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

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Abstract
Inhibitor formation in patients with haemophilia receiving factor VIII (FVIII) 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 effective T‐cell/B‐cell interaction. We studied the expression of the cell‐surface molecules involved with these interactions using multiparameter flow cytometry and a whole blood stimulation assay–phytohaemaglutinin (PHA) to activate T cells and Escherichia coli lipopolysaccharide (LPS) to activate monocytes and B cells. Up‐regulation of T‐cell co‐stimulatory receptors CD11a, CD40 ligand (CD40L) and CTLA4 were inhibited in a dose‐dependent manner by plasma‐derived (pd)FVIII, but CD28 was unchanged. Up‐regulation of monocyte and B‐cell co‐stimulatory ligands CD4O, B7‐1 (CD80) and B7‐2 (CD86) were also inhibited in a dose‐dependent manner by pdFVIII, but LFA‐3 (CD58) was unchanged. The combined inhibitory effect of prednisolone, an immunosuppressive agent used in several tolerance induction protocols, with pdFVIII on co‐stimulatory molecules, was additive. There was no significant alteration in T‐cell/APC adhesion or co‐stimulatory molecules noted in the presence of recombinant (rh)FVIII concentrate. The inhibitory effect of pdFVIII on molecules involved in interaction between T cells and APCs may result in immune tolerance in recipients of pdFVIII concentrate. The inhibitory effect of pdFVIII on CD40/CD40L up‐regulation may result in defective antibody formation. We now provide evidence that the use of pdFVIII, through interfering with APC/T‐cell interactions, may be more appropriate than rhFVIII for tolerance induction.