Prevention of the anti-factor VIII memory B-cell response by inhibition of Bruton tyrosine kinase in experimental hemophilia A
Sandrine Delignat,
Jules Russick,
Bagirath Gangadharan,
Julie Rayes,
Mathieu Ing,
Jan Voorberg,
Srinivas V. Kaveri,
Sébastien Lacroix-Desmazes
Affiliations
Sandrine Delignat
INSERM, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France;Université Pierre et Marie Curie-Paris 6, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France;Université Paris Descartes, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France
Jules Russick
INSERM, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France;Université Pierre et Marie Curie-Paris 6, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France;Université Paris Descartes, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France
Bagirath Gangadharan
INSERM, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France;Université Pierre et Marie Curie-Paris 6, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France;Université Paris Descartes, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France
Julie Rayes
INSERM, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France;Université Pierre et Marie Curie-Paris 6, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France;Université Paris Descartes, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France
Mathieu Ing
INSERM, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France;Université Pierre et Marie Curie-Paris 6, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France;Université Paris Descartes, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France
Jan Voorberg
Department of Plasma Proteins, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, the Netherlands
Srinivas V. Kaveri
INSERM, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France;Université Pierre et Marie Curie-Paris 6, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France;Université Paris Descartes, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France
Sébastien Lacroix-Desmazes
INSERM, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France;Université Pierre et Marie Curie-Paris 6, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France;Université Paris Descartes, UMR S 1138, Centre de Recherche des Cordeliers, Paris, France
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 tolerance 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 tyrosine 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 consistently 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 strategy to limit the reactivation of factor VIII-specific memory B cells upon re-challenge with therapeutic factor VIII.