Treatment of murine lupus with cDNA encoding IFN-gammaR/Fc.
IFN-gamma, a pleiotropic cytokine, is a key effector molecule in the pathogenesis of several autoimmune diseases, including lupus. Importantly, deletion of IFN-gamma or IFN-gammaR 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-gammaR/Fc can retard lupus development and progression in MRL-Fas(lpr) mice. Therapy significantly reduced serum levels of IFN-gamma, as well as disease manifestations (autoantibodies, lymphoid hyperplasia, glomerulonephritis, mortality), when treatment was initiated at the predisease stage, particularly when IFN-gammaR/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.
Lawson
B R
BR
Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Prud'homme
G J
GJ
Chang
Y
Y
Gardner
H A
HA
Kuan
J
J
Kono
D H
DH
Theofilopoulos
A N
AN
D000818:Animals; D002843:Chromatin / Q000276:immunology; D018076:DNA, Complementary / Q000627:therapeutic use*; D020022:Genetic Predisposition to Disease; D015316:Genetic Therapy / Q000379:methods; D006965:Hyperplasia; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000235:genetics / Q000627:therapeutic use; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000276:immunology; D007668:Kidney / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000401:mortality / Q000628:therapy*; D008221:Lymphoid Tissue / Q000187:drug effects / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009500:Neutralization Tests; D017471:Receptors, Interferon / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D000096743:Interferon gamma Receptor
D002843:Chromatin; D018076:DNA, Complementary; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007371:Interferon-gamma; D017471:Receptors, Interferon; D011993:Recombinant Fusion Proteins; D000096743:Interferon gamma Receptor