10,11 In contrast, both B/PBSM/FVIII and B/FVIIIM/FVIII mice had residual maternal anti-FVIII IgG. At 8 weeks of age, the different groups of mice were treated with 1 IU FVIII once a week for 4 weeks. Blood was collected 5 days after the fourth FVIII administration, and the anti-FVIII IgG titres were measured (Fig. 3b). As expected, B/FVIIIM/FVIII were protected against the development of FVIII inhibitors. The B/PBSM/FVIII demonstrated anti-FVIII IgG titres (51·4 ± 84·8 μg/ml) that were lower than those measured in the case of B/FVIIIM/PBS (133·1 ± 44·0 μg/ml) and B/PBSM/PBS,

without reaching statistical significance. This suggests that optimal protection is conferred when maternal IgG are transferred during both fetal PS 341 life and lactation. Furthermore, residual levels of anti-FVIII IgG in B/FVIIIM/FVIII mice at 11 weeks of age (third injection of FVIII) were identical to the theoretical values of clearance rates of IgG (Supporting information Fig. S2). Residual levels of anti-FVIII IgG were however higher than the theoretical value in the case of B/PBSM/FVIII mice. This suggests that B/PBSM/FVIII mice were in the process of developing

novel anti-FVIII IgG, whereas B/FVIIIM/FVIII mice were not. At 12 weeks of age (fourth injection), the experimental values of IgG levels were systematically higher than the theoretical ones. We then reconstituted naive FVIII-deficient mice with IgG pools from either FVIII-treated mice that contain anti-FVIII IgG (‘inhibitor+’, Fig. 3c, selleck compound 131·9 ± 24·1 μg/ml) or naive mice (‘inhibitor−’). Three days later, mice were treated with exogenous FVIII. Naive mice reconstituted with anti-FVIII IgG developed significantly lower titres of anti-FVIII IgG than control mice (Fig. 3d, P < 0·05). The protective effect of the presence of anti-FVIII IgG was confirmed by a χ2 analysis of the pooled data on pre-treatment anti-FVIII IgG titres and anti-FVIII IgG titres

measured after the fourth FVIII administration from Figs 2 and 3 (odds ratio = 7·2; 95% confidence interval, 1·64–31·54, P < 0·01). In this work, we have shown that maternally transferred anti-FVIII IgG can delay the development of the anti-FVIII immune response. 3-oxoacyl-(acyl-carrier-protein) reductase The offspring from FVIII-treated mothers, who received maternal anti-FVIII IgG in utero and during lactation, developed lower levels of inhibitory anti-FVIII IgG, and demonstrated reduced FVIII-specific proliferative T-cell responses. The reduced capacity of the immune system of the offspring to mount an anti-FVIII immune response was transient as the effect diminished if these offspring were nursed by naive mothers. However, the suppression of the anti-FVIII response could be reproduced upon reconstitution of naive mice with ‘purified’ anti-FVIII IgG, so replicating the classic studies of Bystryn et al.13 which demonstrated that passive antibody can inhibit the subsequent immune response.