Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung

Willinger, Tim; Rongvaux, Anthony; Takizawa, Hajime; Yancopouloš, George D.; Valenzuela, David M.; Murphy, Andrew J.; Auerbach, Wojtek; Eynon, Elizabeth E.; Stevens, Sean; Manz, Markus G.; Flavell, Richard A.

doi:10.1073/pnas.1019682108

Cited by 209 publications

(200 citation statements)

References 34 publications

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“…Similarly, knockin of human M-CSF gene into the corresponding mouse locus in the recipient mice resulted in a significant increase in the circulating human monocytes, although the increase in tissue macrophages was much less (17). In GM-CSF/IL-3 knockin mice, the level of human macrophages in the lungs was selectively increased without apparent increase in human monocytes in the circulation or macrophages in other tissues, consistent with the requirement for GM-CSF and IL-3 for alveolar macrophage development (18). Despite these progresses, it is still unclear at what stage M-CSF and GM-CSF are required for human monocyte development and to what extent the different human cytokines affect tissue macrophage development in vivo.…”

mentioning

confidence: 55%

“…In M-CSF knockin mice, the level of human CD14 + monocytes in the circulation was increased ∼6-fold, reaching 30% of human CD45 + cells, whereas the highest level of tissue macrophage reconstitution was still under 5% of human CD45 + cells (17). In GM-CSF/IL-3 knockin mice, the level of human macrophages in the lungs was increased without apparent increase in human monocytes in the circulation or macrophages in other tissues (17,18). In comparison, following expression of M-CSF, circulating monocytes were increased ∼10-fold in humanized mice, and the significant levels of human macrophages were also detected in the spleen, liver, and lungs, reaching 20-70% of human leukocytes in these tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Following LPS stimulation, low levels (∼300 pg/ml) of human IL-6 and TNF-a were induced in the sera of humanized M-CSF knockin mice (17). In humanized GM-CSF/IL-3 knockin mice, the level of human IL-6 reached ∼6000 pg/ml (18). In comparison, we detected much higher levels of IL-6 and TNF-a (∼70,000 pg/ml) following LPS challenge in M-CSF-treated humanized mice.…”

Section: Discussionmentioning

confidence: 99%

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Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice

Chen

Zheng

et al. 2013

The Journal of Immunology

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Engraftment of human CD34+ hematopoietic stem/progenitor cells into immunodeficient mice leads to robust reconstitution of human T and B cells but not monocytes and macrophages. To identify the cause underlying the poor monocyte and macrophage reconstitution, we analyzed human myeloid cell development in humanized mice and found that it was blocked at the promonocyte stage in the bone marrow. Expression of human M-CSF or GM-CSF by hydrodynamic injection of cytokine-encoding plasmid completely abolished the accumulation of promonocytes in the bone marrow. M-CSF promoted the development of mature monocytes and tissue-resident macrophages whereas GM-CSF did not. Moreover, correlating with an increased human macrophages at the sites of infection, M-CSF–treated humanized mice exhibited an enhanced protection against influenza virus and Mycobacterium infection. Our study identifies the precise stage at which human monocyte/macrophage development is blocked in humanized mice and reveals overlapping and distinct functions of M-CSF and GM-CSF in human monocyte and macrophage development. The improved reconstitution and functionality of monocytes/macrophages in the humanized mice following M-CSF expression provide a superior in vivo system to investigate the role of macrophages in physiological and pathological processes.

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mentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice

Chen

Zheng

et al. 2013

The Journal of Immunology

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“…Human cytokines were either delivered exogenously to humanized mice or knock-in models were developed where single human cytokine genes were introduced into the mouse genome, replacing the mouse cytokine gene [63][64][65][66]. 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].…”

Section: Development Of Humanized Mouse Modelsmentioning

confidence: 99%

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

Wegner

2017

Immunotherapy

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CAR-T cell therapy has achieved highly promising results in clinical trials, particulary in B-cell malignancies. However, reports of Serious adverse events (SAE) including a number of patient deaths has raised concerns about safety of this treatment.Presently available pre-clinical models are not designed for predicting toxicities seen in human patients. Besides choosing the right animal model, careful considerations must be taken in CAR T-cell design and the amount of T-cells infused. The development of more sophisticated in vitro models and humanized mouse models for preclinical modeling and toxicity tests will help us to improve the design of clinical trials in cancer immunotherapy.

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“…However, only CD1c + DCs were able to prime influenza specific CD8 + T cell responses that can efficiently home back to epithelial tissues, including the lung. Moreover, influenza A virus infection elicited innate immune recognition in HIS mice, particularly when the lung myeloid compartment was better reconstituted after transgenic introduction of human GM-CSF and IL-3 into HIS mice [73].…”

Section: Orthomyxovirus Infections (Influenza)mentioning

confidence: 99%

Viral infections in mice with reconstituted human immune system components

Münz

2014

Immunology Letters

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Pathogenic viruses are often difficult to study due to their exclusive tropism for humans. The development of mice with human immune system components opens the possibility to study those human pathogens with a tropism for the human hematopoietic lineage in vivo. These include HCMV, EBV, KSHV, HIV, HTLV-1, dengue virus and JC virus. Furthermore, some human pathogens, like HSV-2, adenovirus, HCV, HBV and influenza A virus, with an additional tropism for somatic mouse tissues or for additional transplanted human tissues, mainly liver, have been explored in these models. The cellular tropism of these viruses, their associated diseases and primarily cell-mediated immune responses to these viral infections will be discussed in this review. Already some exciting information has been gained from these novel chimeric in vivo models and future avenues to gain more insights into the pathology, but also potential therapies, will be outlined. Although the respective in vivo models of human immune responses can still be significantly improved, they already provide preclinical systems for in vivo studies of important viral pathogens of humans. AbstractPathogenic viruses are often difficult to study due to their exclusive tropism for humans. The development of mice with human immune system components opens the possibility to study those human pathogens with a tropism for the human hematopoietic lineage in vivo. These include HCMV, EBV, KSHV, HIV, HTLV-1, dengue virus and JC virus. Furthermore, some human pathogens, like HSV-2, adenovirus, HCV, HBV and influenza A virus, with an additional tropism for somatic mouse tissues or for additional transplanted human tissues, mainly liver, have been explored in these models. The cellular tropism of these viruses, their associated diseases and primarily cell-mediated immune responses to these viral infections will be discussed in this review. Already some exciting information has been gained from these novel chimeric in vivo models and future avenues to gain more insights into the pathology, but also potential therapies, will be outlined. Although the respective in vivo models of human immune responses can still be significantly improved, they already provide preclinical systems for in vivo studies of important viral pathogens of humans.Christian Münz 3 Mice with reconstituted human immune system components as models of human immune responsesHuman immune responses can be studied in a correlative fashion in only a few tissues, which can be biopsied from patients or healthy individuals, including peripheral blood, some secondary lymphoid tissues, like tonsils, and the tumor microenvironment, assessing tumor infiltrating lymphocytes (TILs). For a more systematic analysis and in order to study the outcome of manipulations during immune responses, immunologists have primarily turned to the mouse as an in vivo animal model of mammalian immune responses. However, with a more and more detailed analysis of the mouse immune system it has become apparent that significant differences in ...

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Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung

Cited by 209 publications

References 34 publications

Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice

Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice

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

Viral infections in mice with reconstituted human immune system components

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