title: Predominant development of mature and functional human NK cells in a novel human IL-2-producing transgenic NOG mouse.
abstract: We generated a severe immunodeficient NOD/Shi-scid-IL-2Rγ(null) (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(-)CD56(high)CD16(+/-) 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.
authors.affiliation: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan; and Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Katano
authors.affiliation: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan; and takeshi-takahashi@ciea.or.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan; and.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Ito
authors.affiliation: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan; and.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kamisako
authors.affiliation: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan; and.
authors.forename: Takuma
authors.initials: T
authors.lastname: Mizusawa
authors.affiliation: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan; and.
authors.forename: Yuyo
authors.initials: Y
authors.lastname: Ka
authors.affiliation: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan; and.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ogura
authors.affiliation: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan; and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suemizu
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawakami
authors.affiliation: Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan; and.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ito
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D000954:Antigens, Surface / Q000378:metabolism; D002454:Cell Differentiation; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D054340:Receptors, KIR / Q000235:genetics / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D007376:Interleukin-2; D054340:Receptors, KIR