Induction of split tolerance and clinical cure in high-responding hemophiliacs with factor IX antibodies.

An approach to the problem of inducing tolerance in patients with hemophilia complicated by high-responding antibodies is described. Thus, in four patients with severe hemophilia B and high-responding antibodies against factor IX, it has been possible to modify the immune response by giving high doses of intravenous IgG in combination with cyclophosphamide and factor IX, followed by regular factor IX treatment. In three of the patients, the in vivo recovery and half-life of infused factor IX coagulant activity (IX:C) are now normal, while the fourth patient has been converted to a low responder. Hip replacement surgery has been performed successfully in one patient. The tolerant state in these four patients is characterized, and they have all been found to have complexes between factor IX antigen and a "new" antibody without IX:C inhibitory activity. The disappearance rate of the complexed factor IX antigen (i.e., lacking IX:C activity) is considerably prolonged, and the persistence in the circulation of this (probably modified) factor IX molecule may be crucial, since tolerance to factor IX treatment was only induced when immunocomplexes were produced. Since earlier treatment of the patients with cyclophosphamide and factor IX, but without IgG, failed to induce tolerance, it appears to be the IgG that is the prerequisite.