ArticleJournal of thrombosis and haemostasis : JTH2011
T-cell responses in two unrelated hemophilia A inhibitor subjects include an epitope at the factor VIII R593C missense site.
Article in Journal of thrombosis and haemostasis : JTH, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
25 citing papers in PubMed, 43 citations in OpenAlex.
- Trial
- Design of the INHIBIT trial: preventing inhibitors by avoiding 'danger', prolonging half-life and promoting tolerance.Expert review of hematology · 2014Trial
- Immunogenic implications of translational readthrough modulate the association of F8 nonsense mutations with inhibitors in Hemophilia A.Molecular medicine (Cambridge, Mass.) · 2026Article
- Hemophilia A subjects with an intron-22 gene inversion mutation show CD4Frontiers in immunology · 2023Article
- Antigen-specific immunotherapy with apitopes suppresses generation of FVIII inhibitor antibodies in HLA-transgenic mice.Blood advances · 2022Article
- Driving CARs to BARs: The Winding Road to Specific Regulatory T Cells for Tolerance.Frontiers in immunology · 2021Review
- Removal of Mannose-Ending Glycan at AsnFrontiers in immunology · 2020Article
- FVIII Immunogenicity-Bioinformatic Approaches to Evaluate Inhibitor Risk in Non-severe Hemophilia A.Frontiers in immunology · 2020Review
- Specificity of the T Cell Response to Protein Biopharmaceuticals.Frontiers in immunology · 2020Review
- Induction of activated T follicular helper cells is critical for anti-FVIII inhibitor development in hemophilia A mice.Blood advances · 2019Article
- Factor VIII cross-matches to the human proteome reduce the predicted inhibitor risk in missense mutation hemophilia A.Haematologica · 2019Article
- Pathogenic immune response to therapeutic factor VIII: exacerbated response or failed induction of tolerance?Haematologica · 2019Review
- Tolerating Factor VIII: Recent Progress.Frontiers in immunology · 2019Review
- Factor VIII: Perspectives on Immunogenicity and Tolerogenic Strategies.Frontiers in immunology · 2019Review
- Anti-Drug Antibodies: Emerging Approaches to Predict, Reduce or Reverse Biotherapeutic Immunogenicity.Antibodies (Basel, Switzerland) · 2018Review
- FVIII proteins with a modified immunodominant T-cell epitope exhibit reduced immunogenicity and normal FVIII activity.Blood advances · 2018Article
- Comparative profiling of HLA-DR and HLA-DQ associated factor VIII peptides presented by monocyte-derived dendritic cells.Haematologica · 2018Article
- Review
- Engineering less immunogenic and antigenic FVIII proteins.Cellular immunology · 2016Review
- Article
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
Abstract
backgroundDevelopment 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.
objectivesThe 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/
methodsThe 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.
resultsThe 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.
conclusionsHemophilia 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.