Induction of human allergic responses in 2nd generation NOG mice

• Project/Area Number: 26290034
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: Central Institute for Experimental Animals
• Principal Investigator: TAKAHASHI TAKESHI 公益財団法人実験動物中央研究所, その他部局等, 室長 (80335215)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2014: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: ヒト化マウス / アレルギー / 獲得免疫 / T細胞 / クラススイッチ / 病態モデル / 疾患モデル

Outline of Final Research Achievements

We extensively gene-modified immunodeficient NOG mice and 15 different sub-strains (2nd generation NOG mice) were generated. The hematopoiesis and immune functions were investigated after transplantation of human hematopoietic stem cells. For example, NOG-pRORgt-gc transgenic (Tg) mice showed enhanced human IgG production. NOG-human (h)TLSP-IL-13 Tg showed human IgE production. And 3 different NOG-HLA-A Tg and 2 different NOG-HLA-DR Tg mice were generated. We also demonstrated that human food allergy symptoms could be recapitulated in humanized NOG-hGM-CSF/IL-3 Tg mice with multiple lineages of human hematopoietic cells. Lactoglobulin specific IgE recombinant antibody was given to the humanized NOG-hGM-CSF/IL-3 and subsequently they were fed with Lactoglobulin proteins. The mice showed anaphylaxis manifested by the reduction of body temperature.

