Analysis of native immune responses to Epstein-Barr virus in the virus-infected humanized mice

• Project/Area Number: 22590430
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Virology
• Research Institution: National Research Institute for Child Health and Development
• Principal Investigator: FUJIWARA Shigeyoshi 独立行政法人国立成育医療研究センター, 母児感染研究部, 部長 (30173488)
• Co-Investigator(Kenkyū-buntansha): IMADOME Ken-ichi 国立成育医療研究センター, 母児感染研究部, 室長 (70392488)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 感染防御 / ワクチン / EBウイルス / ヒト化マウス / T細胞輸注療法 / リンパ増殖性疾患 / 自然免疫 / NK細胞 / インターフェロン / 細胞治療

Research Abstract

Splenic NK cells isolated from EBV-infected humanized mice two days post-infection and cultured for two days produced higher levels of IFN_<-γ> as compared with the same cells isolated from uninfected humanized mice and processed similarly. Activated T-cell preparations were generated from cord blood by culturing with IL-2 and anti-CD3 antibody. When this activated T-cell preparation was administered to EBV-infected humanized mice generated with hematopoietic stem cells isolated from the same cord blood sample, therapeutic effects was evident as decreased EBV DNA levels in mouse organs and prolonged life span.

Research Products

• [Journal Article] Humanized mouse models of Epstein-Barr virus infection and associated diseases. (2013)
  • Author(s): Fujiwara S, Matsuda G, and Imadome K
  • Journal Title: pathogens Volume: 2 Pages: 153-176
• [Journal Article] Effective control of Epstein-Barr virus infection following pediatric liver transplantation by monitoring of viral DNA load and lymphocyte surface markers. (2012)
  • Author(s): Imadome K, Fukuda A, Kawano F, Imai Y, Ichikawa S, Mochizuki M, Shigeta T, Kakiuchi T, Sakamoto S, Kasahara M, Fujiwara S
  • Journal Title: Pediatr Transplant. Volume: 16(7) Pages: 748-57
• [Journal Article] Sequential monitoring of serum IL-6, TNF-α, and IFN-γ levels in a CAEBV patient treated by plasma exchange and immunochemotherapy. (2012)
  • Author(s): Arai A, Nogami A, Imadome K, Kurata M, Murakami N, Fujiwara S, Miura O.
  • Journal Title: Int J Hematol Volume: 96(5) Pages: 669-73
  • NAID: 10031126766
• [Journal Article] ZNF385B is characteristically expressed in germinal center B cells and involved in B-cell apoptosis. (2012)
  • Author(s): Iijima K, Yamada H, Miharu M, Imadome K, Miyagawa Y, Akimoto S, Kobayashi K, Okita H, Nakazawa A, Fujiwara S, Fujimoto J, Kiyokawa N.
  • Journal Title: Eur J Immunol. Volume: 42(12) Pages: 3405-15
• [Journal Article] Recurrence of chronic active Epstein-Barr virus infection from donor cells after achieving complete response through allogeneic bone marrow transplantation. (2012)
  • Author(s): Arai A, Imadome K, Wang L, Nan W, Kurosu T, Wake A, Ohta Y, Harigai M, Fujiwara S, and Miura O
  • Journal Title: Intern Med Volume: 51 Pages: 777-782
  • NAID: 130002061847
• [Journal Article] Characterization of Epstein-Barr virus (EBV)-infected cells in EBV-associated hemophagocytic lymphohistiocytosis in two patients with X-linked lymphoproliferative syndrome type 1 and type 2. (2012)
  • Author(s): Yang X, Wada T, Imadome K, Nishida N, Mukai T, Fujiwara M, Kawashima H, Kato F, Fujiwara S, Yachie A, Zhao X, Miyawaki T, Kanegane H
  • Journal Title: Herpesviridae Volume: 3 Pages: 1-1
• [Journal Article] Effective control of Epstein-Barr virus infection following pediatric liver transplantation by monitoring of viral DNA load and lymphocyte surface markers (2012)
  • Author(s): Imadome K, Fukuda A
  • Journal Title: Pediatric Transplantation Volume: 16(Epub ahead of print) Issue: 7 Pages: 748-757
  • DOI: 10.1111/j.1399-3046.2012.01750.x
  • Peer Reviewed
• [Journal Article] Sequential monitoring of serum IL-6, TNF-α, and IFN-γ levels in a CAEBV patient treated by plasma exchange and immunochemotherapy. (2012)
  • Author(s): Arai A, Nogami A, Imadome K,et al.
