Summary
Several lines of evidence have shown that antibody responses to coagulation factor
VIII (FVIII) in patients with hemophilia A depend on the help of activated CD4+ T cells. The primary activation of CD4+ T cells requires interaction with mature dendritic cells (DCs) that present antigenic
peptides in the context of MHC class II and express costimulatory molecules. Maturation
of DCs requires danger signals provided by exogenous or endogenous stimuli such as
pathogen-derived products or inflammatory cytokines. We asked the question whether
FVIII itself, FVIII complexed with von Willebrand factor (VWF) or thrombin-activated
FVIII contain danger signals for human DCs that induce the upregulation of costimulatory
molecules or the expression of proinflammatory cytokines necessary for effec tive
activation of CD4+ T cells. Human peripheral monocytes were differentiated into DCs. FVIII, thrombin-activated
FVIII, VWF, VWF-FVIII, lipopolysaccharide (LPS), LPS+FVIII, LPS+VWF or LPS+FVIII-VWF
were added either on day 0 or on day 5 of differentiation cultures. Differentiation
markers, cytokines in cell culture supernatants and the capacity of DCs to stimulate
autologous and allogeneic T cells were analysed after seven days of differentiation
cultures. Our results indicate that neither FVIII, thrombin-activated FVIII, VWF nor
a complex of FVIII and VWF modulate the maturation of human DCs or their capacity
to stimulate autologous or allogeneic T cells. We conclude that neither of these proteins
present danger signals to human DCs.
Keywords
Hemophilia A - FVIII inhibitors - human dendritic cells - danger signals - factor
VIII