Development and function of human innate immune cells in a humanized mouse model

Abstract

Mice repopulated with human hematopoietic cells are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, existing humanized mouse models are unable to support development of human innate immune cells, including myeloid cells and NK cells. Here we describe a mouse strain, called MI(S)TRG, in which human versions of four genes encoding cytokines important for innate immune cell development are knocked in to their respective mouse loci. The human cytokines support the development and function of monocytes/macrophages and natural killer cells derived from human fetal liver or adult CD34+ progenitor cells injected into the mice. Human macrophages infiltrated a human tumor xenograft in MI(S)TRG mice in a manner resembling that observed in tumors obtained from human patients. This humanized mouse model may be used to model the human immune system in scenarios of health and pathology, and may enable evaluation of therapeutic candidates in an in vivo setting relevant to human physiology.

Consensus guidelines for the detection of immunogenic cell death

“…However, the interaction between human immune cells and the murine microenvironment may be negatively influenced by inter-species molecular variations that compromise the ability of the former to mount an appropriate immune response. 279,280 Thus, although attempts are being made to limit such variations, 281 experimental models that allow for the proper evaluation of ICD in the human system require further improvements. Finally, the procedure outlined above for the identification of novel ICD inducers assesses the biochemical processes that are required for the immunogenicity of anthracycline-induced cell death.…”

Chimeric Antigen Receptor T Cells for the Treatment of Cancer and the Future of Preclinical Models for Predicting their Toxicities

“…All of those modifications improved the development of individual cell populations like human NK cells [63], human alveolar macrophages [65] or human monocytes [66] but did not result in a complete reconstitution of a human innate immune system. An attempt to express a range of human cytokine genes in order to enable complete innate immune cell development led to the generation of MITRG mice [67]. These mice harbor a knock-in of human M-CSF, IL-3/GM-CSF and human thrombopoietin (TPO) in their respective gene loci.…”

“…Humanized MITRG mice develop functional myeloid cells, monocytes and NK cells. However, these mice allow human HSC engraftment to a great extent, which in turn leads to massive deficits in mouse red blood cells resulting in severe anemia and the death of the animals [67]. This just leaves a very short experimental window of approximately 2 to 3 weeks, which makes this model not ideal.…”

Viral infections in mice with reconstituted human immune system components

“…Indeed transgenic or congenic expression of either the human or the NOD SIRP [10,11], or mouse CD47 gene transfer into reconstituting human hematopoietic cells GM-CSF and TPO [13]. These MISTRG mice developed myeloid and NK cells more efficiently than NSG mice, but still a significant variation in human immune system component reconstitution could be observed.…”

“…Furthermore, the mouse models differed significantly in their gene expression among each other and were not predictive for the human responses. From these GM-CSF and TPO [13]. These MISTRG mice developed myeloid and NK cells more efficiently than NSG mice, but still a significant variation in human immune system component reconstitution could be observed.…”