Pathway to tolerance in hemophilia

The treatment of hemophilia has been greatly improved over the past decades. However, the development of inhibitory antibodies remains an unresolved challenge. Our current knowledge of the mechanism driving immune responses to FVIII and FIX is still very limited. Liver sinusoidal endothelial cells (LSECs) have been analyzed in this context for their ability to synthesize FVIII and as a unique population of antigen-presenting cells which can promote tolerance. We further studied the interaction of stabilin-2, one of the receptors expressed by LSECs, with FVIII and demonstrated that stabilin-2 is able to bind to FVIII. We explored a novel strategy for inducing immune tolerance using recombinant proteins with FVIII domains fused to Annexin V. The proteins were able to bind phosphatidylserine on red blood cells and were rapidly endocytosed by macrophages. Focusing on inhibitor development in hemophilia B, we identified a single MHC class II binding peptide (NVIRIIPHHNYNA) that was presented on antigen-presenting cells derived from multiple donors. Finally, the potential of modulating the interaction of anti-FVIII antibodies with specific Fc receptors was analyzed. Anti-FVIII antibodies or FVIII-Fc fusion proteins with higher affinity to inhibitory receptors could be used to restore tolerance more efficiently compared to current strategies. The knowledge obtained on FVIII clearance mechanisms as well as antigen presentation of FVIII and FIX may help to design novel approaches for reducing inhibitor formation and improving long-term outcomes in patients with hemophilia. Show more