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Ferrata Storti Foundation
Haematologica 2019 Volume 104(2):236-244
Pathogenic immune response to therapeutic factor VIII: exacerbated response or failed induction of tolerance?
Aditi Varthaman1,2,3,4 and Sébastien Lacroix-Desmazes2,3,4
1MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, UK; 2INSERM, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France; 3Sorbonne Université, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France and 4Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Centre de Recherche des Cordeliers, France
ABSTRACT
Therapeutic factor VIII is highly immunogenic. Despite intensive research in the last decades, the reasons why 5-30% of patients with hemophilia A (of all severities) develop inhibitory anti-factor VIII antibodies (inhibitors) following replacement therapy remain an enigma. Under physiological conditions, endogenous factor VIII is recog- nized by the immune system. Likewise, numerous observations indicate that, in hemophilia A patients without inhibitors, exogenous therapeutic factor VIII is immunologically assessed and tolerated. A large part of the research on the immunogenicity of therapeutic factor VIII is attempting to identify the ‘danger signals’ that act as adjuvants to the deleterious anti-factor VIII immune responses. However, several of the inflammatory assaults concomitant to factor VIII administration initially hypothesized as potential sources of danger signals (e.g., bleeding, infection, and vacci- nation) have been disproved to be such signals. Conversely, recent evi- dence suggests that cells from inhibitor-negative patients are able to acti- vate anti-inflammatory and tolerogenic mechanisms required to suppress deleterious immune responses, while cells from inhibitor-positive patients are not. Based on the available observations, we propose a model in which all hemophilia A patients develop anti-factor VIII immune responses during replacement therapy irrespective of associated danger signals. We further postulate that the onset of clinically relevant factor VIII inhibitors results from an inability to develop counteractive tolero- genic responses to exogenous factor VIII rather than from an exacerbated activation of the immune system at the time of factor VIII administration. A better understanding of the pathogenesis of neutralizing anti-factor VIII antibodies will have repercussions on the clinical management of patients and highlight new strategies to achieve active immune tolerance to ther- apeutic factor VIII.
Introduction
Hemophilia A is a rare X-linked hemorrhagic disorder that results from insuffi- cient levels of pro-coagulant factor VIII (FVIII). Patients with hemophilia A consti- tute a heterogeneous group of individuals. Three severities of hemophilia A are dis- tinguished depending on the levels of circulating endogenous FVIII. They reflect the diversity in the mutations in the gene encoding for FVIII: patients with a severe form of the disease have undetectable FVIII activity in plasma, while patients with mild and moderate hemophilia A have more than 1% of the normal levels of FVIII activity. Patients with severe hemophilia A are further differentiated according to the presence or absence of a non-functional FVIII protein (FVIII:Ag). For instance, among patients with severe hemophilia A, those with the V634M missense muta-
Correspondence:
Sebastien.Lacroix-Desmazes@crc.jussieu.fr
Received: October 4, 2018. Accepted: November 23, 2018. Pre-published: December 4, 2018
doi:10.3324/haematol.2018.206383
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/2/236
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