Effect of factor VIII concentrate on antigen-presenting cell (APC)/T-cell interactions in vitro: relevance to inhibitor formation and tolerance induction

Inhibitor formation in patients with haemophilia receiving factor VIII (FVI II) concentrate is a common problem requiring tolerance induction therapy. Immune tolerance is dependent on defective T cell/antigen-presenting cell ( APC) interactions and inhibitor antibody formation is associated with effec tive T-cell/B-cell interaction. We studied the expression of the cell-surfa ce molecules involved with these interactions using multiparameter flow cyt ometry and a whole blood stimulation assay-phytohaemaglutinin (PHA) to acti vate T cells and Escherichia coil lipopolysaccharide (LPS) to activate mono cytes and B cells. Upregulation of T-cell co-stimulatory receptors CD11a, C D40 ligand (CD40L) and CTLA4 were inhibited in a dose-dependent manner by p lasma-derived (pd)FVIII, but CD28 was unchanged. Up-regulation of monocyte and B-cell costimulatory ligands CD40, B7-1 (CD80) and B7-2 (CD86) were als o inhibited in a dose-dependent manner by pdFVIII, but LFA-3 (CD58) was unc hanged. The combined inhibitory effect of prednisolone, an immunosuppressiv e agent used in several tolerance induction protocols, with pdFVIII on cost imulatory molecules, was additive. There was no significant alteration in T -cell/APC adhesion or co-stimulatory molecules noted in the presence of rec ombinant (rh)FVIII concentrate. The inhibitory effect of pdFVIII on molecul es involved in interaction between T cells and APCs may result in immune to lerance in recipients of pdFVIII concentrate. The inhibitory effect of pdFV III on CD40/CD40L upregulation may result in defective antibody formation. We now provide evidence that the use of pdFVIII, through interfering with A PC/T-cell interactions, may be more appropriate than rhFVIII for tolerance induction.