Thrombotic Microangiopathy after Allogeneic Stem Cell Transplantation (2012)
  • Author(s): Yamada-Fujiwara M, Miyamura K, Fujiwara T, Tohmiya Y, Endo K, Onishi Y, Ishizawa K, Kameoka J, Ito M, Harigae H.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 227 Issue: 1 Pages: 31-37
  • DOI: 10.1620/tjem.227.31
  • NAID: 10030613157
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed
• [Journal Article] Philadelphia-negative acute promyelocytic leukemia in a patient with chronic myeloid leukemia in complete cytogenetic response after treatment with tyrosine kinase inhibitor. (2012)
  • Author(s): Inokura K, Onishi Y, Shimosegawa K, Okitsu Y, Katsuoka Y, Fujiwara T, Fukuhara N, Ishizawa K, Harigae H.
  • Journal Title: Annals of hematology Volume: 91 Issue: 11 Pages: 1825-1826
  • DOI: 10.1007/s00277-012-1477-3
  • Peer Reviewed
• [Journal Article] Gene Expression Profiling Identifies HOXB4 as a Direct Downstream Target of GATA-2 in Human CD34+ Hematopoietic Cells (2012)
  • Author(s): Fujiwara T, Yokoyama H, Okitsu Y, Kamata M, Fukuhara N, Onishi Y, Fujimaki S, Takahashi S, Ishizawa K, Bresnick E and Harigae H
  • Journal Title: PLoS ONE Volume: 7 Issue: 9 Pages: e40959-e40959
  • DOI: 10.1371/journal.pone.0040959
  • Peer Reviewed
• [Journal Article] 妊娠と貧血―診断と対処のしかた (2011)
  • Author(s): 大西康
  • Journal Title: Medical Practice Volume: vol. 28(12) Pages: 2137-2141
• [Presentation] 成人再生不良性貧血の生着不全に対する2回目同種造血幹細胞移植の検討 (2014)
  • Author(s): 大西康、賀古真一、康秀男、森毅彦、中尾眞二、内田直之、大橋一輝、坂巻壽、森島泰雄、加藤剛二、鈴木律朗、山崎宏人
  • Organizer: 第36回日本造血細胞移植学会総会
  • Place of Presentation: 沖縄
• [Presentation] 非寛解期血液悪性疾患に対する臍帯血移植の成績 : 単一施設50例の後方視的検討 (2014)
  • Author(s): 長谷川慎、大西康、大橋圭一、加藤浩貴、近藤愛子、沖津庸子、勝岡優奈、福原規子、藤原亨、藤原実名美、石澤賢一、亀岡淳一、張替秀郎
  • Organizer: 第36回日本造血細胞移植学会総会
  • Place of Presentation: 沖縄
• [Presentation] 同種造血幹細胞移植におけるボリコナゾール血中濃度測定とその有用性についての後方視的検討 (2014)
  • Author(s): 加藤浩貴、大西康、大橋圭一、近藤愛子、長谷川慎、沖津庸子、勝岡優奈、福原規子、藤原亨、藤原実名美、石澤賢一、亀岡淳一、張替秀郎
  • Organizer: 第36回日本造血細胞移植学会総会
  • Place of Presentation: 沖縄
• [Presentation] T細胞性急性リンパ性白血病/リンパ芽球性リンパ腫に対する造血幹細胞移植13例の後方視的解析 (2014)
  • Author(s): 近藤愛子、大西康、大橋圭一、加藤浩貴、長谷川慎、沖津庸子、福原規子、勝岡優奈、藤原実名美、石澤賢一、亀岡淳一、張替秀郎
  • Organizer: 第36回日本造血細胞移植学会総会
  • Place of Presentation: 沖縄
• [Presentation] マントル細胞リンパ腫に対し自己末梢血細胞移植治療後に成人T細胞性白血病/リンパ腫を発症したHTLV-1キャリアの一例 (2014)
  • Author(s): 大橋圭一、大西康、加藤浩貴、近藤愛子、長谷川慎、沖津庸子、勝岡優奈、福原規子、藤原実名美、藤原亨、亀岡淳一、張替秀郎
