Preventing restimulation of memory B cells in hemophilia A: a potential new strategy for the treatment of antibody-dependent immune disorders

Abstract

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 restimula-tion of FVIII-specific memory B cells and their differentiation into anti-FVIII anti-body-producing cells. We were particularly interested in the significance of activated T cells and costimulatory interactions. Our results indicate that the re-stimulation 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.

Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice

“…Our data, however, show clearly that administration of anti-ICOS mAb over an extended period effectively promotes tolerance to the transgene. This is different from the results reported in a hemophilia mouse model reported by Hausl et al, 48 suggesting that the interference with ICOS-ICOSL interaction by anti-ICOSL monoclonal antibody does not inhibit restimulation and differentiation of FVIII-specific memory B cell. This difference could be because the model used was one of an established disease and/or that the blocking antibodies anti-ICOS and anti-ICOSL act differently.…”

Kinetics of Humoral and Memory B Cell Response Induced by the Plasmodium falciparum 19-Kilodalton Merozoite Surface Protein 1 in Mice

“…The protection has been correlated with high levels of induction of growth-inhibitory antibodies and not with effector CD4 ϩ T cells (20,21). But there is a poor understanding of the B cell responses to PfMSP-1 19 that protect against bloodstage infection in vivo in humans.…”

“…In this study we investigated the development of memory B cells and their differentiation into antibody-secreting cells (ASCs) and the protective capacity upon PfMSP-1 19 administration. Our findings indicate that memory responses to PfMSP-1 19 both in the bone marrow (BM) and spleen were impaired, and adoptive transfer of MBCs resulted in the formation of short-lived antibody-secreting plasma cells and a short-lived antibody response.…”

“…falciparum merozoite surface protein 1 (PfMSP-1) is the most abundant protein on the surface of invasive blood-stage merozoites, and its 19-kDa C-terminal, cysteine-rich region of PfMSP-1 (PfMSP-1 19 ) is highly conserved and effective in induction of a protective immune response against malaria parasite infection (9,23,24). The protection has been correlated with high levels of induction of growth-inhibitory antibodies and not with effector CD4 ϩ T cells (20,21).…”

Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A

“…Furthermore, analyses in FVIII-deficient mice have demonstrated that abrogation of T-cell help using antibodies to CD40-ligand (CD154), CD80, or CD86, or using CTLA4-Ig constructs, which impairs the cross-talk between APCs and T cells, prevented the anti-FVIII immune response as well. [89][90][91][92][93] Interestingly, some patients who completely lack the endogenous FVIII molecule, and presumably do not develop natural tolerance to FVIII, never develop FVIII inhibitors, while others do. This suggests that the emergence of FVIII inhibitors in severe hemophilia A patients is not merely due to a lack of natural tolerance to FVIII.…”