NEUTRALIZING ANTIIDIOTYPIC ANTIBODIES TO FACTOR-VIII INHIBITORS AFTERDESENSITIZATION IN PATIENTS WITH HEMOPHILIA-A

Hemophilia A patients producing antibodies towards FVIII are usually t reated with infusions of high doses of FVIII in an attempt to ''desens itize'' them. To examine the mechanisms by which such desensitization operates, sequential plasma samples of two unrelated inhibitor patient s were analyzed for anti-FVIII and antiidiotypic antibodies before and during infusions of high doses of FVIII. Anti-FVIII antibodies were s eparated from antiidiotypic antibodies by immunoaffinity chromatograph y before analysis. We show in the present study that the concentration of anti-FVIII antibodies did not change during a successful desensiti zation and that antibodies maintained their capacity to inhibit the pr ocoagulant function of FVIII, even though the number of Bethesda units in plasma was reduced to undetectable levels. Using a competition ass ay with mAbs, we further show that the specificity of human antibodies did not vary significantly during therapy. Finally, we show that the treatment elicited antiidiotypic antibodies, which neutralized the inh ibitory capacity of anti-FVIII antibodies. Inhibitor antibodies can th erefore not be accurately evaluated in plasma, as their function appea rs to be neutralized by antiidiotypic antibodies. These findings could have implications for the design of new therapies for hemophilia A pa tients with inhibitors.