Granulocyte-Colony Stimulating Factor Reactivates Human Cytomegalovirus in a Latently Infected Humanized Mouse Model

Smith, Margaret H. D.; Goldman, Devorah C.; Bailey, Alexis S.; Pfaffle, Dana L.; Kreklywich, Craig N.; Spencer, Doran; Othieno, Florence A.; Streblow, Daniel N.; García, J. Víctor; Fleming, William H.; Nelson, Jay A.

doi:10.1016/j.chom.2010.08.001

Cited by 120 publications

(146 citation statements)

References 33 publications

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“…Although studies of infection in humanized mice have only recently begun, this approach promises to provide unprecedented insights into mechanisms of host interaction with human pathogens including hepatitis viruses, HIV, CMV, EpsteinBarr virus, dengue virus, N. meningitidis, and Plasmodium falciparum (e.g., Bente 2005;Jimé-nez-Díaz 2009;Smith et al 2010;Berges and Rowan 2011;Sato et al 2011;Zeisel et al 2011;Melican et al 2013).…”

Section: Humanized Micementioning

confidence: 99%

Host Specificity of Bacterial Pathogens

Bäumler

Fang

2013

Cold Spring Harbor Perspectives in Medicine

173

134

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Section: Humanized Micementioning

confidence: 99%

Host Specificity of Bacterial Pathogens

Bäumler

Fang

2013

Cold Spring Harbor Perspectives in Medicine

173

134

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“…However, human myelopoiesis is not efficient in these models due to a lack of species cross-reactivity of nonhematopoietic cell-derived growth factors including CSF-1, GM-CSF, IL-3, and erythropoietin. This has resulted in poor differentiation and/or function of cells of the monocyte/macrophage lineage unless supported by the addition of human cytokines (22)(23)(24)(25)(26)(27) (28)(29)(30)(31), but whether fully functional specialized myeloid DC subsets develop has not been addressed. Although DC phenotypically resembling human blood CD141 + DC by expression of CD141, CLEC9A, NECL2, and TLR3 were found in spleens of humanized mice, their low frequency has limited functional characterization (7).…”

mentioning

confidence: 99%

FLT3-Ligand Treatment of Humanized Mice Results in the Generation of Large Numbers of CD141+ and CD1c+ Dendritic Cells In Vivo

Ding

Wilkinson

Idris

et al. 2014

The Journal of Immunology

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We established a humanized mouse model incorporating FLT3-ligand (FLT3-L) administration after hematopoietic cell reconstitution to investigate expansion, phenotype, and function of human dendritic cells (DC). FLT3-L increased numbers of human CD141+ DC, CD1c+ DC, and, to a lesser extent, plasmacytoid DC (pDC) in the blood, spleen, and bone marrow of humanized mice. CD1c+ DC and CD141+ DC subsets were expanded to a similar degree in blood and spleen, with a bias toward expansion of the CD1c+ DC subset in the bone marrow. Importantly, the human DC subsets generated after FLT3-L treatment of humanized mice are phenotypically and functionally similar to their human blood counterparts. CD141+ DC in humanized mice express C-type lectin-like receptor 9A, XCR1, CADM1, and TLR3 but lack TLR4 and TLR9. They are major producers of IFN-λ in response to polyinosinic-polycytidylic acid but are similar to CD1c+ DC in their capacity to produce IL-12p70. Although all DC subsets in humanized mice are efficient at presenting peptide to CD8+ T cells, CD141+ DC are superior in their capacity to cross-present protein Ag to CD8+ T cells following activation with polyinosinic-polycytidylic acid. CD141+ DC can be targeted in vivo following injection of Abs against human DEC-205 or C-type lectin-like receptor 9A. This model provides a feasible and practical approach to dissect the function of human CD141+ and CD1c+ DC and evaluate adjuvants and DC-targeting strategies in vivo.

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“…However, many more hurdles have to be overcome [27,28,88], the manipulation of human immune system components will generate potent preclinical models for relevant human diseases, which might yield results that can be more easily translated into the clinic. Hepatitis B virus (HBV) Liver disease [41] Herpes simplex virus 2 (HSV-2) Inflammation at mucosal infection site [16] Human cytomegalovirus (HCMV) GM-CSF mediated reactivation from myeloid cells [17] Epstein Barr virus (EBV) Tumor formation, hemophagocytic lymphohistiocytosis, erosive arthritis [89] Kaposi Sarcoma associated herpesvirus (KSHV) Persistent infection in B cells [39] Adenovirus Liver disease [40] Human immunodeficiency virus (HIV) CD4 + T cell depletion [43] Human T cell leukemia virus 1 (HTLV-1)…”

Section: Discussionmentioning

confidence: 99%

“…Among the -herpesviruses, human cytomegalovirus (HCMV) infection was explored in huNSG mice [17]. In a first study HCMV was found to infect the reconstituted human myeloid compartment and could be reactivated from it by G-CSF treatment.…”

Section: Herpesvirus Infections (Hsv Hcmv Ebv Kshv)mentioning

confidence: 99%

“…These studies suggested that HIS mice can respond to HSV-2 infection by innate and adaptive immune responses, which in part are specific for this virus and seem to control infection. However, in these studies it remained unclear which murine and human cells were infected and how the human leucocytes were able to immune survey mouse tissues and controlled HSV2 within these.Among the -herpesviruses, human cytomegalovirus (HCMV) infection was explored in huNSG mice [17]. In a first study HCMV was found to infect the reconstituted human myeloid compartment and could be reactivated from it by G-CSF treatment.…”

mentioning

confidence: 99%

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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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Granulocyte-Colony Stimulating Factor Reactivates Human Cytomegalovirus in a Latently Infected Humanized Mouse Model

Cited by 120 publications

References 33 publications

Host Specificity of Bacterial Pathogens

Host Specificity of Bacterial Pathogens

FLT3-Ligand Treatment of Humanized Mice Results in the Generation of Large Numbers of CD141+ and CD1c+ Dendritic Cells In Vivo

Viral infections in mice with reconstituted human immune system components

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