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Development and function of human innate immune cells in a humanized mouse model
Open accessAbstract
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 cannot support development of human innate immune cells, including myeloid cells and natural killer (NK) cells. Here we describe two mouse strains called MITRG and MISTRG, in which human versions of four genes encoding cytokines important for innate immune cell development are knocked into their respective mouse loci. The human cytokines support the development and function of monocytes, macrophages and NK cells derived from human fetal liver or adult CD34(+) progenitor cells injected into the mice. Human macrophages infiltrated a human tumor xenograft in MITRG and MISTRG 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.
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“Species-specific differences between animals and humans cause differences in drug efficacy and toxicity tests in physiology and cell biology31–37.”
From Tumor-on-a-chip: from bioinspired design to biomedical application (2021) · cites this paper as [34]
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“MITRG mice allow for xenotransplantation and is designed to support human myeloid engraftment.”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Rongvaux et al., 2014
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“Similarly, mice reconstituted with a functional human immune system (humanized mice) can be used for studying the therapeutic effects of nanomedicines against autoimmune diseases such as diabetes, or to harbour patient-derived tumours for preclinical testing of cancer immune nanomedicines95.”
From How to design preclinical studies in nanomedicine and cell therapy to maximize the prospects of clinical translation (2018) · cites this paper as [95]
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Human CD4 T cells coordinate antitumor immunity through indirect antigen presentationPreprint
Roy, G., Ruterbusch, M., Bakhtiari, J., Shasha, C., Lee, S. M., Moshiri, A. S., Wood, C., Hopwo, K. S., Witkowski, M., Szeto, J. L., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.30.755788
Translational modelling of human microglia from cultures to chimeras
Lee, J., & Yoo, Y. (2026) · Experimental & Molecular Medicine · doi:10.1038/s12276-026-01866-1
“Although early models 29,57 such as MITRG mice expressed several human cytokines (hCSF1, IL-3, GM-CSF, SIRP α and TPO), more recent data have demonstrated that hCSF1 alone is suf fi cient to sustain robust microglial engraftment 29 .”
Zheng, X. (., Brehm, M. A., D'Abronzo, L. S., Yang, G., Wong, J. K., Parry, B. H., Yang, J., Keck, J., & Yao, L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1967450
Tumour assembloids recapitulate tumour–CAF–T cell crosstalk in renal cancer
Kim, E., 강민용, Han, J. H., Lee, J.-H., Kim, Y., Jeong, C. W., Lee, H., Kim, H. J., & Shin, K. (2026) · Nature · doi:10.1038/s41586-026-11208-w
Gomes, J. P. D. A. (2014) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/d.41.2014.tde-16012015-150237
Mouse Genetic Background and Human Hematopoietic Stem Cells Biology; Tips for Humanization
Kovtonyuk, L. V., & Takizawa, H. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1655-9_4
“[1 25 ]”
Method
Metadata
- Authors
- Rongvaux, A., Willinger, T., Martinek, J., Strowig, T., Gearty, S. V., Teichmann, L. L., Saito, Y., Marches, F., Halene, S., Palucka, A. K., Manz, M. G., & Flavell, R. A.
- Affiliations
- Yale University (US)
- University Hospital Bonn (DE)
- University Hospital Zurich (CH)
- Yale Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Manz, Markus G
- Flavell, Richard A
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2014-03-16
- Volume
- 32
- Issue
- 4
- Pages
- 364-372
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC4017589
- OpenAlex
- W2007987850
- Cited by
- 789
- References
- 50
- Citations by year
- 2026: 48 · 2025: 52 · 2024: 61 · 2023: 69 · 2022: 70 · 2021: 94 · 2020: 70 · 2019: 67 · 2018: 65 · 2017: 62 · 2016: 62 · 2015: 46 · 2014: 23
- FWCI
- 45.61
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-12-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA140602, CA84512, P01CA084512, R01CA129350, CA129350, R01CA156689, CA156689, CA140602)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Surgery › Xenotransplantation and immune response
- Keywords
- humanized mice, innate immune cells, myeloid cell development, natural killer cells, monocytes, macrophages, CD34+ cells, tumor xenografts
- MeSH terms
- Animals, Humans, Immunity, Innate, Killer Cells, Natural, Mice, Transgenic, Neoplasms, Experimental, Transplantation, Heterologous, Leukemic Infiltration, Myeloid Cells, Mice
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