Preventing restimulation of memory B cells in hemophilia A: a potential new strategy for the treatment of antibody-dependent immune disorders.
Memory B cells are responsible for the rapidly emerging antibody response after antigen reexposure. The signals required for the restimulation of memory B cells have not been fully explained. We used a murine model of anti-factor VIII (FVIII) antibody responses in hemophilia A to study the requirements for the restimulation of FVIII-specific memory B cells and their differentiation into anti-FVIII antibody-producing cells. We were particularly interested in the significance of activated T cells and costimulatory interactions. Our results indicate that the restimulation of FVIII-specific memory B cells is strictly dependent on interactions with activated T cells. These activated T cells can be specific for either FVIII or third-party antigens. Restimulation by T cells specific for third-party antigens requires the presence of FVIII, indicating that signals induced by B-cell receptor (BCR) triggering and by interactions with activated T cells are important. The blockade of B7-1 or B7-2 as well as the blockade of CD40L inhibits the restimulation and differentiation of FVIII-specific memory B cells in vitro and in vivo. The interference with inducible costimulator-inducible costimulator ligand (ICOS-ICOSL) interactions, however, does not cause any modulation. As expected, the production of anti-FVIII antibodies by plasma cells is not dependent on any of the costimulatory interactions tested.
Hausl
Christina
C
Biomedical Therapeutics Research, Vienna, Austria.
Ahmad
Rafi U
RU
Schwarz
Hans Peter
HP
Muchitsch
Eva M
EM
Turecek
Peter L
PL
Dorner
Friedrich
F
Reipert
Birgit M
BM
D000818:Animals; D000906:Antibodies / Q000276:immunology* / Q000378:metabolism; D000918:Antibody Specificity; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005169:Factor VIII / Q000235:genetics / Q000276:immunology; D006467:Hemophilia A / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D016207:Cytokines; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D011947:Receptors, Antigen, B-Cell; D011994:Recombinant Proteins; D023201:CD40 Ligand; D005169:Factor VIII