Inhibitors-Recent insights.

The development of inhibitory antibodies to therapeutic factor VIII (FVIII) in haemophilia A (HA) patients is the major complication in treatment/prevention of haemorrhages. The reasons some HA patients develop inhibitors while others do not remain unclear. This review briefly summarizes our understanding of anti-FVIII immune responses, the roles of T cells, both effector and regulatory, and generally discusses the interplay between FVIII and the immune system, both in factor replacement therapy and gene therapy, with some comparisons to factor IX and haemophilia B therapies. Notably, we propose that the prevailing observed active tolerance to FVIII in both HA and non-HA individuals rests to greater or lesser extents on peripherally induced immune tolerance. We also propose that the immune systems of inhibitor-negative HA patients do not merely ignore therapeutic FVIII, but rather have immunologically assessed and actively tolerized the patients to exogenous FVIII. Induction of such peripheral immune tolerance may further be triggered in HA patients who failed to tolerize upon initial FVIII exposure by 'appropriate' stimulation of their immune system, eg by immune tolerance induction therapy via intensive FVIII therapy, by oral administration of FVIII, by cellular therapies or by gene therapy directed to immuno-tolerogenic sites such as the liver.