FIGURE 7.

Synergistic inhibition of TLR7- and TLR9-induced IFN-regulated genes by the combination of BMS-986126 and prednisolone. PBMCs from a healthy control donor were stimulated in vitro either with the TLR9 agonist ODN2216 (300 nM) (A) or the TLR7 agonist heat-inactivated influenza virus (0.02 μl) (B) in the presence and absence of suboptimal concentrations of prednisolone, BMS-986126, and the combination of both. Expression of IFIT1 was quantitated by real-time PCR and normalized to the housekeeping gene GAPDH. Data represent fold induction relative to unstimulated controls. One representative experiment of three is shown. Comparisons were performed as shown using a one-way Student t test. *p < 0.01, **p < 0.001, ***p < 0.0001. (C and D) MRL/lpr mice were dosed orally with suboptimal doses of BMS-986126 (0.3 or 1 mg/kg/d), two doses of prednisolone (pred, 1 or 10 mg/kg/d), or the combination of BMS-986126 with prednisolone (0.3 + 1; 1 + 1). Following 8 wk of dosing, serum titers of dsDNA-specific autoantibodies (C) and urine protein levels (D) were measured. Mean and SEM for each group are plotted. Data are from one experiment with 10 animals per group. *p < 0.01, **p < 0.001, ***p < 0.0001 versus vehicle by one way ANOVA with Dunnett’s test.