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2011 Fiscal Year Final Research Report

• Project Area: Immunological Self Recognition and its Disorders
• Project/Area Number: 19059001
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: 地方独立行政法人宮城県立病院機構 宮城県立がんセンター(研究所) (2011); Miyagi Cancer Center Research Institute (2009-2010); Tohoku University (2007-2008)
• Principal Investigator: SUGAMURA Kazuo 地方独立行政法人宮城県立病院機構 宮城県立がんセンター(研究所), 発がん制御研究部, 特任部長 (20117360)
• Co-Investigator(Kenkyū-buntansha): ISHIKAWA Fumihiko 独立行政法人理化学研究所, ヒト疾患モデル研究ユニット, ユニットリーダー (30403918) ; ITOH Mamoru (財)実験動物中央研究所, 免疫研究室長 (00176364)
• Project Period (FY): 2007 – 2011
• Keywords: ヒト免疫系 / ヒト化マウス / 免疫不全症

Research Abstract

In the present study,we established humanized immune mice by using immunodeficient NOG mice. We first established HLAtgMHCII(-/-) NOG mice by crossing of NOG mice which were transfected with HLA-DRB1*0405 gene onto NOG mice which were dencient of MHC class II gene. Susequently, the HLAtgMHCII(-/-) NOG mice were transfused with human cord blood stem cells expressing HLA-DRB1*0405 haplotype gene to establish humanized immune NOG mice. We compared T cell functions and immune responses between HLAtgMHCII(-/-)NOG mice carrying haplotype-matched human leukocytes and haplotype-mismatched human leukocytes. We detected signincant increases of the naive T cell population and cytokine production of T cells and antigen-specific IgG production in sera after TNP-OVA peptide antigen stimulation. These results indicate that the humanized HLAtgMHCII(-/-)NOG mice gain the function of human immune responses.

