Abstract
The occurrence of neutralizing anti-FVIII antibodies is a major complication in the treatment of patients affected by hemophilia A. The immune response to FVIII is a complex, multi-factorial process that has been extensively studied for the past two decades. The reasons why only a proportion of hemophilic patients treated with FVIII concentrates develop a clinically significant immune response is incompletely understood. The “danger theory” has been proposed as a possible explanation to interpret the findings of some observational clinical studies highlighting the possible detrimental impact of inflammatory stimuli at the time of replacement therapy on inhibitor development. The host immune system is often challenged to react to FVIII under steady state or inflammatory conditions (e.g., bleeding, infections) although fine tuning of mechanisms of immune tolerance can control this reactivity and promote long-term unresponsiveness to the therapeutically administered factor. Recent studies have provided evidence that multiple interactions involving central and peripheral mechanisms of tolerance are integrated by the host immune system with the environmental conditions at the time of FVIII exposure and influence the balance between immunity and tolerance to FVIII. Here we review evidences showing the involvement of two key immunoregulatory oxygenase enzymes (IDO1, HO-1) that have been studied in hemophilia patients and pre-clinical models, showing that the ability of the host immune system to induce such regulatory proteins under inflammatory conditions can play important roles in the balance between immunity and tolerance to exogenous FVIII.
Highlights
Hemophilia is a recessive X-linked inherited bleeding disorder caused by a deficient or defective protein needed for blood clotting
In patients affected by severe hemophilia that require prophylactic administration of exogenous Factor VIII (FVIII), the occurrence of neutralizing FVIIIspecific IgG antibodies directed toward the infused clotting factor is frequent
Decades of effort in investigating the immune response to FVIII have clearly highlighted the complexity of the process, which involves central and peripheral mechanisms of tolerance that are integrated by the host immune system with the environmental conditions at the time of FVIII exposure
Summary
Hemophilia is a recessive X-linked inherited bleeding disorder caused by a deficient or defective protein needed for blood clotting. Hemophilia A patients with less severe mutations that can still allow for a partial or complete production of FVIII antigen are still at risk of developing inhibitors These findings suggest that central tolerance is a first barrier against unwanted immune reactions against FVIII, but is not fool-proof and needs to be complemented with peripheral means of tolerance acquired during the adult life. Even though this has not been extensively studied in hemophilia yet, some evidence has been presented that mechanisms of peripheral tolerance are associated with a negative inhibitor status in hemophilia A patients and can be exploited to control the immune response against exogenous FVIII.
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