Inhibitor Formation in Congenital Hemophilia A: an Immunological Perspective
Résumé
Hemophilia A (HA) is an X-linked inherited disorder caused by a defect in the gene encoding coagulation factor VIII (FVIII). The disease is typically divided in three categories of severity based on the circulating levels of pro-coagulant FVIII detected in plasma. HA is "mild" (5-40% of residual FVIII compared with normal plasma), "moderate" (1-5%), or "severe" (<1%). The most efficient strategy to correct or prevent bleeding in the patients relies on the intravenous administration of exogenous therapeutic FVIII that is either plasma derived (pdFVIII) or recombinant (rFVIII). Currently, the most serious complication of FVIII replacement therapy is the development of anti-FVIII antibodies with neutralizing properties that are referred to as "FVIII inhibitors." While anti-drug antibodies typically arise in 1 to 5% of patients, FVIII inhibitors develop in up to 30% of the patients with HA. 1 In addition, the intravenous route of administration is classically considered as non-immunogenic. 2 The elevated rate of development of inhibitory antibodies to FVIII is thus intriguing from an immunological standpoint. Here, we will review the current knowledge on the anti-FVIII immune response with a specific focus on the molecular interactions at play in the recognition of FVIII by the cells of the innate and adaptive immune system and on the intuitively proposed risk factors for FVIII alloimmunization. The review will also propose a short summary of the different immuno-intervention approaches validated in preclinical models of HA to confer tolerance to exogenous FVIII. Dynamics of the anti-FVIII Immune Response The Primary Immune Response to Therapeutic FVIII The development of FVIII inhibitors results from a classical allogenic immune response that is dependent on CD4 T cells. 3 The implication of T cells has been suggested empirically in inhibitor-positive patients who became tolerant to exogenous FVIII following human immunodeficiency virus Keywords ► hemophilia A ► factor VIII ► immunogenicity Abstract The immunogenicity of therapeutic factor VIII (FVIII) in patients with hemophilia A has been puzzling scientific and clinical communities for more than 3 decades. Indeed, the development of inhibitory antibodies to FVIII remains a major clinical challenge and is associated with enormous societal costs. Thus, the reasons for which a presumably innocuous, short-lived, intravenously administered glycoprotein triggers such a dele-terious, long-lasting neutralizing immune response is an enigma. This review does not pretend to bring an answer to this challenging question. It will however summarize the latest findings regarding the molecular interactions at play in the recognition of FVIII by the immune cells, the validity of the proposed risk factors for FVIII alloimmunization, and the different solutions that allow induction of FVIII-specific tolerance in preclinical models of hemophilia A.
Domaines
Immunologie
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