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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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“The reason for these differences needs to be further explored but might be in part attributable to extramedullary mouse hematopoiesis and/or differences in migration potential of human cells.(11) Irrespective of this observation and more importantly, adult recipient MISTRG mice transplanted with mobilized PB CD34 cell…”
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“Animal experimentation, reconstitution, in vivo imaging, and tissue processing and staining M-CSFh;IL-3/GM-CSFh;hSIRPAtg;TPOh;Rag2 ;cc (MISTRG; Rongvaux et al, 2014) and MISTRG mice additionally expressing IL-6h (MISTRG6; Das et al, 2016) were obtained from a local repository.”
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“Newer murine multiple myeloma (MM) models that recapitulate human disease have been developed to some extent, but their ability to predict clinical responses remains limited.(2-5) The limitations of the murine tumor xenografts model include the need for human fetal bone fragments to support tumor growth, low efficienc…”
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“immunodeficient mouse developed on the Rag2IL2Rγ background, termed MISTRG, which expresses the human cytokines M-CSF, IL-3, thrombopoietin, GM-CSF as well as SIRP1α, from the respective murine loci(19) and is known to support improved (orthotopic) growth of various myeloid neoplasias and solid tumors.(20,14,21) MISTR…”
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“he inability 4 to isolate the impact of specific microenvironmental conditions on transport and tissue response (Engelman & Kerr, 2012, Hintze et al., 2014, Kang & Kim, 2016, J. B. Kim, 2005, Rongvaux et al., 2014, Seok et al., 2013). Furthermore, animals and humans have different physiology, and recent studie…”
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Patient-derived xenotransplants can recapitulate the genetic driver landscape of acute leukemias
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Preclinical Evaluation of CAR T Cell Function: In Vitro and In Vivo Models
Si, X., Xiao, L., Brown, C. E., & Wang, D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063154 · Cited by 70
Hanazawa, A., Ito, R., Katano, I., Kawai, K., Goto, M., Suemizu, H., Kawakami, Y., Ito, M., & Takahashi, T. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00152 · Cited by 66
“For example, ~3-fold high number of CD33+ total myeloid cells developed in NOG-hGM/3 Tg compared to NOG mice (13), ~3-fold increase of CD33+ cells in frequency in NSGSGM3 (15), and ~10-fold CD33+ cells in MITRG compared to NSG mice (16).”
BackgroundMethodInfluentialUBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO
Goyama, S., Schibler, J., Gasilina, A., Shrestha, M., Lin, S., Link, K. A., Chen, J., Whitman, S. P., Bloomfield, C. D., Nicolet, D., et al. (2015) · Leukemia · doi:10.1038/leu.2015.275 · Cited by 64
PTPN22 inhibition resets defective human central B cell tolerance
Schickel, J., Kuhny, M., Baldo, A., Bannock, J. M., Massad, C., Wang, H., Katz, N., Oe, T., Menard, L. C., Soulas-Sprauel, P., et al. (2016) · Science Immunology · doi:10.1126/sciimmunol.aaf7153 · Cited by 65
Audigé, A., Rochat, M.-A., Li, D., Ivic, S., Fahrny, A., Muller, C. K. S., Gers-Huber, G., Myburgh, R., Bredl, S., Schlaepfer, E., et al. (2017) · BMC Immunology · doi:10.1186/s12865-017-0209-9 · Cited by 64
“MISTRG, in which the percentage of these cells closely resembles that in humans [20].”
Epiregulin is a dendritic cell–derived EGFR ligand that maintains skin and lung fibrosis
Odell, I. D., Steach, H. R., Gauld, S. B., Reinke-Breen, L., Kármán, J., Carr, T. L., Wetter, J. B., Phillips, L. A., Hinchcliff, M., & Flavell, R. A. (2022) · Science Immunology · doi:10.1126/sciimmunol.abq6691 · Cited by 72
Mian, S. A., Anjos‐Afonso, F., & Bonnet, D. A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.619236 · Cited by 62
“(CSF2,IL3)Flv Thpo Il2rg/J) (41) -similar to BRG”
BackgroundResultInfluentialPlatelets and SARS-CoV-2 During COVID-19: Immunity, Thrombosis, and Beyond
Sciaudone, A. R., Corkrey, H. A., Humphries, F., & Koupenova, M. (2023) · Circulation Research · doi:10.1161/circresaha.122.321930 · Cited by 68
Humanized Mice as a Model for Aberrant Responses in Human T Cell Immunotherapy
Vudattu, N. K., Waldron-Lynch, F., Truman, L. A., Deng, S., Preston‐Hurlburt, P., Torres, R., Raycroft, M. T., Mamula, M. J., & Herold, K. C. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302455 · Cited by 65
“been their failure to reconstitute human innate immune cells (55).”
