title: High-dose factor VIII inhibits factor VIII-specific memory B cells in hemophilia A with factor VIII inhibitors.
abstract: Hemophilia A in its severe form is a life-threatening hemorrhagic disease that is caused by mutations in the factor VIII (FVIII) gene (symbol F8). About 25% of patients who receive replacement therapy develop neutralizing antibodies that inhibit the function of substituted FVIII. Long-term application of high doses of FVIII has evolved as an effective therapy to eradicate the antibodies and to induce long-lasting immune tolerance. Little is known, however, about the immunologic mechanisms that cause the down-modulation of anti-FVIII antibodies by high doses of FVIII. We report that high doses of FVIII inhibit the restimulation of FVIII-specific memory B cells and their differentiation into antibody-secreting plasma cells in vitro and in vivo in a murine model of hemophilia A. The inhibition of memory B-cell responses is irreversible and not mediated by FVIII-specific T cells. Furthermore, it seems to involve the activation of caspases. We conclude that the inhibition of FVIII-specific memory B cells might be an early event in the down-modulation of anti-FVIII antibodies in patients with hemophilia A who receive high doses of FVIII.
authors.affiliation: Biomolecular Therapeutics GmbH (BMT) Research, Vienna, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Hausl
authors.forename: Rafi U
authors.initials: RU
authors.lastname: Ahmad
authors.forename: Maria
authors.initials: M
authors.lastname: Sasgary
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Doering
authors.forename: Pete
authors.initials: P
authors.lastname: Lollar
authors.forename: Günter
authors.initials: G
authors.lastname: Richter
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Schwarz
authors.forename: Peter L
authors.initials: PL
authors.lastname: Turecek
authors.forename: Birgit M
authors.initials: BM
authors.lastname: Reipert
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology*; D019774:Blood Coagulation Factor Inhibitors / Q000276:immunology*; D020169:Caspases / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D005169:Factor VIII / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D006467:Hemophilia A / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010950:Plasma Cells / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000906:Antibodies; D019774:Blood Coagulation Factor Inhibitors; D005169:Factor VIII; D020169:Caspases