title: Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms.
abstract: The presence of autoantibodies specific for nucleic acid-associated antigens is the hallmark of systemic lupus erythematosus (SLE). We have recently developed a specific inhibitor of TLR7 and TLR9, called immunoregulatory sequence (IRS) 954, and showed that it inhibits the induction of IFN-alpha by human plasmacytoid dendritic cells in response to DNA and RNA viruses and isolated immune complexes from lupus patients. In this study, we show that IRS 954 can prevent progression of disease when injected in the lupus prone (NZBxNZW)F1 mice. Following treatment, we observed a significant reduction of serum levels of nucleic acid-specific autoantibodies as well as decreased proteinuria, reduced glomerulonephritis, end-organ damage and increased survival. These data demonstrate that in addition to its ability to block IFN-alpha, IRS 954 can reduce symptoms in a lupus model and thus represents a promising therapeutic agent for the treatment of SLE.
authors.affiliation: Dynavax Technologies Corporation, Berkeley, CA 94710, USA. fbarrat@dynavax.com
authors.forename: Franck J
authors.initials: FJ
authors.lastname: Barrat
authors.forename: Thea
authors.initials: T
authors.lastname: Meeker
authors.forename: Jean H
authors.initials: JH
authors.lastname: Chan
authors.forename: Cristiana
authors.initials: C
authors.lastname: Guiducci
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coffman
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis* / Q000097:blood; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D003433:Crosses, Genetic; D004247:DNA / Q000494:pharmacology / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000628:therapy*; D008181:Lupus Nephritis / Q000473:pathology / Q000517:prevention & control; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D008814:Mice, Inbred NZB; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors* / Q000502:physiology; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D001323:Autoantibodies; C526793:IRS 954; D007166:Immunosuppressive Agents; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D004247:DNA