  • Journal Title: Int J Hematol. Volume: 96(5) Issue: 5 Pages: 669-673
  • DOI: 10.1007/s12185-012-1170-2
  • NAID: 10031126766
  • Peer Reviewed
• [Journal Article] Recurrence of Chronic Active Epstein-Barr Virus Infection from Donor Cells after Achieving Complete Response Through Allogeneic Bone Marrow Transplantation (2012)
  • Author(s): Arai A, et al
  • Journal Title: Internal Medicine Volume: 51 Issue: 7 Pages: 777-782
  • DOI: 10.2169/internalmedicine.51.6769
  • NAID: 130002061847
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] Characterization of Epstein-Barr virus (EBV)-infected cells in EBV-associated hemophagocytic lymphohistiocytosis in two patients with X-linked lymphoproliferative syndrome type1 and 2 (2012)
  • Author(s): Yang X*, Wada T*, Imadome K*,et al.
  • Journal Title: Herpesviridae. Volume: 10;3(1) Issue: 1 Pages: 1-6
  • DOI: 10.1186/2042-4280-3-1
  • Peer Reviewed
• [Journal Article] Novel Mouse Xenograft Models Reveal a Critical Role of CD4+ T Cells in the Proliferation of EBV-Infected T and NK Cells. (2011)
  • Author(s): Imadome K, Yajima M, Arai A, Nakazawa A, Kawano F, Ichikawa S, Shimizu N, Yamamoto N, Morio T, Ohga S, Nakamura H, Ito M, Miura O, Komano J, and Fujiwara S
  • Journal Title: PLoS Pathogens Volume: 7(10)
• [Journal Article] Epstein-Barr Virus Induces Erosive Arthritis in Humanized Mice. (2011)
  • Author(s): Kuwana Y, Takei M, Yajima M, Imadome K, Inomata H, Shiozaki M, Ikumi N, Nozaki T, Shiraiwa H, Kitamura N, Takeuchi J, Sawada S, Yamamoto N, Shimizu N, Ito M, and Fujiwara S
  • Journal Title: PLoS ONE Volume: 6(10)
• [Journal Article] Bortezomib Induces Apoptosis in T Lymphoma Cells and Natural Killer Lymphoma Cells Independent of Epstein-Barr Virus Infection. (2011)
  • Author(s): Iwata S, Yano S, Ito Y, Ushijima Y, Gotoh K, Kawada J, Fujiwara S, Sugimoto K, Isobe Y, Nishiyama Y, Kimura H
  • Journal Title: Int J Cancer Volume: 129 Pages: 2263-2273
• [Journal Article] Clinical features of adult-onset chronic active Epstein-Barr virus infection: a retrospective analysis. (2011)
  • Author(s): Arai A, Imadome K, Watanabe Y, Takahashi M, Kawaguchi T, Nakaseko C, Fujiwara S, Miura O
  • Journal Title: Int J Hematol Volume: 93(5) Pages: 602-9
  • NAID: 10029535036
• [Journal Article] CD4^+T cells have a critical role in the proliferation of EBV-infected T and NK cells (2011)
  • Author(s): Imadome K, Yajima M, Arai A, Nakagawa-Nakazawa A, Kawano F, Ichikawa S, Shimizu N, Yamamoto N, Morio T, Ohga S, Nakamura H, Ito M, Miura O, Komano J, Fujiwara S
  • Journal Title: PLOS Pathogen Volume: (in press) Issue: 10 Pages: 1-14
  • DOI: 10.1371/journal.ppat.1002326
  • Peer Reviewed
• [Journal Article] Epstein-Barr Virus Induces Erosive Arthritis in Humanized Mice (2011)
  • Author(s): Kuwana Y, et al
  • Journal Title: PLoS ONE Volume: 6 Issue: 10 Pages: e26630-e26630
  • DOI: 10.1371/journal.pone.0026630
  • Peer Reviewed
• [Journal Article] Clinical features of adult-onset chronic active Epstein-Barr virus infection : a retrospective analysis. (2011)
  • Author(s): Arai A, Imadome K, Watanabe Y, Takahashi M, Kawaguchi T, Nakaseko C, Fujiwara S, Miura O.
  • Journal Title: International Journal of Hematology Volume: (Epub ahead of print)
  • NAID: 10029535036
  • Peer Reviewed
• [Journal Article] Autoimmune hemolytic anemia accompanied by reactivation of an Epstein-Barr virus infection with suppressed CTL response to EBV-infected cells in an elderly man. (2010)
  • Author(s): Arai, A., Imadome, K., Fujiwara, S. and Miura O
  • Journal Title: Inter Med Volume: 49 Pages: 325-329
  • NAID: 130000152617
• [Journal Article] Autoimmune hemolytic anemia accompanied by reactivation of an Epstein-Barr virus infection with suppressed CTL response to EBV-infected cells in an elderly man. (2010)
  • Author(s): Arai, A., Imadome, K., Fujiwara, S., Miura O.