Research Products

• [Journal Article] Induction of human humoral immune responses in a novel HLA-DR-expressing transgenic NOD/Shi-scid/ γ cnull mouse. (2012)
  • Author(s): Suzuki M, Takahashi T, Katano T, Ito R, Ito M, Harigae H, Ishii N, Sugamura K.
  • Journal Title: Int. Immunol. Volume: 24 Pages: 243-252
• [Journal Article] In vivo assay of human NK-dependent ADCC using NOD/SCID/γc^<null> (NOG) mice. (2010)
  • Author(s): Shiokawa, M., Takahashi, T., Murakami, A., Kita, S., lto, M., Sugamura, K. and Ishii, N.
  • Journal Title: Biochem.Biophy. Res. Comm. Volume: 399 Pages: 733-737
• [Journal Article] Regulatory T cells are necessary for implantation and maintenance of early pregnancy but not ate pregnancy in allogeneic mice. (2010)
  • Author(s): Shima, T., Sasaki, Y., Itoh, M., Nakashima, A., Ishii, N., Sugamura, K. and Saito, S.
  • Journal Title: J. Rep. Immunol. Volume: 85 Pages: 121-129
• [Journal Article] Characterization of the EpCAM^+ cell population in hepatocellular carcinoma cell lines (2010)
  • Author(s): Kimura, 0., Takahashi, T., Ishii, N., Inoue, Y., Ueno, Y., Kogure, T., Fukushima, K., Shiina, M., Yamagiwa, Y., Kondo, Y., Inoue, J., Kakazu, E., Iwasaki, T., Kawagishi, N., Shimosegawa, T., and Sugamura, K
  • Journal Title: Cancer Sci. Volume: 101 Pages: 2145-2155
• [Journal Article] Highly sensitive model for xenogenic GVHD using severe immunodeficient NOG mice. (2009)
  • Author(s): Ito R, Katano I, Kawai K, Hirata H, 0gura T, Kamisako T, Eto T, and Ito M.
  • Journal Title: Transplantaion Volume: 87 Pages: 1654-1658
• [Journal Article] The analysis of the functions of human B and T cells in humanized NOD/shi-scid/{gamma}cnull(NOG) mice (hu-HSC NOG mice). (2009)
  • Author(s): Watanabe Y, Takahashi T, 0kajima A, Shiokawa M, Ishii N, Katano I,Ito R, Ito M, Minegishi M, Minegishi N, Tsuchiya S and Sugamura K.
  • Journal Title: Int. Immunol. Volume: 21 Pages: 843-858
• [Journal Article] The differentiative and regenerative properties of human hematopoietic stem/progenitor cells in the NOD-SCTD/IL2rg^<null> mice. (2008)
  • Author(s): Ishikawa F, Saito Y, Yoshida S, Harada M, Shultz LD.
  • Journal Title: Curr TopMicrobiol Immunol Volume: 324 Pages: 87-94
• [Journal Article] NOD/Shi IL2rg<null>(NOG) mice appropriate for humanized mouse models. (2008)
  • Author(s): Ito M, Kobayashi K, Nakahata T
  • Journal Title: "Humanized mice" , Nomura T, et al.(eds.), Current Topics in Microbiol. and Immunol., Springer-Verlag Berlin Heidelberg Volume: 324 Pages: 53-76
• [Journal Article] Interleukin-4-transgenic hu-PBL-SCID mice: A model for the screening of antiviral drugs and immunotherapeutic agents against X4 HIV-1 viruses. (2008)
  • Author(s): Okuma K, Tanaka r, Ogura T, Ito M, Kumakura S, Yanaka M, Nishizawa M, Sugiura W, Yamamoto N, Tanaka Y
  • Journal Title: J. Infect. Dis. Volume: 197 Pages: 134-141
• [Journal Article] The origins of blood: induction of hematopoietic stem cells from different sources. (2008)
  • Author(s): Saito Y and Ishikawa F.
  • Journal Title: Cell Stem Cell Volume: 3 Pages: 8-10
• [Journal Article] Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival. (2008)
  • Author(s): Kikushige Y, Yoshimoto G, Miyamoto T, Iino T, Mori Y, Iwasaki H, Niiro H, Takenaka K, Nagafuji K, Harada M, Ishikawa F, Akashi K.
  • Journal Title: J Immunol. Volume: 180 Pages: 7358-67
• [Journal Article] Quiescent human hematopoietic stem cells in the bone marrow niches organize the hierarchical structure of hematopoiesis. (2008)
  • Author(s): Yahata, T, Muguruma Y, Yumino S, Sheng Y, Uno T, Matsuzawa H, Ito M, Kato S, Hotta T, and Ando K.
  • Journal Title: Stem Cells Volume: 26 Pages: 3228-3236
• [Journal Article] NOD/Shi-scid IL2rgamma(null)(NOG) mice more appropriate for humanized mouse models. (2008)
  • Author(s): Ito M, Kobayashi K and Nakahata T.
  • Journal Title: Curr. Top. Microbiol. Immunol. Volume: 324 Pages: 53-76
• [Journal Article] Hematopoietic stem cell-engrafted NOD/SCID/IL2Rgamma null mice develop human lymphoid systems and induce long-lasting HIV-1 infection with specific humoral immune responses. (2007)
