The induction mechanism of anti-idiotypic antibodies in patients with Hemophilia A and inhibitors

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In order to clarify the induction mechanism of anti-idiotypic antibodies by immune tolerance induction(ITI) for hemophiliacs with inhibitors, we studied the mode of FVIII:C inactivation in the presence of high-titer anti-FVIII antibodies. We used 7 kinds of alloantibodies and 4 kinds of monoclonal antibodies against human FVIII. The former contains 3 alloantibodies recognizing A2 domain in the heavy chain and 4 alloantibodies recognizing C2 domain in the light chain. The latter contains each monoclonal antibody recognizing A1 and A2 domain, and 2 monoclonal antibodies recognizing C2 domain. Ten or twenty Bethesda units(BU)/ml of inhibitor IgG diluted with FVIII deficient plasma were mixed with normal plasma. The mixture was removed after incubation for 120 min, and then maximum coagulation acceleration (|min2|) and FVIII:C were measured by MDAII. In the presence of 10 BU/ml inhibitors, FVIII:C were detected in 4 alloantibodies (0.4-1.1 U/dl) and 3 monoclonal antibodies (0.2-5.7 U/dl), whereas |min2| were detected in 3 alloantibodies (0.128-0.152) and 4 monoclonal antibodies (0.102-0.367). In the presence of 20 BU/ml inhibitors, FVIII:C was detected in an alloantibody (0.8 U/dl) and 2 monoclonal antibodies (0.3-3.2 U/dl), whereas |min2| were detected in 3 alloantibodies (0.111-0.131) and a monoclonal antibody (0.329). Especially, the low levels of FVIII:C were detected in the alloantibodies and monoclonal antibody recognizing A2 domain in the heavy chain. These findings suggested that residual FVIII:C after FVIII infusion during ITI treatment may result in the prophylactic effect even in the presence of high responding inhibitor, and may result from the induction of anti-idiotypic antibody.