Predominant development of mature and functional human NK cells in a novel human IL-2 - Producing transgenic NOG mouse

Ikumi Katano, Takeshi Takahashi, Ryoji Ito, Tsutomu Kamisako, Takuma Mizusawa, Yuyo Ka, Tomoyuki Ogura, Hiroshi Suemizu, Yutaka Kawakami, Mamoru Ito

Research output: Contribution to journalArticle

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Abstract

We generated a severe immunodeficient NOD/Shi-scid-IL-2Rγ<sup>null</sup> (NOG) mouse substrain expressing the transgenic human IL-2 gene (NOG-IL-2 Tg). Upon transfer of human cord blood-derived hematopoietic stem cells (HSCs), CD3<sup>-</sup>CD56<sup>high</sup>CD16<sup>+/-</sup> cells developed unexpectedly, predominantly in the NOG-IL-2 Tg (hu-HSC NOG-IL-2 Tg). These cells expressed various NK receptors, including NKp30, NKp44, NKp46, NKG2D, and CD94, as well as a diverse set of killer cell Ig-like receptor molecules at levels comparable to normal human NK cells from the peripheral blood, which is evidence of their maturity. They produced levels of granzyme A as high as in human peripheral blood-derived NK cells, and a considerable amount of perforin protein was detected in the plasma. Human NK cells in hu-HSC NOG-IL-2 Tg produced IFN-γ upon stimulation, and IL-2, IL-15, or IL-12 treatment augmented the in vitro cytotoxicity. Inoculation of K562 leukemia cells into hu-HSC NOG-IL-2 Tg caused complete rejection of the tumor cells, whereas inoculation into hu-HSC NOG fully reconstituted with human B, T, and some NK cells did not. Moreover, when a CCR4<sup>+</sup> Hodgkin's lymphoma cell line was inoculated s.c. into hu-HSC NOG-IL-2 Tg, the tumor growth was significantly suppressed by treatment with a therapeutic humanized anti-CCR4 Ab (mogamulizumab), suggesting that the human NK cells in the mice exerted active Ab-dependent cellular cytotoxicity in vivo. Taken together, these data suggest that the new NOG-IL-2 Tg strain is a unique model that can be used to investigate the biological and pathological functions of human NK cells in vivo.

Original languageEnglish
Pages (from-to)3513-3525
Number of pages13
JournalJournal of Immunology
Volume194
Issue number7
DOIs
Publication statusPublished - 2015 Apr 1

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Natural Killer Cells
Transgenic Mice
Interleukin-2
Hematopoietic Stem Cells
Natural Cytotoxicity Triggering Receptor 3
Granzymes
Interleukin-15
Perforin
K562 Cells
Interleukin-12
Hodgkin Disease
Fetal Blood
Neoplasms
Leukemia
Cell Line
Growth
Genes

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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Predominant development of mature and functional human NK cells in a novel human IL-2 - Producing transgenic NOG mouse. / Katano, Ikumi; Takahashi, Takeshi; Ito, Ryoji; Kamisako, Tsutomu; Mizusawa, Takuma; Ka, Yuyo; Ogura, Tomoyuki; Suemizu, Hiroshi; Kawakami, Yutaka; Ito, Mamoru.

In: Journal of Immunology, Vol. 194, No. 7, 01.04.2015, p. 3513-3525.

