Inhibitors - cellular aspects and novel approaches for tolerance

Abstract

The immune response against therapeutic clotting factors VIII and IX (FVIII and FIX) is a major adverse event that can effectively thwart their effectiveness in correcting bleeding disorders. Thus, a significant number of haemophilia patients form antibodies, called inhibitors, which neutralize the procoagulant functions of therapeutic cofactors FVIII (haemophilia A) or FIX (haemophilia B). Understanding the cellular and molecular aspects of inhibitor formation is critical to designing tolerogenic therapies for clinical use. This review will focus on the basis of the immune response to FVIII, in particular, and will discuss emerging efforts to not only reduce immunogenicity but also to prevent and/or reverse inhibitor formation.

Keywords: factor VIII; gene therapy; haemophilia; immunoglobulin fusions; regulatory T cells.

Fig. 1

Principles of B-cell-delivered gene therapy approach for tolerance induction.

Fig. 2

Anti-FVIII antibody levels in E16 mice treated with nanoparticles. Mice were injected with FVIII in combination with tolerogenic nanoparticles (Groups 1 and 2), empty particles (Group 3), or IVIG (Group 4). Groups 1 and 2 contain a tolerogenic immunomodulator but vary with respect to antigen content. Four weeks after the last treatment, the mice were immunized repeatedly with FVIII alone as challenge. Data represent titres at day 143, more than 3 months after the last treatment. Anti-FVIII antibody levels were measured by ELISA assay; for quantification, a standard curve was generated with a mixture of the mAbs of against the FVIII A2 and C2 domains. Error bars indicate SE of the mean value, *P < 0.05.

Fig. 3

Potential application of engineered Tregs to the prevention of inhibitor formation.