Summary
Treatment of haemophilia A by infusions of the clotting factor VIII (FVIII) results
in the development of inhibitors/anti-drug antibodies in up to 25 % of patients. Mechanisms
leading to immunogenicity of FVIII products are not yet fully understood. Amongst
other factors, danger signals as elicited upon infection or surgery have been proposed
to play a role. In the present study, we focused on effects of danger signals on maturation
and activation of dendritic cells (DC) in the context of FVIII application. Human
monocyte-derived DC were treated with FVIII alone, with a danger signal alone or a
combination of both. By testing more than 60 different healthy donors, we show that
FVIII and the bacterial danger signal lipopolysaccharide synergise in increasing DC
activation, as characterised by increased expression of co-stimulatory molecules and
secretion of pro-inflammatory cytokines. The degree and frequency of this synergistic
activation correlate with CD86 expression levels on immature DC prior to stimulation.
In our assay system, plasma-derived but not recombinant FVIII products activate human
DC in a danger signal-dependent manner. Further tested danger signals, such as R848
also induced DC activation in combination with FVIII, albeit not in every tested donor.
In our hands, human DC but not human B cells or macrophages could be activated by
FVIII in a danger signal-dependent manner. Our results suggest that immunogenicity
of FVIII is a result of multiple factors including the presence of danger, predisposition
of the patient, and the choice of a FVIII product for treatment.
Keywords
Haemophilia A - inhibitors - danger signals - dendritic cells - early immune responses
