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The Analysis of Intestinal, Oral, and Nasal Bacterial Flora of Chronic Active Epstein-Barr Virus Patients

Research Project

Project/Area Number 20K08720
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionSt. Marianna University School of Medicine

Principal Investigator

ARAI AYAKO  聖マリアンナ医科大学, 医学部, 教授 (70359678)

Co-Investigator(Kenkyū-buntansha) 須田 亙  国立研究開発法人理化学研究所, 生命医科学研究センター, 副チームリーダー (20590847)
吉森 真由美  東京医科歯科大学, 大学院医歯学総合研究科, 日本学術振興会特別研究員 (20816053)
澤田 めぐみ  東京家政大学, 家政学部, 教授 (30291339)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords慢性活動性EBウイルス感染症 / サイトカイン / EBウイルス / T細胞 / NK細胞 / リンパ増殖症 / CAEBV / Epstein-Barr virus / 細菌叢 / dysbiosis
Outline of Research at the Start

慢性活動性EBウイルス感染症(CAEBV)はEBVに感染したTもしくはNK細胞の腫瘍性増殖に慢性炎症を伴う難治性疾患である。本研究ではCAEBV発症の背景にdysbiosisが存在するという仮説を立て、患者の腸、口腔、鼻腔の細菌叢を次世代シーケンサーで解析、① その特徴、②発症との関連、③発症の背景にある免疫異常との関連を明らかにする。Dysbiosisとの関連が明らかになれば、根治には造血幹細胞移植しかなかった本疾患が、抗生剤等で予防、治療し得る疾患となり得る。また、dysbiosisの関与という、新たな造血器腫瘍発症メカニズムの解明にもつながると期待される。

Outline of Final Research Achievements

We have completed the collection of stool samples from 10 patients with chronic active EBV infection (CAEBV). We analyzed the microbiota using a next-generation sequencer and in March and are currently analyzing their contents. We found that plasma levels of IL-1β and IFN-γ are biomarkers for vasculitis and disease activity, respectively in CAEBV. We also found that X concentration in plasma of CAEBV patients is significantly higher than that in healthy controls and correlates with disease activity; and that X receptor inhibitors contribute to suppression of CAEBV tumor cell growth and cytokine production. We have applied for an international patent, PCT for the above results as "Method for Detection of Chronic Active Epstein-Barr Virus Infection (CAEBV)".

Academic Significance and Societal Importance of the Research Achievements

CAEBV発症の背景に存在する後天性の免疫異常の原因として細菌叢の異常が明らかになれば未解明であった病態解明につながり得、学術的意義は大きい。CAEBVに根治をもたらし得る薬剤は開発されていない。この研究で同定された病態に関与する複数のサイトカインと、その伝達する細胞内シグナリングにはいずれも阻害薬が存在し治療薬候補になり得、社会的意義も多い。

Report

(3 results)
  • 2022 Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (34 results)

All 2022 2021 2020

All Journal Article (13 results) (of which Peer Reviewed: 10 results,  Open Access: 8 results) Presentation (17 results) (of which Int'l Joint Research: 6 results,  Invited: 1 results) Book (4 results)

  • [Journal Article] Registry data analysis of hematopoietic stem cell transplantation on systemic chronic active Epstein-Barr virus infection patients in Japan2022

    • Author(s)
      Yamamoto M, Sato M, Onishi Y, Sasahara Y, Sano H, Masuko M, Nakamae H, Matsuoka KI, Ara T, Washio K, Onizuka M, Watanabe K, Takahashi Y, Hirakawa T, Nishio M, Sakashita C, Kobayashi T, Sawada A, Ichinohe T, Fukuda T, Hashii Y, Atsuta Y, Arai A
    • Journal Title

      American Journal of Hematology

      Volume: ー Issue: 6 Pages: 780-790

    • DOI

      10.1002/ajh.26544

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Antineoplastic and anti-inflammatory effects of bortezomib on systemic chronic active EBV infection2021

    • Author(s)
      Yoshimori Mayumi、Shibayama Haruna、Imadome Ken-Ichi、Kawano Fuyuko、Ohashi Ayaka、Nishio Miwako、Shimizu Norio、Kurata Morito、Fujiwara Shigeyoshi、Arai Ayako
    • Journal Title