  • Journal Title: Internal Medicine Volume: 49 Pages: 325-329
  • NAID: 130000152617
  • Peer Reviewed
• [Journal Article] Bortezomib Induces Apoptosis in T Lymphoma Cells and Natural Killer Lymphoma Cells Independent of Epstein-Barr Virus Infect (2010)
  • Author(s): Iwata S, Yano S, Ito Y, Ushijima Y, Gotoh K, Kawada J, Fujiwara S, Sugimoto K, Isobe Y, Nishiyama Y, Kimura H..
  • Journal Title: International Journal of Cancer Volume: (Epub ahead of print)
  • Peer Reviewed
• [Presentation] 小児生体肝移植後のEBVゲノム定 量モニタリングの重要性と免疫抑制剤減 量に伴うEBV特異的CTL誘導の検討 (2012)
  • Author(s): 今留謙一、福田晃也、川野布由子、望月雅 司、山田千尋、阪本靖介、笠原群生、藤原 成悦
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2012-11-15
• [Presentation] ヒト化マウスを用いたEBウイル ス関連リンパ増殖性疾患に対する免疫細 胞治療のモデル実験 (2012)
  • Author(s): 松田剛、今留謙一、矢島美彩子、落合央、 望月雅司、川野布由子、山田千尋、今井由美、濱崎霞、浅田恵理子、原口摩耶、千葉祐規乃、清水則夫、駒野淳、山本直樹、藤原成悦
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2012-11-14
• [Presentation] Chronic active Epstein-Barr virus infection成人例に対する骨髄非破壊的前処置を用いた造血幹細胞移植成績仁多美奈子、新井文子、今留謙一、吉森真 由美、王路丹、小山高敏、斉藤愛記、山岡 昇司、藤原成悦、三浦修 (2012)
  • Author(s): 仁多美奈子、山本正英、今留謙一、藤原成 悦、三浦修、新井文子
  • Organizer: 第34回日本造血細胞移植学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2012-02-24
• [Presentation] Inflammatory cytokines can be molecular targets for treatment of CAEBV. (2012)
  • Author(s): Ayako Arai. Ken-Ichi Imadome, Ludan Wang, Honami Komatsu, Takatoshi Koyama, Ayako Nogami, Shigeyoshi Fujiwara, Osamu Miura
  • Organizer: 第74回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] EBV infection enhances T-cell adhesion and survival contributing to EBV-T-LPD development. (2012)
  • Author(s): Honami Komatsu, Takatoshi Koyama, Shigeyoshi Fujiwara, Osamu Miura, Ayako Arai
  • Organizer: 第74回日本血液学会総会
  • Place of Presentation: 京都
• [Presentation] Models of Epstein-Barr virus-related diseases based on NOG mice (2011)
  • Author(s): Fujiwara S
  • Organizer: 3rd International Workshop on Humanized mice
  • Place of Presentation: Pittsburgh
  • Year and Date: 2011-10-30
• [Presentation] ウイルス感染に対する獲得免疫-EBV感染ヒト化マウスにおけるT細胞応答の宿主防御的役割について- (2011)
  • Author(s): 藤原成悦
  • Organizer: 日本ヘルペス感染症フォーラム
  • Place of Presentation: Pittsburgh
  • Year and Date: 2011-10-30
• [Presentation] EBV infection to T or NK cells activates NF-kB leading to lymphoproliferative diseases development. (2011)
  • Author(s): 仁多美奈子、新井文子、今留謙一、吉森真由美、王路丹、小山高敏、斉藤愛記、山岡 昇司、藤原成悦、三浦修
  • Organizer: 日本血液学会学術集会
• [Presentation] EBウイルスはTあるいはNK細胞に感染後NF-活性化を介して腫瘍発症に寄与する (2011)
  • Author(s): 新井文子、斉藤愛記、山岡昇司、藤原成悦、三浦修
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] NOVEL MOUSE XENOGRAFT MODELS OF CAEBV AND EBV-HLH REVEAL A CRITICAL ROLE OF CD4+ T CELLS IN THE PROLIFERATION OF EBV-INFECTED T AND NK CELLS (2011)
  • Author(s): Imadome K, et al
  • Organizer: 15^<th> International Congress of Virology
  • Place of Presentation: 札幌
