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.
| Original language | English |
|---|---|
| Article number | e84259 |
| Journal | PLoS ONE |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 9 Jan 2014 |
Bibliographical note
Merck-KGaAThis study was funded by a research grant awarded to GS from Merck-KGaA. Authors AZ, PS and SP are/were members of Merck-Serono, a division of Merck KGaA. The Weizmann Institute of Science holds patent rights to the interferon superagonists described in this paper. Scientists from the funding agency (AZ,PS,SP) have contributed to this paper with advice of how to enhance pharmacodynamic studies, and thus are listed as co-authors and have additionally contributed to proof-reading this manuscript. Members of the funding agency however have had no role in data collection and analysis, decision to publish, nor have constrained in any way conclusions reached by the senior authors of this study.All Science Journal Classification (ASJC) codes
- General