Modulation of factor VIII‐specific memory B cells

Summary.  The development of inhibitory antibodies against factor VIII (FVIII) is the major complication in patients with haemophilia A who are treated with FVIII products. Memory B cells play an essential role in maintaining established antibody responses. Upon re‐exposure to the same antigen, they are rapidly re‐stimulated to proliferate and differentiate into antibody‐secreting plasma cells (ASC) that secrete high‐affinity antibodies. It is, therefore, reasonable to believe that memory B cells have to be eradicated or inactivated for immune tolerance induction therapy to be successful in patients with haemophilia A and FVIII inhibitors. The aim of our studies was the development of strategies to prevent FVIII‐specific memory B cells from becoming re‐stimulated. We established a 6‐day in vitro culture system that enabled us to study the regulation of FVIII‐specific murine memory‐B‐cell re‐stimulation. We tested the impact of the blockade of co‐stimulatory interactions, of different concentrations of FVIII and of ligands for toll‐like receptors (TLR). The blockade of B7‐CD28 and CD40‐CD40 ligand interactions prevented FVIII‐specific murine memory B cells from becoming re‐stimulated by FVIII in vitro and in vivo. Furthermore, high concentrations of FVIII blocked re‐stimulation of FVIII‐specific murine memory B cells. Triggering of TLR7 amplified re‐stimulation by low concentrations of FVIII and prevented blockade by high concentrations of FVIII. We conclude that we defined modulators that either amplify or inhibit the re‐stimulation of FVIII‐specific murine memory B cells. Currently, we are investigating whether the same modulators operate in patients with haemophilia A and FVIII inhibitors.