FVIII knockout mice (B6 129S4- F8 tm2Kaz/J) were crossed with FcgRIIb knockout mice (B6 129S4-Fcgr2b tm1Ttk/J). Here, we studied the potential role of this receptor in the regulation of memory B cell response to FVIII. The Fc gamma receptor IIb (FcgRIIb) is expressed on B cells and mediates inhibitory signals after crosslinking with the B cell receptor. Studies in a hemophilia A mouse model demonstrated that very high doses of FVIII can induce apoptosis in FVIII-specific memory B cells and prevent their differentiation into antibody-secreting cells. Patients with inhibitors are treated with very high doses of FVIII, over prolonged periods of time, to induce immune tolerance. The formation of inhibitory antibodies to factor VIII (FVIII) is the foremost complication of replacement therapy in hemophilia A.
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