• [Presentation] CD137 EXPRESSION IS INDUCED BY EPSTEIN-BARR VIRUS (EBV) INFECTION AND ACTIVATES NF-κB CONTRIBUTING TO THE DEVELOPMENT OF EBV-POSITIVE T/NK-CELL LYMPHOPROLIFERATIVE DISEASE (2011)
  • Author(s): Mayumi Y, et al
  • Organizer: Annual Meeting of the European Hematology Association
  • Place of Presentation: London
• [Presentation] L-asparaginase Monotherapy for T- and NK-Cell Type of Chronic Active Epstein-Barr Virus Infection in adults : A Pilot Study (2011)
  • Author(s): Arai A, et al
  • Organizer: Annual Meeting of the American Association for Hematology
  • Place of Presentation: San Diego
• [Presentation] EBウイルス関連血球貪食症候群モデルマウスの作製と解析 (2010)
  • Author(s): 今留謙一、矢島美彩子、川野布由子、市川紗弓、清水則夫、中村浩幸、松田剛、駒野 淳、山本直樹、藤原成悦
  • Organizer: 第58回日本ウイルス学会学術集会
  • Place of Presentation: 徳島
  • Year and Date: 2010-11-09
• [Presentation] EBウイルス関連血球食食症候群モデルマウスの作製と解析 (2010)
  • Author(s): 今留謙一、矢島美彩子、川野布由子、市川紗弓、清水則夫、中村浩幸、松田剛、駒野淳、山本直樹、藤原成悦
  • Organizer: EBウイルス関連血球貧食症候群モデルマウスの作製と解析
  • Place of Presentation: 徳島市
  • Year and Date: 2010-11-09
• [Presentation] EBウイルス関連T/NKリンパ増殖性疾患モデルマウスの作製と解析 (2010)
  • Author(s): 今留謙一、矢島美彩子、川野布由子、新井文子、中澤温子、市川紗弓、中村浩幸、清水則夫、伊藤守、山本直樹、藤原成悦
  • Organizer: 第7回EBウイルス研究会
  • Place of Presentation: 札幌市
  • Year and Date: 2010-07-09
• [Presentation] NOGマウスを利用したEBウイルス感染細胞の同定 (2010)
  • Author(s): 田中久美子、今留謙一、川野布由子、市川紗弓、松田剛、藤原成悦
  • Organizer: 第7回EBウイルス研究会
  • Place of Presentation: 札幌市
  • Year and Date: 2010-07-09
• [Presentation] EBウイルス関連T/NKリンパ増殖性疾患モデルマウスの作製と解析 (2010)
  • Author(s): 今留謙一、矢島美彩子、川野布由子、中澤温子、市川紗弓、中村浩幸、清水則夫、伊藤守、山本直樹、藤原成悦
  • Organizer: 第25回ヘルペスウイルス研究会
  • Place of Presentation: 浜松市
  • Year and Date: 2010-05-27
• [Presentation] P-glycoprotein expression is enhanced in EBV-infected T or NK cells in CAEBV and may cause its chemoresistance. (2010)
  • Author(s): Morito Kurata, Takatoshi Koyama, Shigeyoshi Fujiwara, Osamu Miura, Ayako Arai
  • Organizer: 日本血液学会総会
• [Presentation] Mouse models of Epstein-Barr virus-related diseases. 1st Samsung Humanized Mice symposium
  • Author(s): Fujiwara S et al.
  • Organizer: 1st. Samsung Humanized Mice symposium
  • Place of Presentation: Seoul
  • Invited
• [Presentation] EBウイルス関連疾患の病態を再現するモデルマウス
  • Author(s): 藤原成悦
  • Organizer: 北海道大学遺伝子病制御研究所研究集会 「感染・免疫・炎症・発癌」
  • Place of Presentation: 札幌
  • Invited
• [Presentation] EBウイルス関連T/NKリンパ増殖性疾患の病態を再現するモデルマウス
  • Author(s): 藤原成悦
  • Organizer: 第19回ヘルペス感染症フォーラム
  • Place of Presentation: 札幌
  • Invited
• [Presentation] EBウイルス関連疾患の病態を再現するモデルマウス
  • Author(s): 藤原成悦
  • Organizer: 第16回多摩ウイルス感染症研究会
  • Place of Presentation: 東京
  • Invited
• [Presentation] ヒト化マウスを用いたEBウイルス関連リンパ増殖性疾患に対する免疫細胞治療のモデル実験
  • Author(s): 松田剛ら
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪
• [Remarks] 独立行政法人国立成育医療研究センター研究所母児感染研究部
  • URL: http://111.89.135.117/infection/index.htm
• [Remarks]
  • URL: http://111.89.135.117/infection/index.htm
• [Remarks]
  • URL: http://111.89.135.117/infection/index.htm