BackgroundEnhanced development of functional human NK cells in NOD‐ scid‐IL2rg null mice expressing human IL15
Aryee, K., Burzenski, L. M., Yao, L., Keck, J., Greiner, D. L., Shultz, L. D., & Brehm, M. A. (2022) · The FASEB Journal · doi:10.1096/fj.202200045r · Cited by 63
Hepatitis C virus: Is it time to say goodbye yet? Perspectives and challenges for the next decade
Barth, H. (2015) · World Journal of Hepatology · doi:10.4254/wjh.v7.i5.725 · Cited by 60
Humanized Mice Exhibit Increased Susceptibility to Staphylococcus aureus Pneumonia
Prince, A. S., Wang, H., Kitur, K., & Parker, D. (2016) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiw425 · Cited by 60
Experimental animal modeling for immuno-oncology
Li, Q., Feuer, G., Ouyang, X., & An, X. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.002 · Cited by 63
A Hitchhiker's guide to humanized mice: new pathways to studying viral infections
Skelton, J. K., Ortega‐Prieto, A. M., & Dorner, M. (2018) · Immunology · doi:10.1111/imm.12906 · Cited by 60
Microglia promote anti-tumour immunity and suppress breast cancer brain metastasis
Evans, K. T., Blake, K., Longworth, A. J., Coburn, M., Insua‐Rodríguez, J., McMullen, T. P., Nguyen, Q., Ma, D., Lev, T., Hernandez, G. A., et al. (2023) · Nature Cell Biology · doi:10.1038/s41556-023-01273-y · Cited by 64
“…BCBM based on prior work, where MITRG mice (human CSF1 , IL3 and TPO knock-in to Rag2 −/− Il2rγ −/− mice) are reconstituted with human microglia and macrophages following transplantation of human induced pluripotency-derived haematopoietic progenitor cells (iHPSCs) into the postnatal brain 47–49 .”
MethodPatient-derived xenografts as compatible models for precision oncology
Cho, S. (2020) · Laboratory Animal Research · doi:10.1186/s42826-020-00045-1 · Cited by 58
Patient‐derived xenografts as tools in pharmaceutical development
Izumchenko, E., Meir, J., Bedi, A., Wysocki, P., Hoque, M. O., & Sidransky, D. (2016) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.354 · Cited by 59
“system by genetically replacing mouse genes with the human counterpart.(37,38) For example, a mouse with a knock-in of the human CTLA4 gene was used to evaluate the autoimmune side effects and cancer immunity of antihuman CTLA-4 antibodies.”
MethodITPRIPL1 binds CD3ε to impede T cell activation and enable tumor immune evasion
Deng, S., Zhang, Y., Wang, H., Liang, W., Xie, L., Li, N., Fang, Y., Wang, Y., Liu, J., Chi, H., et al. (2024) · Cell · doi:10.1016/j.cell.2024.03.019 · Cited by 59
The challenges of modeling hormone receptor-positive breast cancer in mice
Özdemir, B. C., Sflomos, G., & Brisken, C. (2018) · Endocrine Related Cancer · doi:10.1530/erc-18-0063 · Cited by 57
GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models
Hess, N. J., Brown, M. E., & Capitini, C. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.723544 · Cited by 59
Dai, S., Chen, Y., Cai, W., Dong, S., Zhao, J., Chen, L., & Cheng, C. (2025) · Journal of Hematology & Oncology · doi:10.1186/s13045-025-01739-6 · Cited by 65
“A major thrust is cytokine-humanized strains, which are mice engineered to express human cytokines essential for myeloid and NK cell development, such as the MI(S) TRG model [119].”
Dendritic Cell-Based Vaccination in Cancer: Therapeutic Implications Emerging from Murine Models
Keon, S. M., Ruiz, M. S., Gazzaniga, S., & Wainstok, R. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00243 · Cited by 57
“expressing human cytokines (34)or protocols administering such”
Yoshihara, S., Li, Y., Xia, J., Danzl, N. M., Sykes, M., & Yang, Y. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00186 · Cited by 56
Arnold, I. C., Zhang, X., Urban, S. K., Borán, M. S., Manz, M. G., Ottemann, K. M., & Mueller, A. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.12.015 · Cited by 53
“MISTRG mice are superior to NSG mice in terms of their myeloid cell engraftment in bone marrow and spleen and the full recapitulation of human myeloid development and function (Rongvaux et al., 2014).”
BackgroundFoquet, L., Schäfer, C., Minkah, N. K., Alanine, D. G. W., Flannery, E. L., Steel, R. W. J., Sack, B. K., Camargo, N. M., Fishbaugher, M. E., Betz, W., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00524 · Cited by 55
Humanized Mouse Models of Staphylococcus aureus Infection
Parker, D. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00512 · Cited by 52
“Further studies have shown that the integration of thrombopoietin enhances maintenance and multilineage differentiation and insertion of signal-regulatory protein alpha prevents phagocytosis of the human cells by the remnant murine immune system (90, 91).”
