Factor VIII inhibitors. Potential for prevention of inhibitor formation by immune tolerance.

Factor VIII inhibitory antibodies occur following treatment in more than 30% of subjects with severe factor VIII deficiency. Almost all inhibitor formation occurs in subjects with little if any circulating factor VIII. In the absence of in utero exposure to endogenous or maternal factor VIII, these subjects probably recognize factor VIII as a non-self antigen; in other words, their immune systems fail to become tolerant to factor VIII. This opens up the possibility of preventing inhibitor formation by neonatal induction of tolerance to factor VIII. The various possible approaches include prenatal or neonatal tolerance by the parenteral or oral administration of purified factor VIII protein or factor VIII-encoding DNA. The results of preliminary experiments in mice indicate that feeding newborns a series of low doses of factor VIII does not suppress induction of anti-factor VIII antibody. Whether tolerance can be achieved by feeding mice high doses of factor VIII or by intrauterine or neonatal administration of factor protein or DNA remains to be determined.