Research output: Contribution to journalArticle

Katano, I, Takahashi, T, Ito, R, Kamisako, T, Mizusawa, T, Ka, Y, Ogura, T, Suemizu, H, Kawakami, Y & Ito, M 2015, 'Predominant development of mature and functional human NK cells in a novel human IL-2 - Producing transgenic NOG mouse', Journal of Immunology, vol. 194, no. 7, pp. 3513-3525. https://doi.org/10.4049/jimmunol.1401323
Katano, Ikumi ; Takahashi, Takeshi ; Ito, Ryoji ; Kamisako, Tsutomu ; Mizusawa, Takuma ; Ka, Yuyo ; Ogura, Tomoyuki ; Suemizu, Hiroshi ; Kawakami, Yutaka ; Ito, Mamoru. / Predominant development of mature and functional human NK cells in a novel human IL-2 - Producing transgenic NOG mouse. In: Journal of Immunology. 2015 ; Vol. 194, No. 7. pp. 3513-3525.
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abstract = "We generated a severe immunodeficient NOD/Shi-scid-IL-2Rγnull (NOG) mouse substrain expressing the transgenic human IL-2 gene (NOG-IL-2 Tg). Upon transfer of human cord blood-derived hematopoietic stem cells (HSCs), CD3-CD56highCD16+/- cells developed unexpectedly, predominantly in the NOG-IL-2 Tg (hu-HSC NOG-IL-2 Tg). These cells expressed various NK receptors, including NKp30, NKp44, NKp46, NKG2D, and CD94, as well as a diverse set of killer cell Ig-like receptor molecules at levels comparable to normal human NK cells from the peripheral blood, which is evidence of their maturity. They produced levels of granzyme A as high as in human peripheral blood-derived NK cells, and a considerable amount of perforin protein was detected in the plasma. Human NK cells in hu-HSC NOG-IL-2 Tg produced IFN-γ upon stimulation, and IL-2, IL-15, or IL-12 treatment augmented the in vitro cytotoxicity. Inoculation of K562 leukemia cells into hu-HSC NOG-IL-2 Tg caused complete rejection of the tumor cells, whereas inoculation into hu-HSC NOG fully reconstituted with human B, T, and some NK cells did not. Moreover, when a CCR4+ Hodgkin's lymphoma cell line was inoculated s.c. into hu-HSC NOG-IL-2 Tg, the tumor growth was significantly suppressed by treatment with a therapeutic humanized anti-CCR4 Ab (mogamulizumab), suggesting that the human NK cells in the mice exerted active Ab-dependent cellular cytotoxicity in vivo. Taken together, these data suggest that the new NOG-IL-2 Tg strain is a unique model that can be used to investigate the biological and pathological functions of human NK cells in vivo.",
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AU - Katano, Ikumi

AU - Takahashi, Takeshi

AU - Ito, Ryoji

AU - Kamisako, Tsutomu

AU - Mizusawa, Takuma

AU - Ka, Yuyo

AU - Ogura, Tomoyuki

AU - Suemizu, Hiroshi

AU - Kawakami, Yutaka

AU - Ito, Mamoru

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AB - We generated a severe immunodeficient NOD/Shi-scid-IL-2Rγnull (NOG) mouse substrain expressing the transgenic human IL-2 gene (NOG-IL-2 Tg). Upon transfer of human cord blood-derived hematopoietic stem cells (HSCs), CD3-CD56highCD16+/- cells developed unexpectedly, predominantly in the NOG-IL-2 Tg (hu-HSC NOG-IL-2 Tg). These cells expressed various NK receptors, including NKp30, NKp44, NKp46, NKG2D, and CD94, as well as a diverse set of killer cell Ig-like receptor molecules at levels comparable to normal human NK cells from the peripheral blood, which is evidence of their maturity. They produced levels of granzyme A as high as in human peripheral blood-derived NK cells, and a considerable amount of perforin protein was detected in the plasma. Human NK cells in hu-HSC NOG-IL-2 Tg produced IFN-γ upon stimulation, and IL-2, IL-15, or IL-12 treatment augmented the in vitro cytotoxicity. Inoculation of K562 leukemia cells into hu-HSC NOG-IL-2 Tg caused complete rejection of the tumor cells, whereas inoculation into hu-HSC NOG fully reconstituted with human B, T, and some NK cells did not. Moreover, when a CCR4+ Hodgkin's lymphoma cell line was inoculated s.c. into hu-HSC NOG-IL-2 Tg, the tumor growth was significantly suppressed by treatment with a therapeutic humanized anti-CCR4 Ab (mogamulizumab), suggesting that the human NK cells in the mice exerted active Ab-dependent cellular cytotoxicity in vivo. Taken together, these data suggest that the new NOG-IL-2 Tg strain is a unique model that can be used to investigate the biological and pathological functions of human NK cells in vivo.

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