Humanized mice: novel model for studying mechanisms of human immune-based therapies

Abstract

The lack of relevant animal models is the major bottleneck for understanding human immunology and immunopathology. In the last few years, a novel model of humanized mouse has been successfully employed to investigate some of the most critical questions in human immunology. We have set up and tested in our laboratory the latest technology for generating mice with a human immune system by reconstituting newborn immunodeficient NOD/SCID-γc-/- mice with human fetal liver-derived hematopoietic stem cells. These humanized mice have been deemed most competent as human models in a thorough comparative study with other humanized mouse technologies. Lymphocytes in these mice are of human origin while other hematopoietic cells are chimeric, partly of mouse and partly of human origin. We demonstrate that human CD8 T lymphocytes in humanized mice are fully responsive to our novel cell-based secreted heat shock protein gp96HIV-Ig vaccine. We also show that the gp96HIV-Ig vaccine induces powerful mucosal immune responses in the rectum and the vagina, which are thought to be required for protection from HIV infection. We posit the hypothesis that vaccine approaches tested in humanized mouse models can generate data rapidly, economically and with great flexibility (genetic manipulations are possible), to be subsequently tested in larger nonhuman primate models and humans.

CD38 as a PET Imaging Target in Lung Cancer

“…9,16 Additionally, T-cell expression of CD38 has been shown to be important in a number of diseases, 41–43 such that imaging of this target in humanized mice 44 may provide insight into the behavior of T-cells and their homing to tumors.…”

Combination of immunogenic oncolytic adenovirus ONCOS-102 with anti-PD-1 pembrolizumab exhibits synergistic antitumor effect in humanized A2058 melanoma huNOG mouse model

“…After tumors were harvested and weighed, tumor infiltrating lymphocytes were characterized by cell surface staining with the T-cell markers, human CD3, 27 CD4 and CD8. 28 Although no difference was observed in percentage of human CD45+ cells in the left tumor, the percentage of hCD45+ was higher in the ONCOS-102 + Pembrolizumab 200 µg group relative to the vehicle-treated group (P > 0.05) ( Figure 6A). Percentage of hCD3 + T cells was higher in ONCOS-102-treated groups in left and right flanks relative to the vehicle-treated group (Figure 6B).…”

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

“…82 Canine models and veterinary clinical trials may meet some of these needs. Rodent models of disease that faithfully mimic the human immune microenvironment do not currently exist, although efforts to develop humanized immune competent mice are ongoing.…”

“…Rodent models of disease that faithfully mimic the human immune microenvironment do not currently exist, although efforts to develop humanized immune competent mice are ongoing. 82 Canine models and veterinary clinical trials may meet some of these needs. Efforts have been underway within the COG to develop clinical trials of immune checkpoint inhibitors in combination with chemoradiotherapy based on intriguing preliminary evidence suggesting that radiation might immunosensitize these tumors.…”