Human Interleukin 15 (IL15) Humanized NCG Mice Support the Human Natural Killer Cells Reconstitution and Development

Abstract

NCG (GPT strain ID: T001475), one of the highly immune-deficient mouse models generated so far, is ideal for engraftment of human tissues and cells, such as patient derived tumors (PDX), human cancer cell lines (CDX), human peripheral blood mononuclear cells (PBMC) and human hematopoietic stem cells (HSCs). NK cells that are a critical component of the innate immune system have diverse biological functions, such as recognizing and killing viral-infected and neoplastic cells. Human HSCs (CD34+) could reconstitute human T but not NK cells in NCG mice. The cytokine Interleukin 15 (IL-15) plays a critical role in the generation of NK cells from HSCs. IL-15 is produced by non-lymphoid cells, including monocytes, dendritic and bone marrow stromal cells. Human and mouse IL-15 are only 70% identical to each other in primary amino acid sequence. Mouse IL-15 poorly supports the reconstitution of human NK cells. To overcome this problem, several lines of transgenic mice that express human IL-15 (hIL-15) have been established. However, the non-physiological levels of hIL-15 expression are detrimental to human immune system reconstitution.In the current study, we developed hIL-15 knock-in in NCG mice (NCG-hIL-15), in which the mouse IL-15 (mIL-15) gene was replaced by the hIL-15 gene. We quantified the mRNA expression of hIL-15 and found that the levels of hIL-15 expression in the BM, liver, lung, and small intestine of NCG-hIL-15 mice were similar to those of mIL-15 in NCG mice.Based on these data, we expect that NCG-hIL-15 mice can efficiently support the development, maturation and function of human NK cells. In the future, we will further study human NK cell engraftment and human NK cell-mediated cancer immunotherapy in NCG-hIL-15 mice. Taken together, our newly developed NCG-hIL-15 mice offer a novel mouse model for studying human NK cell biology and human NK-mediated cancer immunotherapy in vivo. Disclosures Ju: GemPharmatech Co., Ltd: Employment. Zhang:GemPharmatech Co., Ltd: Employment. Wu:GemPharmatech Co., Ltd: Employment. Tang:GemPharmatech Co., Ltd: Employment. Li:GemPharmatech Co., Ltd: Employment. Zhao:GemPharmatech Co., Ltd: Employment. Wang:GemPharmatech Co., Ltd: Employment. Gao:GemPharmatech Co., Ltd: Employment.

The role of interleukin-15 in the development and treatment of hematological malignancies

“…Various IL-15 transgenic mouse models that carry cloned IL-15 under a variety of different foreign promoters have been instrumental in understanding the role of IL-15 in immunity and blood cancers. Depending on the promoters, genetic background and expression levels, IL-15 mice show either altered immunity or development of aggressive T-/NK-cell leukemia, and cutaneous T-cell lymphoma (13,(28)(29)(30)(31)(32). Conversely, IL-15 deficiency has been linked to leukemia development in an immunodeficient mouse model, suggesting a protective role of IL-15 against leukemia (31).…”