      Blood Advances

      Volume: 5 Issue: 7 Pages: 1805-1815

    • DOI

      10.1182/bloodadvances.2020002417

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The clinicopathological analysis of organising pneumonia in myelodysplastic syndrome: high frequency in der(1;7)(q10; p10)2021

    • Author(s)
      Matsunawa Manabu、Inoue Yasuyuki、Yagihashi Kunihiro、Aida Yoshio、Uchida Akiko、Uemura Yu、Saiki Yusuke、Takimoto Madoka、Sano Fumiaki、Miura Ikuo、Arai Ayako
    • Journal Title

      British Journal of Haematology

      Volume: 194 Issue: 1 Pages: 214-217

    • DOI

      10.1111/bjh.17473

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Interferon-γ Produced by EBV-Positive Neoplastic NK-Cells Induces Differentiation into Macrophages and Procoagulant Activity of Monocytes, Which Leads to HLH2021

    • Author(s)
      Yoshimori Mayumi、Nishio Miwako、Ohashi Ayaka、Tateishi Megumi、Mimura Ayaka、Wada Naomi、Saito Minori、Shimizu Norio、Imadome Ken-Ichi、Arai Ayako
    • Journal Title

      Cancers

      Volume: 13 Issue: 20 Pages: 5097-5097

    • DOI

      10.3390/cancers13205097

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chronic Active Epstein-Barr Virus Infection: The Elucidation of the Pathophysiology and the Development of Therapeutic Methods2021

    • Author(s)
      Arai Ayako
    • Journal Title

      Microorganisms

      Volume: 9 Issue: 1 Pages: 180-180

    • DOI

      10.3390/microorganisms9010180

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Biopsy remains indispensable for evaluating bone marrow involvement in DLBCL patients despite the use of positron emission tomography2021

    • Author(s)
      Saiki Yusuke、Tomita Naoto、Uchida Akiko、Uemura Yu、Suzuki Yoshinori、Hirakawa Tsuneaki、Kato Masayuki、Hoshikawa Masahiro、Kawano Tsuyoshi、Nakamura Naoya、Miura Ikuo、Arai Ayako
    • Journal Title

      International Journal of Hematology

      Volume: NA Issue: 5 Pages: 675-681

    • DOI

      10.1007/s12185-021-03080-3

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Nationwide survey of systemic chronic active EBV infection in Japan in accordance with the new WHO classification2020

    • Author(s)
      Yonese Ichiro、Sakashita Chizuko、Imadome Ken-Ichi、Kobayashi Tohru、Yamamoto Masahide、Sawada Akihisa、Ito Yoshinori、Fukuhara Noriko、Hirose Asao、Takeda Yusuke、Makita Masanori、Endo Tomoyuki、Kimura Shun-ichi、Ishimura Masataka、Miura Osamu、Ohga Shouichi、Kimura Hiroshi、Fujiwara Shigeyoshi、Arai Ayako
    • Journal Title

      Blood Advances

      Volume: 4 Issue: 13 Pages: 2918-2926

    • DOI

      10.1182/bloodadvances.2020001451

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gene expression profiling of primary vitreoretinal lymphoma2020

    • Author(s)
      Arai Ayako、Takase Hiroshi、Yoshimori Mayumi、Yamamoto Kouhei、Mochizuki Manabu、Miura Osamu
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 4 Pages: 1417-1421

    • DOI

      10.1111/cas.14347

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Multimodal imaging of secondary vitreoretinal lymphoma with optic neuritis and retinal vasculitis2020

    • Author(s)
      Ishida Tomoka、Takase Hiroshi、Arai Ayako、Ohno-Matsui Kyoko
    • Journal Title

      American Journal of Ophthalmology Case Reports

      Volume: 18 Pages: 100696-100696

    • DOI

      10.1016/j.ajoc.2020.100696

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mortality and risk of progression to adult T-cell leukemia/lymphoma in HTLV-1-associated myelopathy/tropical spastic paraparesis.2020

    • Author(s)
      Nagasaka M, Yamagishi M, Yagishita N, Araya N, Kobayashi S, Makiyama J, Kubokawa M, Yamauchi J, Hasegawa D, Coler-Reilly ALG, Tsutsumi S, Uemura Y, Arai A, Takata A, Inoue E, Hasegawa Y, Watanabe T, Suzuki Y, Uchimaru K, Sato T, Yamano Y.
    • Journal Title

