Barrat FJ et al. (2007) Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms. Eur J Immunol 37: 3582–3586

In the autoimmune disease systemic lupus erythematosus (SLE), stimulation of Toll-like receptors (TLR) 7 and 9 by self nucleic acids is postulated to induce plasmacytoid dendritic cells (PDCs) to overproduce interferon-α, a key cytokine in the pathogenesis of SLE. TLR7 and TLR9 are also thought to be involved in B-cell-mediated production of autoantibodies specific to nucleic acids, thereby triggering and then promoting SLE.

Barrat et al. have described previously an oligonucleotide-based inhibitor of TLR7 and TLR9, called immunoregulatory sequence (IRS) 954, which can block B-cell activation and interferon-α production by PDCs. Using the (NZB × NZW)F1 mouse model of SLE, they have now investigated its potential as a therapy for SLE. Mice were injected twice weekly with IRS 954 from the age of 4 months, when they normally start showing signs of SLE. At the age of 9 months, IRS 954-treated mice had significantly lower serum levels of nucleic-acid-specific autoantibodies than untreated mice. They also exhibited decreased proteinuria, reduced glomerulonephritis and end-organ damage, and increased survival.

The authors conclude that IRS 954 is able to reduce symptoms and prolong survival in the (NZB × NZW)F1 mouse model of SLE, supporting the hypothesis that blockade of TLR7 and TLR9 in both B cells and PDCs could be used as a novel therapeutic strategy for the treatment of SLE.