Research Products

• [Journal Article] A novel xenogeneic graft-versus-host disease model for investigating the pathological role of human CD4+ or CD8+ T cells using immunodeficient NOG mice. (2017)
  • Author(s): Ito R, Katano I, Kawai K, Yagoto M, Takahashi T, Ka Y, Ogura T, Takahashi R, Ito M
  • Journal Title: American Journal of Transplantation Volume: 5 Issue: 5 Pages: 1216-1228
  • DOI: 10.1111/ajt.14116
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Sodium taurocholate cotransporting polypeptide inhibition efficiently blocks hepatitis B virus spread in mice with a humanized liver (2016)
  • Author(s): Tasuku Nakabori, Hayato Hikita, Kazuhiro Murai, Yasutoshi Nozaki, Yugo Kai, Yuki Makino, Yoshinobu Saito, Satoshi Tanaka, Hiroshi Wada, Hidetoshi Eguchi, Takeshi Takahashi, Hiroshi Suemizu, Ryotaro Sakamori, Naoki Hiramatsu, Tomohide Tatsumi, and Tetsuo Takehara
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 27782-27782
  • DOI: 10.1038/srep27782
  • Peer Reviewed / Open Access
• [Journal Article] Generation of a Nonhuman Primate Model of Severe Combined Immunodeficiency Using Highly Efficient Genome Editing. (2016)
  • Author(s): Sato K, Oiwa R, Kumita W, Henry R, Sakuma T, Ito R, Nozu R, Inoue T, Katano I, Sato K, Okahara N, Okahara J, Shimizu Y, Yamamoto M, Hanazawa K, Kawakami T, Kametani Y, Suzuki R, Takahashi T, Weinstein EJ, Yamamoto T, Sakakibara Y, Habu S, Hata J, Okano H, Sasaki E.
  • Journal Title: Cell Stem Cell Volume: 19 Issue: 1 Pages: 127-138
  • DOI: 10.1016/j.stem.2016.06.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Predominant Development of Mature and Functional Human NK Cells in a Novel Human IL-2-Producing Transgenic NOG Mouse (2015)
  • Author(s): Katano, I. Takahashi, T. Ito, R. Kamisako, T. Mizusawa, T. Ka, Y. Ogura, T. Suemizu, H. Kawakami, Y. Ito, M.
  • Journal Title: J Immunol Volume: 194 Issue: 7 Pages: 3513-3525
  • DOI: 10.4049/jimmunol.1401323
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Hepatitis B Virus Genotype Affects the Persistence of Viral Replication in Immunodeficient NOG Mice. (2015)
  • Author(s): Yokoyama Y, Miyagi T, Hikita H, Yoshioka T, Mukai K, Nawa T, Sakamori R, Ohkawa K, Hiramatsu N, Takahashi T, Suemizu H, Ryo A, Tatsumi T, Takehara T.
  • Journal Title: PLoS One. Volume: 10(12) Issue: 12 Pages: e0144775-e0144775
  • DOI: 10.1371/journal.pone.0144775
  • Peer Reviewed / Open Access
• [Journal Article] ヒト化マウスを用いたヒトアレルギーモデルの確立 (2015)
  • Author(s): 伊藤亮治
  • Journal Title: アレルギーの臨床 Volume: 478 Pages: 1164-1168
• [Journal Article] Visualization of the human CD4(+) T-cell response in humanized HLA-DR4-expressing NOD/Shi-scid/gammac(null) (NOG) mice by retrogenic expression of the human TCR gene (2015)
  • Author(s): Takahashi, T. Katano, I. Ito, R. Ito, M.
  • Journal Title: Biochem Biophys Res Commun Volume: 456 Issue: 1 Pages: 219-224
  • DOI: 10.1016/j.bbrc.2014.11.062
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] A novel xenogeneic graft-versus-host disease model for investigating the pathological role of human CD4+ or CD8+ T cells using immunodeficient NOG mice. (2016)
  • Author(s): Ryoji Ito, Ikumi Katano, Takeshi Takahashi, Mamoru Ito
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄コンベンションセンター
  • Year and Date: 2016-12-05
• [Presentation] Development and applications of novel humanized mice with improved human immune system (2016)
  • Author(s): Takeshi Takahashi
  • Organizer: 7th AFLAS congress
  • Place of Presentation: Raffles City Convention Center, Singapore
  • Year and Date: 2016-11-08
  • Int'l Joint Research / Invited
• [Presentation] Generation of 2nd generation NOG mice and application to human immunology (2016)
  • Author(s): Takeshi Takahashi
  • Organizer: International symposium of humanized mouse models
  • Place of Presentation: Nanjing, China
  • Year and Date: 2016-09-01
  • Int'l Joint Research / Invited
• [Presentation] NOG hIL-3/GM-CSF/IL-5Tgマウスを用いたヒト喘息モデルの開発 (2016)
  • Author(s): 伊藤亮治、布村聡、片野いくみ、川井健司、高橋武司、後藤元人、小倉智幸、高橋利一、伊藤守
  • Organizer: 第63回日本実験動物学会総会
  • Place of Presentation: ミューザ川崎シンフォニーホール
  • Year and Date: 2016-05-18
• [Presentation] LTi特異的なIL-2Rg鎖発現によるNOGマウスでのリンパ節復元 (2016)
  • Author(s): 高橋武司、杉山文博、水野聖哉、阿部隼人、伊藤守
  • Organizer: 第63回日本実験動物学会総会
  • Place of Presentation: ミューザ川崎シンフォニーホール
  • Year and Date: 2016-05-18
• [Presentation] Generation of human asthmatic airway inflammation model by administration of IL-33 into novel humanized IL-3/GM-CSF/IL-5 transgenic NOG mice. (2016)
  • Author(s): Ryoji Ito
  • Organizer: International workshop on humanized mice 5
  • Place of Presentation: Zurich
  • Year and Date: 2016-01-28
  • Int'l Joint Research
• [Presentation] Development of 2nd generation NOG mice in CIEA (2016)
  • Author(s): Takeshi Takahashi
  • Organizer: International workshop on humanized mice 5
  • Place of Presentation: Zurich
  • Year and Date: 2016-01-28
  • Int'l Joint Research
• [Presentation] The reconstitution of human tumor microenvironment in NOG-human IL-6 transgenic mice (2016)
  • Author(s): Asami Hanazawa
  • Organizer: International workshop on humanized mice 5
  • Place of Presentation: Zurich
  • Year and Date: 2016-01-28
  • Int'l Joint Research
• [Presentation] Human interleukin-15 transgenic NOG mice support the long-term maintenance of human mature NK cells from peripheral blood (2016)
  • Author(s): Ikumi Katano
  • Organizer: International workshop on humanized mice 5
  • Place of Presentation: Zurich
  • Year and Date: 2016-01-28
  • Int'l Joint Research
• [Presentation] Reconstitution of human immune systems in next generation humanized mice and their application (2015)
  • Author(s): Takeshi Takahashi
  • Organizer: 第14回中華実験動物学会
  • Place of Presentation: 台北
  • Year and Date: 2015-11-27
  • Int'l Joint Research / Invited
• [Presentation] Intratracheal administration of IL-33 effectively induces eosinophilic airway inflammation in novel humanized NOG mice (2015)
  • Author(s): 伊藤亮治
  • Organizer: 第44回日本免疫学会総会
  • Place of Presentation: 札幌国際会議場
  • Year and Date: 2015-11-18
• [Presentation] The reconstitution of human tumor microenvironment in NOG-human IL-6 transgenic mice (2015)
  • Author(s): 花澤麻美
  • Organizer: 第44回日本免疫学会総会
  • Place of Presentation: 札幌国際会議場
  • Year and Date: 2015-11-18
• [Presentation] Human interleukin-15 transgenic NOG mice support the long-term maintenance of human mature NK cells from peripheral blood (2015)
  • Author(s): 片野いくみ
  • Organizer: 第44回日本免疫学会総会
  • Place of Presentation: 札幌国際会議場
  • Year and Date: 2015-11-18
• [Presentation] ヒトIL-15遺伝子導入NOGマウスはヒト末梢血由来成熟NK細胞を長期間維持できる (2015)
  • Author(s): 片野いくみ
  • Organizer: 第６２回日本実験動物学会総会
  • Place of Presentation: 京都テルサ
  • Year and Date: 2015-05-28
• [Presentation] ヒトIL-5遺伝子導入型NOGマウスのヒト好酸球分化能の解析 (2014)
  • Author(s): 片野いくみ、高橋武司、伊藤亮治、上迫努、何裕遥、小倉智幸、高橋利一、末水洋志、河上裕、伊藤守
  • Organizer: 第６１回 実験動物学会
  • Place of Presentation: 札幌
  • Year and Date: 2014-05-14 – 2014-05-17
• [Book] Humanized Mice for HIV Reserach (2014)
  • Author(s): Takahashi Takeshi
  • Total Pages: 525
  • Publisher: Springer