NCG-hIL15 humanized mice - an ideal model for human immune reconstitution of NK cells

Abstract

Immunodeficient NCG mice were unable to reconsituted human NK cells, but after knockin of human IL-15 (hIL-15), the NCG-hIL15 mice could assist the reconstitution of human NK cells. Compared with NCG, the level of hIL-15 was significantly increased in heterozygous and homozygous NCG-hIL15 mice. After transplanting human PBMC (huPBMC-NCG-hIL15) or NK cells into NCG-hIL15 (huNK-NCG-IL15), the level of peripheral blood hCD56+ NK cells in huNK-NCG-hIL15 mice were much higher than that in huPBMC-NCG-hIL15 mice. However, the reconstituted proportion of human CD3+ T cells in huNK-NCG-hIL15 mice was not comparable in huPBMC-NCG-hIL15 mice. The level of NK cell reconstitution is also highly dependent on the donor NK cells. The expression of perforin in the peripheral blood of huNK-NCG-hIL15 mice was significantly higher than that in huPBMC-NCG-hIL15 mice. In vitro functional analysis of NK cells from huPBNK-NCG-hIL15 and huPBMC-NCG-hIL15 showed Granzyme B expression in peripheral blood were comparable and human NK cells purified from splenocytes of huPBNK-NCG-hIL15 mice were cytotoxic upon coculture with Raji cells in the presence of Rituximab. Based on these in vitro data, we established huNK-NCG-hIL15 mice subcutaneously engrafted with Raji cells, and the in vivo efficacy of rituximab was evaluated. Efficacy study data showed that rituximab significantly inhibited the Raji tumor cells growth in huNK-NCG-hIL15 mice. Both huPBMC-NCG-hIL15 and huNK-NCG-hIL15 mouse model can rapidly reconstitute functional human NK cells compared to CD34+ HSC engrafted NCG-hIL15 mice. The development of huNK-NCG-hIL15 is an ideal mouse model to specifically evaluate the anti-tumor efficacy of drugs targeting human NK cells.