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

Abstract

Therapeutic factor VIII is highly immunogenic. Despite intensive research in the last decades, the reasons why 5-30% of patients with hemophilia A (of 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 is attempting to identify the ‘danger signals’ that act as adjuvants to the 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, and vaccination) have been disproved to be such signals. 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-factor VIII 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 will have repercussions on the clinical management of patients and highlight new strategies to achieve active immune tolerance to therapeutic factor VIII.

An update on the ‘danger theory’ in inhibitor development in hemophilia A

“…The infused clotting factor is perceived by the immune system as a foreign protein and as such it is hard to demonstrate a contributing effect of a danger signal. In a recent published paper, it even proposes that all hemophilia A patients develop anti-FVIII immune responses regardless the presence of danger signals and that particularly the ability to develop counteractive tolerogenic reactions determines if a patients will develop clinically significant inhibitors or not [86].…”

Tolerating Factor VIII: Recent Progress

“…The uptake of blood coagulation FVIII by antigen presenting cells has been studied intensively in the last decade. Most of these studies have been performed in model systems like human monocyte-derived dendritic cells as well as mouse bone marrowderived dendritic cells (32)(33)(34). In parallel, immuno-localization of FVIII in the spleen following its infusion into mice has generated very interesting findings on the topology of FVIII association with, and possibly uptake by, different populations of antigen presenting cells in specific niches within the splenic architecture (Figure 1).…”

Advances in knowledge of inhibitor formation in severe haemophilia A

“…Lastly, an alternative hypothesis has suggested that inhibitor development must result from ineffective tolerance induction to FVIII rather than being primarily driven by environmental signals or antigen fluctuations (Varthaman & Lacroix‐Desmazes, ). Unfortunately, whether FVIII‐specific tolerance is generated primarily due to central or peripheral mechanisms is still unresolved.…”