  • Organizer: 第36回日本造血細胞移植学会総会
  • Place of Presentation: 沖縄
• [Presentation] 成人再生不良性貧血の生着不全に対する２回目同種造血幹細胞移植の検討 (2014)
  • Author(s): 大西康、賀古真一、康秀男、森毅彦、中尾眞二、内田直之、大橋一輝、坂巻壽、森島泰雄、加藤剛二、鈴木律朗、山崎宏人
  • Organizer: 第３６回日本造血細胞移植学会総会
  • Place of Presentation: 沖縄
• [Presentation] 非寛解期血液悪性疾患に対する臍帯血移植の成績：単一施設50例の後方視的検討 (2014)
  • Author(s): 長谷川慎、大西康、大橋圭一、加藤浩貴、近藤愛子、沖津庸子、勝岡優奈、福原規子、藤原亨、藤原実名美、石澤賢一、亀岡淳一、張替秀郎
  • Organizer: 第３６回日本造血細胞移植学会総会
  • Place of Presentation: 沖縄
• [Presentation] melioration of pulmonary artery hypertension after cord blood transplantation in an CAEBV patient (2013)
  • Author(s): Yasushi Onishi, Koichiro Sugimura, Yoko Okitsu, Yuna Katsuoka, Noriko Fukuhara, Tohru Fujiwara, Junichi Kameoka, Kenichi Ishizawa, Heideo Harigae
  • Organizer: 第75回日本血液学会
  • Place of Presentation: 札幌
• [Presentation] Progressive multifocal leukoencephalopathy by JCV in a PCL patient treated with bor/lem/dex therapy (2013)
  • Author(s): Yukiko Kamogawa, Yasuhi Onishi, Makiko Suzuki, Yoko Okitsu, Yuna Katsuoka, Noriko Fukuhara, Toru Fujiwara, Junichi Kameoka,, Kenichi Ishizawa, Hideo Harigae
  • Organizer: 第75回日本血液学会
  • Place of Presentation: 札幌
• [Presentation] Addition of oral cyclophosphamide is effective for myeloma refractory to lenalidomide/dexamethasone (2013)
  • Author(s): Hiroki Kato, Yasuhi Onishi, Keiichi Ohashi, Aiko Kondou, Shin Hasegawa, Youko Okitsu, Yuuna Katsuoka, Noriko Fukuhara, Tohru Fujiwara, Junichi Kameoka, Kenichi Ishizawa, Masanori Takagawa, Hideo Harigae
  • Organizer: 第75回日本血液学会
  • Place of Presentation: 札幌
• [Presentation] 成人再生不良貧血に対する同種造血幹細胞移植におけるフルダラビン+シクロフォスファミドを含む前処置の検討 (2013)
  • Author(s): 大西康、甲斐龍幸、松本勇人、原崎頼子、佐々木治、木村秀夫、小川一英、張替秀郎
  • Organizer: 第35回日本造血細胞移植学会
  • Place of Presentation: 金沢
• [Presentation] Amelioration of pulmonary artery hypertension after cord blood transplantation in an CAEBV patient (2013)
  • Author(s): Yasushi Onishi, Koichiro Sugimura, Yoko Okitsu, Yuna Katsuoka, Noriko Fukuhara, Tohru Fujiwara, Junichi Kameoka, Kenichi Ishizawa, Heideo Harigae
  • Organizer: 第75回日本血液学会総会
  • Place of Presentation: 札幌
• [Presentation] Progressive multifocal leukoencephalopathy by JCV in a PCL patient treated with bor/lem/dex therapy (2013)
  • Author(s): Yukiko Kamogawa, Yasuhi Onishi, Makiko Suzuki, Yoko Okitsu, Yuna Katsuoka, Noriko Fukuhara, Toru Fujiwara, Junichi Kameoka, Kenichi Ishizawa, Hideo Harigae
