Abstract
We generated a novel mouse strain expressing transgenic human interleukin-15 (IL-15) using the severe immunodeficient NOD/Shi-scid-IL-2Rγnull (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.
Highlights
Mounting evidence has demonstrated that severely immune-deficient mouse strains, including NOD/Shi-scid-IL2Rγnull (NOG)[1] and NOD/LtSz-scid-IL-2Rγnull (NSG)[2] mice, allow for long-term engraftment of various xenogeneic tissues
Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that most mouse tissues contained the transgene-derived transcription (Fig. 1b), suggesting that human IL-15 was produced in a constitutive manner in NOG-IL-15 Tg mice
The abundant human IL-15 in NOG-IL-15 Tg plasma prompted us to examine whether human natural killer (NK) cells from normal healthy donors could be maintained upon transplantation
Summary
Mounting evidence has demonstrated that severely immune-deficient mouse strains, including NOD/Shi-scid-IL2Rγnull (NOG)[1] and NOD/LtSz-scid-IL-2Rγnull (NSG)[2] mice, allow for long-term engraftment of various xenogeneic tissues. These include human cancer cells[3,4], multiple human blood cell lineages[5,6], and some tissues differentiated from human ES/iPS cells[7,8,9]. In vitro-expanded highly pure NK cells, which were prepared for clinical cell therapy, were successfully maintained in NOG-IL-15 Tg mice, but not in NOG-non-Tg mice These cells suppressed tumor growth in the presence of a therapeutic antibody. Our results suggest that NOG-IL-15 Tg mice provide unique opportunities to study and exploit the function of hu-PB-NK cells
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