      Proc Natl Acad Sci U S A

      Volume: 117(21) Issue: 21 Pages: 11685-11691

    • DOI

      10.1073/pnas.1920346117

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 慢性活動性EBウイルス感染症~病態、臨床像、治療~2020

    • Author(s)
      新井文子
    • Journal Title

      日本検査血液学会誌

      Volume: 21 Pages: 121-126

    • Related Report
      2020 Research-status Report
  • [Journal Article] 慢性活動性EBウイルス感染症に対する新規治療薬2020

    • Author(s)
      新井文子
    • Journal Title

      臨床雑誌内科

      Volume: 126 Pages: 464-466

    • Related Report
      2020 Research-status Report
  • [Journal Article] 慢性活動性EBウイルス感染症~本邦の診療実態からみたWHO2017~2020

    • Author(s)
      新井文子
    • Journal Title

      血液内科

      Volume: 81 Pages: 599-603

    • Related Report
      2020 Research-status Report
  • [Presentation] 発熱、肝障害、進行する皮膚病変を認めた全身型慢性活動性EBウイルス感染症に対するJAK1/2阻害剤ルキソリチニブ治療2022

    • Author(s)
      木戸礼乃, 齊木祐輔, 内田晶子, 上村悠, 平川経晃, 加藤雅之, 富田直人, 山本浩平, 今留謙一, 新井文子
    • Organizer
      第16回日本血液学会関東甲信越地方会
    • Related Report
      2021 Research-status Report
  • [Presentation] 消化管悪性リンパ腫治療における消化管関連合併症の検討-びまん性大細胞型B細胞リンパ腫(DLBCL)を中心に-2022

    • Author(s)
      神野正敏, 齊木祐輔, 内田晶子, 上村悠, 平川経晃, 加藤雅之, 富田直人, 井上靖之, 新井文子
    • Organizer
      第58回腹部救急医学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 全身性慢性活動性EBウイルス感染症患者の血漿中INF-γ濃度の意義2021

    • Author(s)
      上村悠, 吉森真由美, 大橋彩香, 平川経晃, 和田尚美, 今留謙一, 新井文子
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 慢性活動性EBV感染症患者血漿中のIL-1βは血管病変のバイオマーカーとなり得る2021

    • Author(s)
      大橋彩香, 上村悠, 吉森真由美, 和田尚美, 今留謙一, 遊道和雄, 西尾美和子, 新井文子
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] HLHに伴う高サイトカイン血症に対するPEとCHDFの効果2021

    • Author(s)
      内田晶子, 上村悠, 平川経晃, 大橋 彩香, 吉森真由美, 小島茂樹, 櫻田勉, 新井文子
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 健常若年成人におけるEBV感染の実態2021

    • Author(s)
      熊木優喜, 齊藤美緑, 吉森真由美, 中家瞳, 澤田めぐみ, 西尾美和子, 新井文子
    • Organizer
      第83回日本血液学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] What Plasma Level of Interferon-γ Indicates in Systemic Chronic Active Epstein-Barr Virus Infection2021

    • Author(s)
      Yu Uemura, Mayumi Yoshimori, Ayaka Ohashi, Tsuneaki Hirakawa, Naomi Wada, Ken-ichi Imadome, Ayako Arai
    • Organizer
      19th International Symposium on Epstein-Barr Virus and Associated Disease
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Plasma level of IL-1β in Chronic Active EBV Infection can be a biomarker of angiopathy2021

    • Author(s)
      Ayaka Ohashi, Yu Uemura, Mayumi Yoshimori, Naomi Wada, Ken-Ichi Imadome, Kazuo Yudo, Miwako Nishio, Ayako Arai
    • Organizer
      19th International Symposium on Epstein-Barr Virus and Associated Disease
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] IFN-γ produced by EBV-Positive Neoplastic NK-Cells Induces Macrophage Differentiation and upregulates blood coagulation causing HLH2021

    • Author(s)
      Mayumi Yoshimori, Megumi Tateishi, Ayaka Ohashi, Shixing Wu, Ken-Ichi Imadome, Norio Shimizu, Miwako Nishio, Ayako Arai
    • Organizer
      19th International Symposium on Epstein-Barr Virus and Associated Disease
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] The Outcomes of Systemic Chronic Active EBV Infection Treatment By Allogeneic Hematopoietic Stem Cell Transplantation: An Analysis of Japanese Registry Data2021