BackgroundTong, B., & Wang, M. (2018) · Future Oncology · doi:10.2217/fon-2018-0035 · Cited by 56
Humanized Mouse Models to Evaluate Cancer Immunotherapeutics
Guil‐Luna, S., Sedlik, C., & Piaggio, E. (2021) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-050520-100526 · Cited by 57
CD116+ fetal precursors migrate to the perinatal lung and give rise to human alveolar macrophages
Evren, E., Ringqvist, E. E., Doisne, J., Thaller, A., Sleiers, N., Flavell, R. A., Santo, J. P. D., & Willinger, T. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20210987 · Cited by 60
Tumour neoantigen mimicry by microbial species in cancer immunotherapy
Boesch, M., Baty, F., Rothschild, S. I., Tamm, M., Joerger, M., Früh, M., & Brutsche, M. H. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01365-2 · Cited by 53
Potential Applications and Perspectives of Humanized Mouse Models
Ye, W., & Chen, Q. (2021) · Annual Review of Animal Biosciences · doi:10.1146/annurev-animal-020420-033029 · Cited by 59
A Humanized Mouse Model Generated Using Surplus Neonatal Tissue
Brown, M. E., Zhou, Y., McIntosh, B. E., Norman, I. G., Lou, H. E., Biermann, M., Sullivan, J. A., Kamp, T. J., Thomson, J. A., Anagnostopoulos, P. V., et al. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.02.011 · Cited by 55
“These include mice modified to produce human cytokines (Rongvaux et al., 2014; Saito et al., 2016), that express specific human major histocompatibility complex (MHC) types (Shultz et al., 2010) and that do not require irradiation for xenoengraftment (McIntosh et al., 2015).”
BackgroundNanomaterials for modulating innate immune cells in cancer immunotherapy
Le, Q., Yang, G., Wu, Y., Jang, H. W., Shokouhimehr, M., & Oh, Y. (2018) · Asian Journal of Pharmaceutical Sciences · doi:10.1016/j.ajps.2018.07.003 · Cited by 53
Griessinger, C. M., Olafsen, T., Mascioni, A., Jiang, Z. K., Zamilpa, C., Jia, F., Torgov, M. Y., Romero, J. M., Marchioni, F., Satpayev, D., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-3269 · Cited by 53
Fit-For-All iPSC-Derived Cell Therapies and Their Evaluation in Humanized Mice With NK Cell Immunity
Flahou, C., Morishima, T., Takizawa, H., & Sugimoto, N. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.662360 · Cited by 55
“In this regard, we recently showed that HIS MSTRG mice treated with IL-15/IL-15Ra to enhance human NK cell reconstitution significantly rejected HLA class-I knockout iPSC-derived hematopoietic progenitor cells (70).”
BackgroundMethodInfluentialFujiwara, S., & Nakamura, H. (2020) · Pathogens · doi:10.3390/pathogens9020116 · Cited by 52
“Knock‐in insertion of human genes encoding macrophage colony‐stimulating factor (M‐CSF), IL‐3, granulocyte macrophage colony‐stimulating factor (GM‐ CSF), and thrombopoietin to BRG mice enhanced the development of human myeloid and monocyte/macrophage lineages and improved innate immune responses to viral and bacteria…”
BackgroundTurjeman, S., Rozera, T., Elinav, E., Ianiro, G., & Koren, O. (2025) · Cell · doi:10.1016/j.cell.2025.01.038 · Cited by 58
A functional DC cross talk promotes human ILC homeostasis in humanized mice
Lopez‐Lastra, S., Masse‐Ranson, G., Fiquet, O., Darche, S., Serafini, N., Li, Y., Dusséaux, M., Strick‐Marchand, H., & Santo, J. P. D. (2017) · Blood Advances · doi:10.1182/bloodadvances.2017004358 · Cited by 54
Phagocytes, Antibiotics, and Self-Limiting Bacterial Infections
Levin, B. R., Baquero, F., Ankomah, P., & McCall, I. C. (2017) · Trends in Microbiology · doi:10.1016/j.tim.2017.07.005 · Cited by 51
“Hypotheses Are for Testing, Not Championing, and Certainly Not Implementing Most importantly, the hypotheses derived from the analysis of the properties of these models can be tested (and rejected) with experimental infections in laboratory animals, in particular knockout mice with different inherited defects in the e…”
BackgroundWalter, J. M., Ren, Z., Yacoub, T. J., Reyfman, P. A., Shah, R. D., Abdala‐Valencia, H., Nam, K.-W., Morgan, V. K., Anekalla, K. R., Joshi, N., et al. (2018) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201804-0650oc · Cited by 51
“MISTRG mice (Jax 017712) were reconstituted with CD341 stem cells isolated from human cord blood obtained from a commercial vendor (StemCell Technologies) (23).”
MethodSelective expansion of myeloid and NK cells in humanized mice yields human-like vaccine responses
Douam, F., Ziegler, C. G. K., Hrebikova, G., Fant, B., Leach, R. W., Parsons, L. R., Wang, W., Gaska, J. M., Winer, B. Y., Heller, B. L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07478-2 · Cited by 51
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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