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Neutralizing Type I IFN Antibodies Trigger an IFN-Like Response in Endothelial Cells¹

Department of Surgery Research Laboratories, Medical University of Vienna, Vienna General Hospital, Vienna, Austria

Neutralizing Abs to type I IFNs are of therapeutic significance, i.e., are currently evaluated for the treatment of autoimmune diseases with pathogenic IFN- production such as for systemic lupus erythematosus. Unexpectedly, we observed that several neutralizing Abs reportedly known to counteract IFN- or IFN-β activity triggered an "IFN-like" response in quiescent primary human endothelial cells leading to activation of the transcription factor IFN-stimulated gene factor 3 and the expression of IFN-responsive genes. Furthermore, these Abs were found to enhance rather than inhibit type I IFN signals, and the effect was also detectable for distinct other cell types such as PBMCs. The stimulatory capacity of anti-IFN-/β Abs was mediated by the constitutive autocrine production of "subthreshold" IFN levels, involved the type I IFNR and was dependent on the Fc Ab domain, as Fab or F(ab')₂ fragments potently inhibited IFN activity. We thus propose that a combined effect of IFN recognition by the Ab paratope and the concomitant engagement of the Fc domain may trigger an IFN signal via the respective type I IFNR, which accounts for the observed IFN-like response to the neutralizing Abs. With respect to clinical applications, the finding may be of importance for the design of recombinant Abs vs Fab or F(ab')₂ fragments to efficiently counteract IFN activity without undesirable activating effects.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant 7 from the Austrian Center of Excellence in Clinical and Experimental Oncology and by Grant P20074-B13 from the Austrian Science Fund.

² H.P.M. and H.F. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Christine Brostjan, Medical University of Vienna, Surgery Department, Research Laboratories, Vienna General Hospital 8G9.13, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail address: Christine.Brostjan{at}meduniwien.ac.at

⁴ Abbreviations used in this paper: ISGF, IFN-stimulated gene factor; EC, endothelial cell; HDMEC, human dermal microvessel EC; IFIT-1, IFN-induced protein with tetratricopeptide repeats 1; IFNAR, IFN- receptor; IFNGR, IFN- receptor; ISG, IFN-stimulated gene; ISRE, IFN-stimulated response element; siRNA, small interfering RNA.

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