Sensitization of CD4(+) T cells to coagulation factor VIII: Response in congenital and acquired hemophilia patients and in healthy subjects

Antibodies (Ab) that inhibit factor VIII (fVIII) may develop in patients wi th hemophilia A and rarely in individuals without congenital fVIII deficien cy (acquired hemophilia). Synthesis of fVIII inhibitors requires CD4(+) T c ells. We investigated the proliferative response of blood CD4(+) cells from 11 patients with congenital or acquired hemophilia and 12 healthy subjects , to recombinant human fVIII, and to pools of overlapping synthetic peptide s spanning the sequences of individual fVIII domains. All patients had CD4( +) cells that responded to fVIII. The intensity of the responses fluctuated over time: several patients had brief periods when they did not respond to fVIII. All healthy subjects had transient CD4(+) responses to fVIII that w ere significantly lower than those of hemophilia patients. Also, healthy su bjects responded to fVIII less frequently and for shorter periods than hemo philia patients. All patients and healthy subjects recognized several fVIII domains: the A3 domain was recognized most strongly and frequently. The tr ansient sensitization of CD4(+) cells to fVIII in healthy subjects suggests that inadequate tolerization of CD4(+) cells to fVIII, due to lack of endo genous fVIII, is an important factor in the development of clinically signi ficant anti-fVIII antibodies in hemophilia A.