Antigen-specific immunotherapy with apitopes suppresses generation of FVIII inhibitor antibodies in HLA-transgenic mice.
| Autor: | Pletinckx K; Apitope International NV, Diepenbeek, Belgium., Nicolson KS; Apitope International NV, Diepenbeek, Belgium.; School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom; and., Streeter HB; School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom; and.; Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom., Sanderson WJ; Apitope International NV, Diepenbeek, Belgium.; School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom; and., Schurgers E; Apitope International NV, Diepenbeek, Belgium., Jansson L; Apitope International NV, Diepenbeek, Belgium., Wraith DC; Apitope International NV, Diepenbeek, Belgium.; School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom; and.; Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. |
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| Jazyk: | angličtina |
| Zdroj: | Blood advances [Blood Adv] 2022 Apr 12; Vol. 6 (7), pp. 2069-2080. |
| DOI: | 10.1182/bloodadvances.2021004451 |
| Abstrakt: | Hemophilia A (HA) is a blood clotting disorder that is caused by various genetic deficiencies in the factor VIII (FVIII)-encoding F8 gene. Patients receiving FVIII-replacement therapy are at risk for developing neutralizing antibodies (FVIII inhibitors), rendering the FVIII-replacement therapy ineffective. Immunological tolerance toward FVIII can be achieved through immune tolerance induction protocols in some patients, but this is a lengthy and costly desensitization program. Long-term eradication of inhibitors in patients with HA could be achieved by antigen-specific immunotherapy targeting CD4+ T-cells, because formation of FVIII inhibitors is T-cell dependent. Here, we report a peptide-based antigen-specific immunotherapy that is designed to specifically reestablish immune tolerance to FVIII through the development of antigen-processing-independent epitopes (apitopes). We identified 2 FVIII immunodominant peptides in immunized HLA-DRA*0101/DRB1*1501 transgenic (HLA-DR2tg) mice that were optimized for tolerogenicity. These modified peptide analogs were initially screened for recognition using FVIII-specific T-cell hybridoma clones from FVIII-immunized HLA-DR2tg mice. The FVIII apitopes were promiscuous and bound common human HLA-DRB1* allelic variants. The combination of these 2 FVIII apitopes (ATX-F8-117), administered according to a dose-escalation protocol, promoted T-cell tolerance toward FVIII in HLA-DR2tg mice. Furthermore, treatment with ATX-F8-117 significantly reduced FVIII inhibitor formation. ATX-F8-117 regulates anti-FVIII T-cell and B-cell responses, specifically the generation of FVIII inhibitors, revealing peptide-based antigen-specific immunotherapy as a promising approach to suppress and treat inhibitor formation in susceptible patients with HA. (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.) |
| Databáze: | MEDLINE |
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