Pathogenic immune response to therapeutic factor VIII: exacerbated response or failed induction of tolerance?

Therapeutic factor VIII presents with elevated immunogenicity. Despite intensive research in the last decades, the reasons for which 5-30% of patients with hemophilia A (encompassing all severities) develop inhibitory anti-factor VIII antibodies (inhibitors) following replacement therapy remain an enigma. Under physiological conditions, endogenous factor VIII is recognized by the immune system. Likewise, numerous observations indicate that, in hemophilia A patients without inhibitors, exogenous therapeutic factor VIII is immunologically assessed and tolerated. A large part of the research on the immunogenicity of therapeutic factor VIII attempts to identify the 'danger signals' that adjuvant deleterious anti-factor VIII immune responses. However, several of the inflammatory assaults concomitant to factor VIII administration initially hypothesized as potential sources of danger signals (e.g., bleeding, infection, vaccination, etc) have been disproved. Conversely, recent evidence suggests that cells from inhibitor-negative patients are able to activate anti-inflammatory and tolerogenic mechanisms required to suppress deleterious immune responses, while cells from inhibitor-positive patients are not. Based on the available observations, we propose a model in which all hemophilia A patients develop anti-FVIII immune responses during replacement therapy irrespective of associated danger signals. We further postulate that the onset of clinically relevant factor VIII inhibitors results from an inability to develop counteractive tolerogenic responses to exogenous factor VIII rather than from an exacerbated activation of the immune system at the time of factor VIII administration. A better understanding of the pathogenesis of neutralizing anti-factor VIII antibodies shall have repercussions on the clinical management of the patients and highlight new strategies to achieve active immune tolerance towards therapeutic factor VIII.