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Characterization of the immune response to factor VIII using hemophilia A* mice.

Inhibitor antibody formation is a major complication of factor VIII replacement therapy in patients with hemophilia A. In order to understand the pathogenesis of this immunologic reaction better, we have characterized the immune response to human factor VIII in a murine model of hemophilia A. Mice with severe factor VIII deficiency caused by targeted gene disruptions were injected intravenously with human factor VIII. A human factor VIII-specific T-cell proliferative response was detected with spleen cells obtained three days after a single injection with human factor VIII and anti-factor VIII antibodies were detected after two intravenous injections. Subsequent exposures led to high titer anti-factor VIII antibodies in both ELISA and inhibitor assays. The anti-factor VIII inhibitor antibody response was shown to be T-cell dependent by its absence in hemophilic mice also deficient for the T-cell co-stimulatory ligand B7-2. In separate experiments, injection of murine CTLA4-Ig completely blocked the primary response to factor VIII in hemophilic mice with intact B7 function. This reagent also prevented or diminished further increases in anti-factor VIII when given to hemophilic mice with low anti-factor VIII antibody titers.