Mechanisms of action of immune tolerance induction against factor VIII in patients with congenital haemophilia A and factor VIII inhibitors

Abstract

SummaryIn its most severe form, haemophilia A is a life-threatening haemorrhagic bleeding disorder that is caused by mutations in the factor VIII (FVIII) gene. About 25% of patients who receive replacement therapy with intravenous FVIII products develop neutralising antibodies (FVIII inhibitors) that inhibit the function of substituted FVIII. Long-term application of high or low doses of FVIII has evolved as an effective strategy for eradicating antibodies and inducing long-lasting immune tolerance. Despite clinical experience with the therapy, little is known about the immunological mechanisms that cause the downmodulation of FVIII-specific immune responses or the induction of long-lasting immune tolerance against FVIII. This review summarises current knowledge of the immunological mechanisms that might be involved in the induction of immune tolerance against FVIII in patients with haemophilia A who have FVIII inhibitors. In addition to data from patients with haemophilia A, data from patients who have had organ transplants or have immune-related disorders, such as autoimmune diseases, are considered as well as data from animal models.

F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis

“…by guest www.bloodjournal.org From any production of circulating FVIII polypeptides, and this explains why patients with these mutations have an increased risk for developing inhibitors. 58 Based on the recent finding that patients with the intron 22 inversion express the entire FVIII protein as 2 polypeptide chains, it has been suggested that intracellular production of parts of an endogenous FVIII protein may lead to some degree of tolerance toward replacement FVIII proteins and to a reduced risk of inhibitor development. 59 When considered together with the findings from the present meta-analysis, which demonstrate that intron 22 inversions confer a lower inhibitor risk as large, multi-exon deletions, this hypothesis may be an explanation for the difference in inhibitor risks among patients with F8 genotypes that do not result in extracellular protein production.…”

A Novel Strategy To Reduce the Immunogenicity of Biological Therapies

“…Other postulated mechanisms for high-zone tolerance are inhibition of B cell Ag presentation (29) or cathepsin-induced apoptosis of T cells (30). Inflammatory mediators or "danger signal" may provoke immunogenicity (28), so, for instance, concomitant infection reduces the efficacy of the Bonn protocol (31). Drugs, such as alemtuzumab, that lyse hematopoietic cells, appear to create adjuvanticity for themselves and are consequently particularly immunogenic (12).…”

FVIII inhibitors: pathogenesis and avoidance

“…Here, frequent exposure to the deficient factor in the absence of systemic inflammation may induce Tregs with a subsequent lack of T-helper cells, preventing B-cell differentiation and promoting tolerance through B-cell anergy and/or deletion. 24 In this process, dosing has been implicated as a crucial factor in that high doses in a murine model of hemophilia A irreversibly inhibited the memory B cells via an indirect effect on both APCs and T cells. 25 This may explain the benefits of high-dose immune tolerance protocols, but because only 1 randomized ITI study has been completed in humans and that study focused on "good-risk" patients, the extent to which these in vitro findings are applicable is not clear.…”