title: Bridging the species divide: transgenic mice humanized for type-I interferon response.
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.
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Harari
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Renne
authors.initials: R
authors.lastname: Abramovich
authors.affiliation: MS Platform, Merck-Serono, (a division of Merck KGaA), Geneva, Switzerland.
authors.forename: Alla
authors.initials: A
authors.lastname: Zozulya
authors.affiliation: MS Platform, Merck-Serono, (a division of Merck KGaA), Geneva, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Smith
authors.affiliation: MS Platform, Merck-Serono, (a division of Merck KGaA), Geneva, Switzerland.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Pouly
authors.affiliation: Helmholtz Centre for Infection Research, Dept. Gene Regulation and Differentiation, Braunschweig, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Köster
authors.affiliation: Helmholtz Centre for Infection Research, Dept. Gene Regulation and Differentiation, Braunschweig, Germany.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Hauser
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Gideon
authors.initials: G
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D002460:Cell Line; D006720:Homozygote; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism* / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D014162:Transfection; D019076:Transgenes
chemical_list: D007370:Interferon Type I; D008156:Luciferases