The EDUC8 European Training Network unites experts in different disciplines and aims at developing novel diagnostic and therapeutic approaches to reduce the development of FVIII inhibitors in patients with hemophilia A. The results will be crucial for the development of innovative methods to predict patients at risk of developing ADA in response to treatment, and to prevent or treat ongoing neutralizing immune responses. The research program includes 2 scientific work packages (WP):
The immune response to therapeutic FVIII is a classical immune response against an exogenous antigen, wherein exogenous FVIII transiently accumulates in secondary lymphoid organs, is internalized by antigen-presenting cells (APCs) and presented to naïve FVIII-specific CD4+ T cells. Upon activation, FVIII-specific T cells proliferate and provide help to naïve FVIII-specific B cells that differentiate into memory B cells or plasmocytes secreting inhibitory anti-FVIII IgG. Different risk factors for the development of an anti-FVIII immune response have been identified. Yet, it is impossible to predict whether a given patient will develop FVIII inhibitors. The general goal of WP1 is to decipher at the molecular and cellular levels the interplay between FVIII and cellular and humoral components of the immune system. Using original and complementary approaches, we will identify predictors of allo-immunization to therapeutic FVIII and potential biomarkers for clinical outcome. We will also develop tools to follow the anti-FVIII immune response in the course of FVIII replacement therapy. A first objective of WP1 is to determine the specificity, the diversity and the clonal frequency of FVIII-specific T cells. The second objective will identify HLA-DP4-restricted FVIII immuno-dominant T-cell epitopes. Our third objective is to analyse the repertoires of antibodies present in naïve and allo-immunized patients. Lastly, we will determine the degree of risk for inhibitor development that is associated with different types of HA-causative genetic abnormalities.
WP1 is led by Dr Jan Voorberg from Stichting Sanquin Bloedvoorziening, Amsterdam, The Netherlands, and by Dr Bernard Maillère from Commissariat à l’énergie atomique et énergies alternatives, Gif-sur-Yvette, France.
There is currently no efficient strategy to impose tolerance to therapeutic FVIII in patients with hemophilia A and prevent the onset of FVIII inhibitors. Elimination of ongoing neutralizing anti-FVIII antibodies relies on ITI and/or use of B-cell depleting anti-CD20 monoclonal antibodies. These approaches are inefficient, prohibitively expensive, associated with adverse events and require extreme patient compliance. WP2 will explore 4 original strategies to induce FVIII-specific tolerance. We will exploit recent advances on the characterization of FVIII-derived immuno-dominant T cell epitopes to induce specific tolerance upon targeting of Liver sinusoidal endothelial cells (LSECs) or tolerogenic lectin receptors on innate immune cells. In another approach, we will focus on the gestational period to introduce FVIII during foetal life through the materno-foetal interface in order to induce FVIII-specific Tregs. Lastly, we will adapt the revolutionary CAR technology to FVIII-specific Tregs. Importantly, progress on the delineation of the MHCII-restricted FVIII peptidome, generation of novel immuno-monitoring tools (DNA barcoded DR/DP Dextramer reagents) and identification of potent mimotopes (WP1) will be implemented in WP2.
WP2 is led by Dr Sébastien Lacroix-Desmazes from the National Institute of Health and Medical Research (INSERM), Paris, France and by Dr Christoph Koenings from Goethe University, Frankfurt-am-Main, Germany.