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1226 NCG-hIL15 humanized mice – an excellent model for human immune reconstitution of NK cells
  1. Xing Liu,
  2. Meirong Wu,
  3. Huiyi Wang,
  4. Weiwei Yu,
  5. Hongyan Sun,
  6. Cunxiang Ju,
  7. Hongyu Wang,
  8. Zhiying Li,
  9. Mark Moore,
  10. Jing Zhou,
  11. Xiang Gao and
  12. Santi Suryani Chen
  1. GePharmatech, Nanjing, China


Background IL-15 is a four α-helix bundle cytokine produced by dendritic cells, monocytes, and epithelial cells. IL-15 is necessary for the development, survival, and activation of natural killer (NK) cells.

Methods Human IL-15 (hIL-15) was knocked into NCG mice to create a model (NCG-hIL15) that can assist the reconstitution of human NK cells.

Results Compared with NCG, hIL-15 expression was significantly increased in NCG-hIL15het and NCG-hIL15homo. The development and function of human NK cells were evaluated in the NCG-hIL15 mouse reconstituted with three different types of human cell sources: (1) purified NK from human PBMC, (2) human PBMC, and (3) human CD34+ hematopoietic stem cells (HSC). In PBMC and CD34+ HSC-reconstituted mice, NK cell development was evident, with approximately 20% of hCD45+hCD56+ NK cells detected in the peripheral blood within weeks of engraftment. The level of hCD45+hCD3+ T cells reached 10 to 30% within 12 weeks of HSC reconstitution, while it reached greater than 80% within 2 weeks of PBMC reconstitution. In the purified NK engrafted cohort, the hCD45+hCD56+ NK cell numbers increased by at least two-fold within the first 3 weeks. Human NK cells were detected in multiple tissues and organs of all reconstituted NCG-hIL15 mice regardless of source of engraftment, except the colon, in the hPBMC-reconstituted NCG-IL15 mice. It was also noted that the level of NK cells post-engraftment varied depending on the donor of the PBMC.

To determine whether the reconstituted NK cells remain functional, purified NK cells from CD34+ HSC engrafted NCG-IL15 were isolated. Data showed that the NK cells could exert cell cytotoxicity when tested in vitro with leukemia cells, Raji, and Rituximab. Similarly, in vivo tumor growth inhibition (TGI= 49%) was observed with Raji.

Conclusions Overall, the addition of human IL-15, via genetic engineering in immunodeficient NCG mice provides excellent support for NK cell development. The NCG-hIL15 is a valuable tool for NK cell research and preclinical agent evaluation that requires NK and T cell activity.

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