T cell response to FVIII.

Several lines of evidence indicate that the immune response to Factor VIII (FVIII) in patients with hemophilia A is T cell-dependent. This review highlights the link between the epitope specificity of FVIII-specific T cells and their potential roles in different categories of patients. FVIII-specific T cells able to recognize wild-type (i.e. therapeutic) FVIII but not the mutated self FVIII of hemophilia patients have been identified in patients with mild/moderate hemophilia carrying some point mutations. Such T cells likely contribute to the higher frequency of neutralizing anti-FVIII antibodies (inhibitors) development in these patients. In contrast, as yet no T cells have been identified that can differentiate between FVIII molecules with non-hemophilia-causing single amino acid variants encoded by non-synonymous single-nucleotide polymorphisms in the F8 gene. Other mechanisms are therefore still to be identified that will explain the clinically noted differences in the incidence of inhibitor development between patients of different races who are known to have differences at these sites. Beside information about the mechanism of inhibitor development, the analysis of FVIII-specific T cells has provided tools to develop novel diagnostic and therapeutic approaches, such as the generation of FVIII-specific regulatory T cells that may be useful in preventing or suppressing the immune response to FVIII.