Treatment of murine lupus with cDNA encoding IFN-γR/Fc
Brian R. Lawson, Gerald J. Prud’homme, Yigang Chang, Humphrey A. Gardner, Jason Kuan, Dwight H. Kono, Argyrios N. Theofilopoulos
Brian R. Lawson, Gerald J. Prud’homme, Yigang Chang, Humphrey A. Gardner, Jason Kuan, Dwight H. Kono, Argyrios N. Theofilopoulos
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Treatment of murine lupus with cDNA encoding IFN-γR/Fc

Abstract

IFN-γ, a pleiotropic cytokine, is a key effector molecule in the pathogenesis of several autoimmune diseases, including lupus. Importantly, deletion of IFN-γ or IFN-γR in several lupus-predisposed mouse strains resulted in significant disease reduction, suggesting the potential for therapeutic intervention. We evaluated whether intramuscular injections of plasmids with cDNA encoding IFN-γR/Fc can retard lupus development and progression in MRL-Faslpr mice. Therapy significantly reduced serum levels of IFN-γ, as well as disease manifestations (autoantibodies, lymphoid hyperplasia, glomerulonephritis, mortality), when treatment was initiated at the predisease stage, particularly when IFN-γR/Fc expression was enhanced by electroporation at the injection site. Remarkably, disease was arrested and even ameliorated when this treatment was initiated at an advanced stage. This therapy represents a rare example of disease reversal and makes application of this nonviral gene therapy in humans with lupus (and perhaps other autoimmune/inflammatory conditions) highly promising.

Authors

Brian R. Lawson, Gerald J. Prud’homme, Yigang Chang, Humphrey A. Gardner, Jason Kuan, Dwight H. Kono, Argyrios N. Theofilopoulos

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IgG deposits and expression of MHC class II, ICAM-1, and MCP-1 proteins ...
IgG deposits and expression of MHC class II, ICAM-1, and MCP-1 proteins in kidney tissues from MRL-Faslpr mice treated from 1 month of age with blank (VR1255) or active (VR1255-IFNγR/Fc) plasmid with electroporation. Active plasmid–treated mice had substantially reduced glomerular IgG deposits, as well as decreased levels of MHC class II, ICAM-1, and MCP-1. Similar reductions were observed in mice treated from 4 months of age with active plasmid (data not shown). IgG deposits were detected with FITC–anti-IgG antibody (×45), and the immunoperoxidase procedure for detection of MHC class II, ICAM-1, and MCP-1 was performed as described in Figure 5 (×25). Photomicrographs are representative samples from four mice per group.