Modulation of factor VIII-specific memory B cells.
The development of inhibitory antibodies against factor VIII (FVIII) is the major complication in patients with haemophilia A who are treated with FVIII products. Memory B cells play an essential role in maintaining established antibody responses. Upon re-exposure to the same antigen, they are rapidly re-stimulated to proliferate and differentiate into antibody-secreting plasma cells (ASC) that secrete high-affinity antibodies. It is, therefore, reasonable to believe that memory B cells have to be eradicated or inactivated for immune tolerance induction therapy to be successful in patients with haemophilia A and FVIII inhibitors. The aim of our studies was the development of strategies to prevent FVIII-specific memory B cells from becoming re-stimulated. We established a 6-day in vitro culture system that enabled us to study the regulation of FVIII-specific murine memory-B-cell re-stimulation. We tested the impact of the blockade of co-stimulatory interactions, of different concentrations of FVIII and of ligands for toll-like receptors (TLR). The blockade of B7-CD28 and CD40-CD40 ligand interactions prevented FVIII-specific murine memory B cells from becoming re-stimulated by FVIII in vitro and in vivo. Furthermore, high concentrations of FVIII blocked re-stimulation of FVIII-specific murine memory B cells. Triggering of TLR7 amplified re-stimulation by low concentrations of FVIII and prevented blockade by high concentrations of FVIII. We conclude that we defined modulators that either amplify or inhibit the re-stimulation of FVIII-specific murine memory B cells. Currently, we are investigating whether the same modulators operate in patients with haemophilia A and FVIII inhibitors.
Reipert
B M
BM
BMT Research, Vienna, Austria. birgit_reipert@baxter.com
Allacher
P
P
Hausl
C
C
Pordes
A G
AG
Ahmad
R U
RU
Lang
I
I
Ilas
J
J
Windyga
J
J
Klukowska
A
A
Muchitsch
E M
EM
Schwarz
H P
HP
D000293:Adolescent; D000328:Adult; D000818:Animals; D000906:Antibodies / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology; D002454:Cell Differentiation; D002648:Child; D005169:Factor VIII / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000276:immunology*; D006467:Hemophilia A / Q000276:immunology* / Q000628:therapy; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D013154:Spleen / Q000166:cytology / Q000276:immunology; D055815:Young Adult
D000906:Antibodies; D015703:Antigens, CD; D023201:CD40 Ligand; D005169:Factor VIII