Inflammatory signaling–deficient mice are less likely to develop FVIII inhibitors. (A) Experimental timeline. WT C57BL/6, MyD88^–/–, and IFNAR^–/– mice received 4 weekly injections of FVIII (2.5 IU) IV (n = 13-15 per group). Blood samples were collected for ELISA and Bethesda assays 1 week after the last injection. (B) Inhibitor and FVIII-specific IgG1 titers in WT and knockout mice 1 week after the last FVIII injection. The dotted horizontal line is an approximate sensitivity cut-off for ELISA. Shown are medians ± IQRs. (C) Experimental timeline. S129/C57BL/6 HA mice received 4 weekly injections of FVIII, FIX, or OVA (300 ng each) IV (n = 7-9 per group). Blood samples were collected for ELISA and Bethesda assays 1 week after the last injection. (D) FVIII-, FIX-, or OVA-specific IgG1 titers 1 week after the last injection. Shown are mean ± SD, and P values from analysis of variance. ELISA, enzyme-linked immunosorbent assay.