2.50
Hdl Handle:
http://hdl.handle.net/10033/311717
Title:
Bridging the species divide: transgenic mice humanized for type-I interferon response.
Authors:
Harari, Daniel; Abramovich, Renne; Zozulya, Alla; Smith, Paul; Pouly, Sandrine; Köster, Mario; Hauser, Hansjörg; Schreiber, Gideon
Abstract:
We have generated transgenic mice that harbor humanized type I interferon receptors (IFNARs) enabling the study of type I human interferons (Hu-IFN-Is) in mice. These "HyBNAR" (Hybrid IFNAR) mice encode transgenic variants of IFNAR1 and IFNAR2 with the human extracellular domains being fused to transmembrane and cytoplasmic segments of mouse sequence. B16F1 mouse melanoma cells harboring the HyBNAR construct specifically bound Hu-IFN-Is and were rendered sensitive to Hu-IFN-I stimulated anti-proliferation, STAT1 activation and activation of a prototypical IFN-I response gene (MX2). HyBNAR mice were crossed with a transgenic strain expressing the luciferase reporter gene under the control of the IFN-responsive MX2 promoter (MX2-Luciferase). Both the HyBNAR and HyBNAR/MX2-Luciferase mice were responsive to all Hu-IFN-Is tested, inclusive of IFNα2A, IFNβ, and a human superagonist termed YNSα8. The mice displayed dose-dependent pharmacodynamic responses to Hu-IFN-I injection, as assessed by measuring the expression of IFN-responsive genes. Our studies also demonstrated a weak activation of endogenous mouse interferon response, especially after high dose administration of Hu-IFNs. In sharp contrast to data published for humans, our pharmacodynamic readouts demonstrate a very short-lived IFN-I response in mice, which is not enhanced by sub-cutaneous (SC) injections in comparison to other administration routes. With algometric differences between humans and mice taken into account, the HyBNAR mice provides a convenient non-primate pre-clinical model to advance the study of human IFN-Is.
Citation:
Bridging the species divide: transgenic mice humanized for type-I interferon response. 2014, 9 (1):e84259 PLoS ONE
Journal:
PloS one
Issue Date:
2014
URI:
http://hdl.handle.net/10033/311717
DOI:
10.1371/journal.pone.0084259
PubMed ID:
24416207
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
Publications of Dept. Gene Regulation and Differentiation (RDIF)

Full metadata record

DC FieldValue Language
dc.contributor.authorHarari, Danielen
dc.contributor.authorAbramovich, Renneen
dc.contributor.authorZozulya, Allaen
dc.contributor.authorSmith, Paulen
dc.contributor.authorPouly, Sandrineen
dc.contributor.authorKöster, Marioen
dc.contributor.authorHauser, Hansjörgen
dc.contributor.authorSchreiber, Gideonen
dc.date.accessioned2014-01-23T08:38:49Z-
dc.date.available2014-01-23T08:38:49Z-
dc.date.issued2014-
dc.identifier.citationBridging the species divide: transgenic mice humanized for type-I interferon response. 2014, 9 (1):e84259 PLoS ONEen
dc.identifier.issn1932-6203-
dc.identifier.pmid24416207-
dc.identifier.doi10.1371/journal.pone.0084259-
dc.identifier.urihttp://hdl.handle.net/10033/311717-
dc.description.abstractWe have generated transgenic mice that harbor humanized type I interferon receptors (IFNARs) enabling the study of type I human interferons (Hu-IFN-Is) in mice. These "HyBNAR" (Hybrid IFNAR) mice encode transgenic variants of IFNAR1 and IFNAR2 with the human extracellular domains being fused to transmembrane and cytoplasmic segments of mouse sequence. B16F1 mouse melanoma cells harboring the HyBNAR construct specifically bound Hu-IFN-Is and were rendered sensitive to Hu-IFN-I stimulated anti-proliferation, STAT1 activation and activation of a prototypical IFN-I response gene (MX2). HyBNAR mice were crossed with a transgenic strain expressing the luciferase reporter gene under the control of the IFN-responsive MX2 promoter (MX2-Luciferase). Both the HyBNAR and HyBNAR/MX2-Luciferase mice were responsive to all Hu-IFN-Is tested, inclusive of IFNα2A, IFNβ, and a human superagonist termed YNSα8. The mice displayed dose-dependent pharmacodynamic responses to Hu-IFN-I injection, as assessed by measuring the expression of IFN-responsive genes. Our studies also demonstrated a weak activation of endogenous mouse interferon response, especially after high dose administration of Hu-IFNs. In sharp contrast to data published for humans, our pharmacodynamic readouts demonstrate a very short-lived IFN-I response in mice, which is not enhanced by sub-cutaneous (SC) injections in comparison to other administration routes. With algometric differences between humans and mice taken into account, the HyBNAR mice provides a convenient non-primate pre-clinical model to advance the study of human IFN-Is.en
dc.language.isoenen
dc.rightsArchived with thanks to PloS oneen
dc.titleBridging the species divide: transgenic mice humanized for type-I interferon response.en
dc.typeArticleen
dc.identifier.journalPloS oneen

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