4.7 Article

Long-term maintenance of peripheral blood derived human NK cells in a novel human IL-15-transgenic NOG mouse

Journal

SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-17442-7

Keywords

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Funding

  1. Ministry of Education, Culture, Sports, Science, and Technology, Japan [2222007]
  2. Japanese Society for the Promotion of Science (JSPS) [26290034, 25871074, 16K18405]
  3. New Energy and Industrial Technology Development Organization (NEDO) [0527001]
  4. Japan Agency for Medical Research and Development
  5. Grants-in-Aid for Scientific Research [26290034, 26221005, 16K07103, 25871074, 16K18405] Funding Source: KAKEN

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We generated a novel mouse strain expressing transgenic human interleukin-15 (IL-15) using the severe immunodeficient NOD/Shi-scid-IL-2R.null (NOG) mouse genetic background (NOG-IL-15 Tg). Human natural killer (NK) cells, purified from the peripheral blood (hu-PB-NK) of normal healthy donors, proliferated when transferred into NOG-IL-15 Tg mice. In addition, the cell number increased, and the hu-PB-NK cells persisted for 3 months without signs of xenogeneic graft versus host diseases (xGVHD). These in vivo-expanded hu-PB-NK cells maintained the original expression patterns of various surface antigens, including NK receptors and killer cell immunoglobulin-like receptor (KIR) molecules. They also contained significant amounts of granzyme A and perforin. Inoculation of K562 leukemia cells into hu-PB-NK-transplanted NOG-IL-15 Tg mice resulted in significant suppression of tumor growth compared with non-transplanted mice. Furthermore, NOG-IL-15 Tg mice allowed for engraftment of in vitro-expanded NK cells prepared for clinical cell therapy. These cells exerted antibody-dependent cell-mediated cytotoxicity (ADCC) on Her2-positive gastric cancer cells in the presence of therapeutic anti-Her2 antibody, and subsequently suppressed tumor growth. Our results collectively suggest that the NOG-IL-15 Tg mice are a useful model for studying human NK biology and evaluating human NK cell-mediated in vivo cytotoxicity.

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