  • Author(s): Watanabe S, Terashima K, 0hta S, Horibata S, Yajima M, Shiozawa Y, Dewan MZ, Yu Z, Ito M, Morio T, Shimizu N, Honda M, Yamamoto N
  • Journal Title: Blood Volume: 109 Pages: 212-218
• [Journal Article] Humanized NOD/SCTD/IL2R{gamma}null mice transplanted with hematopoietic stem cells under non-myeloablative condition show prolonged lifespans and allow detailed analysis of HIV-1 pathogenesis. (2007)
  • Author(s): Watanabe S, 0hta S, Yajima M, Terashima K, Ito M, Mugishima H, Fujiwara S, Shimizu K, Honda M, Shimizu N, Yamamoto N
  • Journal Title: J. Virol.
• [Journal Article] Identification of a key molecular regulator of liver metastasis in human pancreatic carcinoma using a novel quantitative model of metastasis in NOD/SCID/gammacnull(NOG) mice. (2007)
  • Author(s): Suemizu H, Monnai M, 0hnishi Y, Ito M, Tamaoki N, Nakamura M
  • Journal Title: Int. J. Oncol. Volume: 31 Pages: 741-751
• [Journal Article] Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice. (2007)
  • Author(s): Ninomiya M, Abe A, Katsumi A, Xu J, Ito M, Arai F, Suda T, Ito M, Kiyoi H, Kinoshita T, Naoe T
  • Journal Title: Leukemia Volume: 21 Pages: 136-142
• [Journal Article] Noninvasive and real-time assessment of reconstructed functional human endortrium in NOD/SCID/{gamma}formula immunodeficient mice. (2007)
  • Author(s): Masuda H, Maruyama T, Hiratsu E, Yamane J, Iwanami A, Nagashima T, 0no M, Miyoshi H, 0kano HJ, Ito M, Tamaoki N, Nomura T, 0kano H, Matsuzaki Y, Yoshimura Y
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 104 Pages: 1925-1930
• [Journal Article] Human cord blood CD34+ cells develop into hepatocytes in the livers of NOD/SCTD/gamma(c)null mice through cell fusion. (2007)
  • Author(s): Fujino H, Hiramatsu H, Tsuchiya A, Niwa A, Noma H, Shiota M, Umeda K, Yoshimoto M, Ito M, Heike T, Nakahata T
  • Journal Title: Faseb J. Volume: 21 Pages: 3499-3510
• [Journal Article] Humanized mice in translational biomedical research. (2007)
  • Author(s): Shultz LD, Ishikawa F, Greiner DL.
  • Journal Title: Nature Reviews Immunol Volume: 7 Pages: 118-130
• [Journal Article] Chemotherapy-resistant human AML stem cells home to and engraft within the bone marrow endsteal region. (2007)
  • Author(s): Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, Nakamura R, Tanaka T, Tomiyama H, Saito N, Fukata M, Miyamoto T, Lyons B, 0hshima K, Uchida N, Taniguchi S, 0hara 0, Akashi K, Harada M, Shultz LD.
  • Journal Title: Nature Biotechnol Volume: 25 Pages: 1315-1321
• [Journal Article] The developmental program of human dendritic cells is operated independently of conventional myeloid and lymphoid pathways. (2007)
  • Author(s): Ishikawa F, Niiro H, Iino T, Yoshida S, Saito N, 0nohara S, Miyamoto T, Minagawa H, Fujii SI, Shultz LD, Harada M, Akashi K.
  • Journal Title: Blood Volume: 119 Pages: 3591-3660
• [Journal Article] Development of a multi-step leukemogenesis model of MLL-rearranged leukemia using humanized mice.
  • Author(s): Moriya, K., Suzuki, M., Watanabe, Y., Takahashi, T., Aoki, Y., Uchiyama, T., Kumaki, S., Sasahara, Y., Minegishi, M., Kure, S., Tsuchiya, S., Sugamura, K. and Ishii, N.
  • Journal Title: PLos ONE Volume: (in press)
• [Presentation] The analysis of the functions of human T cells in humanized NOD/shi-scid/γc^<null>(NOG)-HLA transgenic mice. (2010)
  • Author(s): 高橋武司, 他
  • Organizer: 国際免疫学会
  • Year and Date: 2010-08-23
• [Presentation] Understanding normal and diseased human immunity using humanized mouse. (2010)
  • Author(s): 石川文彦
  • Organizer: 国際免疫学会
  • Year and Date: 2010-08-23
• [Presentation] The analysis of the functions of human B and T cells in humanized NOD/shi/ycnu11(NOG)mice (hu-HSC NOGmice). (2009)
  • Author(s): 高橋武司, 他
  • Organizer: 2nd lnt.Workshop on Humanized Mice (Sind 010fskape1/Amsterdam/The Netherlands)
  • Year and Date: 2009-04-04
• [Presentation] Analysis of the functional human T cells in reconstitutional humanized NOGmice (2008)
  • Author(s): 岡嶋亮良, 他
  • Organizer: 日本免疫学会
  • Year and Date: 20080100
• [Presentation] Characterization of human lymphocytes in humanized NOG mice (2007)
  • Author(s): 渡辺庸平, 他
  • Organizer: 日本免疫学会
  • Year and Date: 2007-11-21