Abstract
The most severe side effect in haemophilia A (HA) treatment is the development of
anti-factor VIII antibodies, also called inhibitors. Why inhibitors develop in a proportion
of treated HA patients and how this can be prevented remains largely unanswered. Among
numerous theories, the presence of immunological danger signals, associated with events
such as surgery or infection, has been proposed to play a role. In this study, we
demonstrate that human dendritic cells (DC) synergistically activated by a combination
of factor VIII (FVIII) concentrate plus the bacterial danger signal lipopolysaccharide
(LPS) induce a significantly stronger activation of autologous CD4+ T cells than DC pretreated with FVIII or LPS alone. The observed T cell activation
is dependent on antigen processing, presentation on MHC class II molecules and costimulation
via CD86. Of note, FVIII plus LPS pretreated DC predominantly induce the activation
of memory T cells and a minor proportion of naive T cells. Collectively, our data
support a model in which immunological danger signals plus FVIII concentrates synergistically
increase human CD4+ T cell responses to FVIII protein.
Keywords
anti-FVIII immune response - lipopolysaccharide - T cells - danger signal - inhibitors
