Journal
IMMUNOLOGY LETTERS
Volume 229, Issue -, Pages 55-61Publisher
ELSEVIER
DOI: 10.1016/j.imlet.2020.11.011
Keywords
Humanized mice; NOG mice; PBMC; GVHD; MHC
Categories
Funding
- KAKENHI Specially Designated Research Promotion [25430099]
- Japan Society for the Promotion of Science (JSPS)
- Grants-in-Aid for Scientific Research [25430099] Funding Source: KAKEN
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A novel mouse model named dKO-em was established using CRISPR/Cas9 technology, showing improved support for human PBMC engraftment and prolonged survival. This model may serve as a promising platform for the development and preclinical testing of novel therapeutics for human diseases.
Humanized mice are widely used to study the human immune system in vivo and develop therapies for various human diseases. Human peripheral blood mononuclear cells (PBMC)-engrafted NOD/Shi-scid IL2r gamma(null) (NOG) mice are useful models for characterization of human T cells. However, the development of graft-versus-host disease (GVHD) limits the use of NOG PBMC models. We previously established a NOG-major histocompatibility complex class I/II double knockout (dKO) mouse model. Although humanized dKO mice do not develop severe GVHD, they have impaired reproductive performance and reduced chimerism of human cells. In this study, we established a novel beta-2 microglobulin (B2m) KO mouse model using CRISPR/Cas9. By crossing B2m KO mice with I-Ab KO mice, we established a modified dKO (dKO-em) mouse model. Reproductivity was slightly improved in dKO-em mice, compared with conventional dKO (dKO-tm) mice. dKO-em mice showed no signs of GVHD after the transfer of human PBMCs; they also exhibited high engraftment efficiency. Engrafted human PBMCs survived significantly longer in the peripheral blood and spleens of dKO-em mice, compared with dKO-tm mice. In conclusion, dKO-em mice might constitute a promising PBMC-based humanized mouse model for the development and preclinical testing of novel therapeutics for human diseases.
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