Dissecting dendritic cell subsets as key to installing tolerance to FVIII in hemophilia A

Hemophilia A is an inherited disorder caused by absent or deficient functional clotting factor VIII (FVIII). The availability of high-quality factor concentrates has greatly contributed to an improved quality of life and reduced morbidity in the hemophilia community over the last quarter of century. Yet, one of the most challenging clinical complications for people with hemophilia remains the development of neutralizing antibodies against FVIII, which renders replacement therapy ineffective. Thus, there is an urgent need for more innovative therapies reversing the course of this condition by restoring or boosting immune tolerance to FVIII. Previous studies by our team revealed that the presence of anti-FVIII antibodies in severe hemophilia A patients, is associated with dysfunctional activation of an immune regulatory protein, involved in degradation the aminoacid tryptophan. Interestingly, in a recent study, we found that administration of tryptophan derived compounds, was able to prevent the generation of antibodies to FVIII in animal models of hemophilia A. Specific white blood cells, known as dendritic cells (DC) participate in the enforcement of peripheral tolerance. In this project, we mean to experimentally test the hypothesis that specialized Dendritic Cell subsets, producing tryptophan derivatives may be required to install tolerance to FVIII in hemophilia. We aim to achieve our goal by a using a very innovative approach, never carried out in hemophilia, consisting in administering FVIII, to novel engineered mouse models, mimicking human hemophilia A but lacking selected immune DC subsets. We expect to identify distinct tolerogenic DC subsets carrying a specific genetic program required to promote tolerance to FVIII in vivo, potentially defective in patients with inhibitors. Moreover, these studies will contribute significantly to the implementation of innovative therapies for treating FVIII inhibitors in hemophilia A patients.