NCG-M humanized mice - an excellent model for human immune reconstitution of myeloid lineages

Abstract

Abstract Severely immunodeficient mice engrafted with human hematopoietic stem cells (HSC) have been extensively used in immuno-oncology studies to evaluate the efficacy of cancer therapies. However, because of species differences in the immune system between human and mouse, murine cytokines provide limited support to human immune cells, thus human immune system mice have limited human immune cell engraftment. Increasing evidence has shown that myeloid cells, especially macrophages and dendritic cells, are critical for the induction of anti-tumor immunity. We developed a mouse model, NCG-M, that can support human T, B, NK, and various myeloid and granulocyte cells such that in vivo evaluation of agents that require the interplay between these immune cells can be examined. This model was genetically engineered on the severely immunodeficient strain NCG and can produce human granulocyte/macrophage colony-stimulating factor 2 (GM-CSF, also known as CSF2), interleukin-3 (IL-3) and stem cell factor (SCF, also known as KITLG). Upon human CD34+ HSC cell engraftment, a significant increase in myeloid lineage cells, such as granulocytes, monocytes, neutrophils, macrophages, dendritic cells, and mast cells, was observed in the NCG-M cohort compared to NCG mice. The NCG-M mouse also supports the development of human T cells, and preliminary data showed increased B cells and NK cells. Importantly, the increased efficiency of immune cell reconstitution did not affect the morbitity and mortality of this mouse. The NCG-M is an appropriate mouse model for studying the efficacy of therapeutic agents that require human T cells and myeloid cells.