文摘
We have generated a transgenic mouse model which harbors humanized type I interferon receptors and allows the cross-species study of human type I interferons (Hu-IFN-Is) in mice. These ¡°HyBNAR¡± (Hybrid IFNAR) mice encode transgenic Interferon Receptors, whose extracellular and cytoplasmic segments are encoded by human and mouse sequence respectively, allowing the binding of human IFN-Is to the recombinant receptors but once activated, transduce their signal effectively in a mouse cellular environment. Importantly, the HyBNAR mice were generated by pro-nuclear microinjection retaining the natural mouse IFNARs, thus not disturbing endogenous IFN-I signaling. The pharmacological utility of the HyBNAR mice was first demonstrated testing Hu-IFN-Is, including recombinantly engineered superagonists and long-life variants. One such long-life superagonist was found not only to provide sustained IFN-I signaling that surpasses IFN-Beta, but furthermore provided superior protective therapeutic effectiveness in a preventative model of (MOG-peptide induced) EAE. Depending on the IFN studied, a significant degree of heterogeneity in clinical response was observed. To measure systemic levels of IFN activity for these mice, at the end of each experiment, livers were collected and gene expression of IFN-response genes was determined. To our great surprise, in comparison to healthy samples, we found that EAE control mice that did not receive reparative drug therapy exhibited a clear and strong suppression of basal systemic IFN-I signaling. Injection of Hu-IFNs partially relieved EAE clinical severity, and improvement in clinical response correlated strongly with up-regulation of expression for certain IFN-I response genes. Our emerging data seems to concord with snippets of recent evidence in the literature regarding human multiple sclerosis (MS). Thus on the basis of our work with EAE, we propose that MS may be a disease in which for some patients systemic IFN-I signaling is suppressed, and provides a simple explanation as to why to some IFN-therapy is clinically beneficial.
