Association of anti-idiotypic antibodies with immune tolerance induction for the treatment of hemophilia A with inhibitors

Abstract

BACKGROUND AND OBJECTIVES: Hemophilia A patients with inhibitors can be treated effectively with immune tolerance induction therapy (ITI). One of the underlying mechanisms of ITI is conceived to be a neutralizing activity of anti-idiotypic antibodies on inhibitors. The goal of the present study was to develop an uncomplicated method for assessing antiidiotypic antibodies and to prove the advent of anti-idiotypic antibodies in ITI. DESIGN AND METHODS: We studied a total of 26 plasma samples obtained from 9 hemophilic inhibitor patients who were treated with ITI. The samples were investigated with a novel method for detecting anti-idiotypic antibodies based on a liquid phase blocking immunoprecipitation. RESULTS: Plasma anti-factor VIII (FVIII) antibody titer was reduced by adding plasma from patients who had received completely successful ITI. This anti-FVIII antibody-neutralization activity of the plasma was impaired by treating the plasma with protein G beads. In addition, treating inhibitor plasma from patients in whom ITI had been unsuccessful with FVIII affinity beads resulted in the development of the anti-FVIII antibody-neutralization activity. Furthermore, the anti-FVIII antibody-neutralization activity of anti-FVIII antibody-depleted plasma obtained in a late period of ITI on inhibitor plasmas obtained during ITI increased over time. INTERPRETATION AND CONCLUSIONS: Our results suggest that; (i) plasma from patients in whom ITI was completely successful contained an anti-FVIII antibody-neutralization factor; (ii) the anti-FVIII antibody-neutralization factor was in the IgG fraction (i.e., the factor would be anti-idiotypic antibodies), and (iii) anti-idiotypic antibodies existed even in plasma from patients in whom ITI was unsuccessful. Our observations support the notion that the mechanism of ITI is associated with the development of anti-idiotypic antibodies.