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Ferrata Storti Foundation
Haematologica 2019 Volume 104(5):1046-1054
Coagulation & its Disorders
Prevention of the anti-factor VIII memory B-cell response by inhibition of Bruton tyrosine kinase in experimental hemophilia A
Sandrine Delignat,1,2,3 Jules Russick,1,2,3 Bagirath Gangadharan,1,2,3 Julie Rayes,1,2,3 Mathieu Ing,1,2,3 Jan Voorberg,4 Srinivas V. Kaveri1,2,3 and Sébastien Lacroix-Desmazes1,2,3
1INSERM, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France; 2Université Pierre et Marie Curie-Paris 6, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France; 3Université Paris Descartes, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France and 4Department of Plasma Proteins, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, the Netherlands.
ABSTRACT
Hemophilia A is a rare hemorrhagic disorder caused by the lack of functional pro-coagulant factor VIII. Factor VIII replacement therapy in patients with severe hemophilia A results in the development of inhibitory anti-factor VIII IgG in up to 30% of cases. To date, immune tol- erance induction, with daily injection of large amounts of factor VIII, is the only strategy to eradicate factor VIII inhibitors. This strategy is, however, efficient in only 60-80% of patients. We investigated whether blocking B- cell receptor signaling upon inhibition of Bruton tyrosine kinase prevents anti-factor VIII immune responses in a mouse model of severe hemophilia A. Factor VIII-naïve and factor VIII-sensitized factor VIII-deficient mice were fed with the selective inhibitor of Bruton tyrosine kinase, (R)-5- amino-1-(1-cyanopiperidin-3-yl)-3-(4-[2,4-difluorophenoxyl] phenyl)-1H pyrazole-4-carboxamide (PF-06250112), to inhibit B-cell receptor signaling prior to challenge with exogenous factor VIII. The consequences on the anti-factor VIII immune response were studied. Inhibition of Bruton tyro- sine kinase during the primary anti-factor VIII immune response in factor VIII-naïve mice did not prevent the development of inhibitory anti-factor VIII IgG. In contrast, the anti-factor VIII memory B-cell response was con- sistently reduced upon treatment of factor VIII-sensitized mice with the Bruton tyrosine kinase inhibitor. The Bruton tyrosine kinase inhibitor reduced the differentiation of memory B cells ex vivo and in vivo following adoptive transfer to factor VIII-naïve animals. Taken together, our data identify inhibition of Bruton tyrosine kinase using PF-06250112 as a strate- gy to limit the reactivation of factor VIII-specific memory B cells upon re- challenge with therapeutic factor VIII.
Introduction
Hemophilia A is a rare X-linked hemorrhagic disorder that results from subopti- mal levels of pro-coagulant factor VIII (FVIII). Treatment or prevention of bleeding is managed by replacement therapy using therapeutic FVIII, which restores coagu- lation. However, in up to 30% of patients with severe hemophilia A administration of exogenous FVIII is complicated by the development of anti-FVIII antibodies that neutralize FVIII pro-coagulant activity and are referred to as ‘FVIII inhibitors’.1,2 To date, the most efficient strategy to eradicate inhibitors in inhibitor-positive patients with the severe form of the disease consists in repeated injections of high doses of FVIII and is referred to as ‘immune tolerance induction’ (ITI). Proposed mechanisms of action of ITI include the induction of protective anti-idiotypic antibodies that neutralize FVIII inhibitors, as observed in hemophilia A patients,3,4 and the inhibi-
Correspondence:
SÉBASTIEN LACROIX-DESMAZES
sebastien.lacroix-desmazes@crc.jussieu.fr
Received: June 21, 2018. Accepted: November 22, 2018. Pre-published: December 13, 2018.
doi:10.3324/haematol.2018.200279
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