Journal
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
Volume 9, Issue 4, Pages 689-699Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1538-7836.2011.04202.x
Keywords
factor VIII; hemophilia A; HLA; inhibitor; T-cell clones
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Funding
- CSL Behring, Inc.
- Bayer Hemophilia Award
- NIH [HL R01 07109, 1RC2HL101851-01]
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Background: Development of neutralizing anti-factor (F) VIII antibodies ('inhibitors') is a serious clinical problem in hemophilia A. Increased inhibitor risk has been associated with certain FVIII missense substitutions, including R593C in the A2 domain. Objectives: The aim of the present study was to identify T-cell epitopes in FVIII and characterize T-cell responses in two unrelated hemophilia A subjects sharing F8-R593C and HLA-DRB1*1101 genotypes. We hypothesized that the hemophilic substitution site coincides with an important T-cell epitope. Patients/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 HLA-DRB1*1101-restricted T-cell responses against FVIII(589-608), which contains the hemophilic missense site. Antigen-specific T cells secreted Th1 and Th2 cytokines and proliferated in response to FVIII and FVIII(592-603). FVIII(589-608) bound with physiologically relevant (micromolar) IC(50) values to recombinant DR0101, DR1101 and DR1501 proteins. Conclusions: Hemophilia A patients with R593C missense substitutions and these HLA haplotypes had an increased incidence of inhibitors in our cohorts, supporting a paradigm in which presentation of FVIII epitopes containing the wild-type R593 influences inhibitor risk in this hemophilia A sub-population.
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