T-cell responses in two unrelated XXXX inhibitor subjects include an epitope at the factor VIII @entity72280 missense site.

@entity2801 @entity1 @entity447 @entity72280 @entity1198 @entity1533
BACKGROUND: Development of neutralizing anti-factor (F)VIII antibodies ('inhibitors') is a serious clinical problem in @entity447 . Increased inhibitor risk has been associated with certain @entity2801 missense substitutions, including @entity72280 in the A2 domain. OBJECTIVES: The aim of the present study was to identify T-cell epitopes in @entity2801 and characterize T-cell responses in two unrelated @entity447 subjects sharing F8- @entity72280 and @entity1533 *1101 genotypes. We hypothesized that the hemophilic substitution site coincides with an important T-cell epitope. @entity1 /METHODS: The binding affinities of peptides for recombinant HLA-DR proteins were measured and compared with epitope prediction results. CD4+ T cells were stimulated using peptides and stained with fluorescent, peptide-loaded tetramers. RESULTS: The inhibitor subjects, but not HLA-matched controls, had high-avidity @entity1533 *1101-restricted T-cell responses against @entity2801 (589-608), which contains the hemophilic missense site. Antigen-specific T cells secreted @entity1198 and Th2 cytokines and proliferated in response to @entity2801 and @entity2801 (592-603). @entity2801 (589-608) bound with physiologically relevant (micromolar) IC(50) values to recombinant DR0101, DR1101 and DR1501 proteins. CONCLUSIONS: @entity447 @entity1 with @entity72280 missense substitutions and these HLA haplotypes had an increased incidence of inhibitors in our cohorts, supporting a paradigm in which presentation of @entity2801 epitopes containing the wild-type R593 influences inhibitor risk in this @entity447 sub-population.
