NKG-hIL15 Mice

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Catalog Number：C001513

Strain Name：NOD.Cg-PrkdcscidIl2rgem1Il15em1(hIL15)/Cya

Genetic Background：NKG


Strain Description

NKG mice are a type of severe immunodeficient mouse developed by Cyagen by deleting the Il2rg gene from the NOD-Scid strain. This strain lacks mature T, B, and NK cells, has reduced complement activity, and weak macrophage phagocytosis of human cells. As a result, NKG mice can efficiently engraft human hematopoietic stem cells (HSC), peripheral blood mononuclear cells (PBMC), patient-derived xenografts (PDX), or adult stem cells and tissues.

In the field of immunology research, there are differences between humans and mice in terms of physiology and immune systems, so research conducted directly on mice cannot fully reflect the human situation. By transplanting human peripheral blood mononuclear cells (PBMC) or human hematopoietic stem cells (HSC) into immunodeficient mice, the mouse’s immune system is partially or completely replaced by the human immune system, allowing for the simulation of human immune system function in vivo and providing an effective model for studying the human immune system. However, due to the lack of cytokine necessary for human NK cell development in mice, there are also differences between humans and mice in the relevant regulatory factors. When reconstructing the human immune system in severely immunodeficient mice, the proportion of reconstructed NK cells is relatively low, which is not conducive to drug development targeting NK cells.

Interleukin-15 (IL-15) is a cytokine that regulates the activation and proliferation of T cells and natural killer (NK) cells. It also plays a role in balancing the number of CD8+ memory cells alongside IL-2. Research indicates that IL-15 is essential for the differentiation, function, and survival of NK cells. Providing sufficient human IL-15 can help stabilize the function of human NK cells within a mouse model [1-2]. The NKG-hIL15 mice are constructed by knocking in the human IL15 gene from the NKG mice. Compared to NKG mice, NKG-hIL15 mice significantly enhance the reconstitution proportion of human NK cells after HSC or PBMC transplantation. These mice can be utilized for the development of immunotherapies targeting NK cells and drug evaluation.

 

The human IL15 gene has been knocked in the NKG mice by gene editing technology.

● Construction of the immune system humanized mouse models;

● NK cell development mechanism studies, NK cell-related tumor immunotherapy development, and antibody-dependent NK cell-mediated toxicity (ADCC) studies;

● Research on the human immune system, haematopoietic system;

● Human-derived cell line xenograft (CDX) and patient-derived xenograft (PDX).

1. Expression of the human IL15 protein

Figure 1. ELISA analysis of the human IL15 protein in the 5-week-old female homozygous NKG-hIL15 mice and NKG mice. Compared to NKG mice, NKG-hIL15 mice exhibit significant expression of the human IL15 protein.

 

2. NKG-hIL15 mice for huCD34+ HSC immune system reconstitution studies

a. Survival and growth curves

Figure 2. Survival status of 4-week-old female homozygous NKG-hIL15 mice after huCD34+ HSC transplantation. NKG-hIL15 mice, following myeloablation by irradiation, received a tail vein injection of 0.05M huCD34+ cells. The results demonstrate that NKG-hIL15 mice can maintain normal growth after transplantation, with a gradual increase in body weight. These mice maintain a survival rate of approximately 78% at 225 days post engraftment.

b. Proportion of human leukocytes reconstructed

Figure 3. Variation of the human CD45+ leukocytes in the peripheral blood of NKG-hIL15 mice after HSC transplantation. The results indicate that human leukocytes in the peripheral blood of NKG-hIL15 mice rapidly reconstitute by the 3rd-week post engraftment*.
*The actual efficacy of human immune system reconstitution may vary based on donors and experimental conditions.

c. Human T and B cell reconstitution

Figure 4. Reconstruction effects of human T cells and B cells in NKG-hIL15 mice after HSC transplantation. The results indicate that human T cells in NKG-hIL15 mice begin to reconstitute by the 11th week and gradually increase in proportion. By the 27th week, the proportion of human T cells remains around 25%. Human B cells, on the other hand, fluctuate and gradually stabilize after the 3rd week, reaching stability around the 17th week.

d. Reconstitution of human NK cells

Figure 5. Reconstruction effects of human NK cells in NKG-hIL15 mice after HSC transplantation. The results indicate that human NK cells rapidly reconstitute between the 3rd and 5th weeks, followed by a subsequent decline in proportion. From the 13th week onward, there is a fluctuating increase, gradually stabilizing by the 17th week. Even at the 27th week, approximately 20% of NK cells can be maintained. Additionally, during the reconstruction process, NKG-hIL15 mice harbor NK cells at different developmental stages*. Notably, successful reconstruction of mature NK cells (CD57+) has been achieved.
*NKG2D: expressed during early NK cell development and remains active in mature NK cells; KIR3DL: expressed during mid-to-late NK cell development; CD57: expressed during the final stage of NK cell maturation.

References

[1] Katano I, Nishime C, Ito R, Kamisako T, Mizusawa T, Ka Y, Ogura T, Suemizu H, Kawakami Y, Ito M, Takahashi T. Long-term maintenance of peripheral blood derived human NK cells in a novel human IL-15- transgenic NOG mouse. Sci Rep. 2017 Dec 8;7(1):17230.
[2] Huntington ND, Legrand N, Alves NL, Jaron B, Weijer K, Plet A, Corcuff E, Mortier E, Jacques Y, Spits H, Di Santo JP. IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J Exp Med. 2009 Jan 16;206(1):25-34.