Bridging the species divide: transgenic mice humanized for type-I interferon response

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 fus...

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Bibliographic Details
Published in:PloS one 2014-01, Vol.9 (1), p.e84259-e84259
Main Authors: Harari, Daniel, Abramovich, Renne, Zozulya, Alla, Smith, Paul, Pouly, Sandrine, Köster, Mario, Hauser, Hansjörg, Schreiber, Gideon
Format: Article
Language:English
Subjects:
Activation
Analysis
Animals
Biological response modifiers
Biology
Cell Line
Cytokines
Gene expression
Genes
Genetic engineering
Homozygote
Humans
Interferon
Interferon receptors
Interferon Type I - metabolism
Interferon Type I - pharmacology
Luciferase
Luciferases - metabolism
Medicine
Melanoma
Melanoma, Experimental - metabolism
Melanoma, Experimental - pathology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Multiple sclerosis
Pharmacodynamics
Pharmacology
Phosphorylation
Proteins
Receptors
Reporter gene
Science
Signal Transduction - drug effects
Species Specificity
Stat1 protein
Transfection
Transgenes
Transgenic mice
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0084259