  • Organizer: 第75回日本血液学会総会
  • Place of Presentation: 札幌
• [Presentation] Addition of oral cyclophosphamide is effective for myeloma refractory to lenalidomide/dexamethasone (2013)
  • Author(s): Hiroki Kato, Yasuhi Onishi, Keiichi Ohashi, Aiko Kondou, Shin Hasegawa, Youko Okitsu, Yuuna Katsuoka, Noriko Fukuhara, Tohru Fujiwara, Junichi Kameoka, Kenichi Ishizawa, Masanori Takagawa, Hideo Harigae
  • Organizer: 第75回日本血液学会総会
  • Place of Presentation: 札幌
• [Presentation] 成人再生不良性貧血に対する同種造血幹細胞移植におけるフルダラビン+シクロホスファミドを含む前処置の検討 (2013)
  • Author(s): 大西康、甲斐龍幸、松本勇人、原崎頼子、佐々木治、木村秀夫、小川一英、張替秀郎
  • Organizer: 第３５回日本造血細胞移植学会総会
  • Place of Presentation: 金沢
• [Presentation] Allogeneic HSCT in adult patients with EBV-associated T/NK-cell LPD, ENKL, and ANKL (2012)
  • Author(s): Yasuhi Onishi, Kentaro Nasu, Makiko Suzuki, Shinji Nakajima, Yuna Katsuoka, Yoko Okitsu, Tohru Fujiwara, Noriko Fukuhara, Junichi Kameoka, Kenichi Ishizawa, Ryo Ichinohasama, Hideo Harigae
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都
• [Presentation] 臍帯血移植または非血縁者間骨髄移植を施行された成人急性骨髄性白血病および骨髄異形成症候群の成績 : 単一施設における比較解析 (2012)
  • Author(s): 大西康、八田俊介、斎藤陽、猪倉恭子、小野寺晃一、三浦由希子、木幡桂、勝岡優奈、福原規子、石澤賢一、亀岡淳一、張替秀郎
  • Organizer: 第34回日本造血幹細胞移植学会総会
  • Place of Presentation: 大阪
• [Presentation] Allogeneic HSCT in adult patients with EBV-associated T/NK-cell LPD, ENKL, and ANKL (2012)
  • Author(s): Yasuhi Onishi, Kentaro Nasu, Makiko Suzuki, Shinji Nakajima, Yuna Katsuoka, Yoko Okitsu, Tohru Fujiwara, Noriko Fukuhara, Junichi Kameoka, Kenichi Ishizawa, Ryo Ichinohasama, Hideo Harigae.
  • Organizer: 第７４回日本血液学会学術集会・総会
  • Place of Presentation: 京都
• [Presentation] 臍帯血移植または非血縁者間骨髄移植を施行された成人急性骨髄性白血病および骨髄異形成症候群の成績：単一施設における比較解析 (2012)
  • Author(s): 大西康ら 他11人
  • Organizer: 第34回 日本造血細胞移植学会総会
  • Place of Presentation: 大阪
• [Presentation] Fox03a has a crucial role for immune response in human dendritic cells (2011)
  • Author(s): Mayuko Tsuji, Yasushi Onishi, Mayumi Kamata, Tsuyoshi Shirai, Shinji Nakajima, Rie Ohba, Toru Fujiwara, Kenichi Ishizawa, Hideo Harigae
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
• [Presentation] PS-2-42 FoxO3a has a crucial role for immune response in human dendritic cells (2011)
  • Author(s): 辻 真由子、大西 康ら、他７人
  • Organizer: 第73回 日本血液学会学術集会
  • Place of Presentation: 名古屋
• [Book] Medical Practice 28巻12号 妊娠と貧血－診断と対処のしかた－ (2011)
  • Author(s): 大西 康
  • Publisher: 文光堂