    • Author(s)
      A Arai, M Yamamoto, M Sato, Y Onishi, Y Sasahara, H Sano, M Masuko, H Nakamae, K Matsuoka, T Ara, K Washio, M Onizuka, K Watanabe, T Hirakawa, M Nishio, C Sakashita, T Kobayashi, A Sawada, T Ichinohe, T Fukuda, Y Hashii, Y Atsuta
    • Organizer
      63rd ASH Annual Meeting & Exposition
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] 慢性活動性Epstein-Barrウイルス感染症の克服を目指して(The Road to Treat Chronic Active Epstein-Barr Virus Infection)2020

    • Author(s)
      新井文子
    • Organizer
      第82回日本血液学会学術集会 女性医師シンポジウム
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] EBV陽性NK腫瘍細胞の産生するサイトカインは単球の凝固活性を高めDICを引き起こす(The Cytokines of EBV+Neoplastic NK-Cells Enhance the Procoagulant Activity of Monocytes Causing DIC)2020

    • Author(s)
      立石 萌, 吉森 真由美, 大橋 彩香, 呉 詩星, 清水 則夫, 西尾 美和子, 新井 文子
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 慢性活動性EBウイルス感染症に対する同種移植(Outcome of Hematopoietic Stem Cell Transplantation for Chronic Active Epstein-Barr Virus Infection)2020

    • Author(s)
      山本 正英, 佐藤 真穂, 大西 康, 松岡 賢市, 鬼塚 真仁, 渡邉 健一郎, 菊田 敦, 坂下 千瑞子, 小林 徹, 一戸 辰夫, 福田 隆浩, 井上 雅美, 熱田 由子, 新井 文子
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 慢性活動性EBウイルス感染症におけるウイルス由来miRNAの標的の解明(The Elucidation of Targets of EBV-Derived Micro-RNA in Chronic Active EBV Infection)2020

    • Author(s)
      呉 詩星, 吉森 真由美, 立石 萌, 大橋 彩香, 清水 則夫, 西尾 美和子, 新井 文子
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] EBV陽性NK腫瘍細胞は単球からマクロファージへの分化を誘導し、HLHの原因となり得る(EBV-Positive Neoplastic NK-Cells Induce Macrophage Differentiation from Monocytes, Leading to HLH)2020

    • Author(s)
      吉森 真由美, 立石 萌, 大橋 彩香, 呉 詩星, 今留 謙一, 清水 則夫, 西尾 美和子, 新井 文子
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Products of EBV-Positive Neoplastic NK-Cells Induce Differentiation into Macrophages and Procoagulant Activity of Monocytes, which Leads to HLH2020

    • Author(s)
      Mayumi Yoshimori1, Megumi Tateishi, Ayaka Ohashi, Shixing Wu, Ken-Ichi Imadome, Norio Shimizu, Miwako Nishio, Ayako Arai
    • Organizer
      25th Annual Congress of EHA
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] A case of villous atrophy with CCR4+ T cell infiltration in the small intestine2020

    • Author(s)
      Takashi Nagaishi, Daiki Yamada, Naoya Tsugawa, Taro Watabe, Eiko Saito, Masayoshi Fukuda, Ayako Arai, Kazuo Ohtsuka, Mamoru Watanabe
    • Organizer
      28th United European Gastroenterology Week
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Book] 今日の疾患辞典(アップデート版) 慢性活動性EBウイルス感染症2022

    • Author(s)
      新井文子
    • Publisher
      プレシジョン
    • Related Report
      2021 Research-status Report
  • [Book] 私の治療[2021-22年度版]慢性活動性EBウイルス感染症2021

    • Author(s)
      新井文子
    • Publisher
      日本医事新報社
    • ISBN
      9784784946525
    • Related Report
      2021 Research-status Report
  • [Book] 内科学 第12版 第Ⅴ巻2021

    • Author(s)
      新井文子
    • Total Pages
      462
    • Publisher
      朝倉書店 慢性活動性EBウイルス感染症
    • Related Report
      2021 Research-status Report
  • [Book] 血液・造血器/感染症/悪性腫瘍2021

    • Author(s)
      鈴木義則, 新井文子
    • Total Pages
      395
    • Publisher
      中山書店
    • ISBN
      9784521744551
    • Related Report
      2021 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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