High-dose factor VIII inhibits factor VIII-specific memory B cells in hemophilia A with factor VIII inhibitors.
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.
Hausl
Christina
C
Biomolecular Therapeutics GmbH (BMT) Research, Vienna, Austria.
Ahmad
Rafi U
RU
Sasgary
Maria
M
Doering
Christopher B
CB
Lollar
Pete
P
Richter
Günter
G
Schwarz
Hans Peter
HP
Turecek
Peter L
PL
Reipert
Birgit M
BM
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
D000906:Antibodies; D019774:Blood Coagulation Factor Inhibitors; D005169:Factor VIII; D020169:Caspases