Installing FVIII-specific tolerance in hemophilia A via tryptophan catabolites and aryl hydrocarbon receptor (AhR) activation

Appropriate management of bleeding episodes in severe hemophilia A patients requires replacement therapy with factor VIII (FVIII) to restore hemostasis. The occurrence of neutralizing antibodies (or inhibitors) to exogenous FVIII represents a major drawback of this replacement therapy in terms of mortality, morbidity and social costs.Because of the significant limitations of the current inhibitor treatment options, the development of novel strategies aimed at preventing or suppressing inhibitor formation remain a major priority in the care of hemophilic subjects. Based on our (and other's) results in the field of immune tolerance, we believe that the aryl hydrocarbon receptor (AhR) may be one of the most promising and druggable targets in avoiding or reversing inhibitor formation. The goal of this application is to unravel the role of a panel of nontoxic AhR ligands (i.e., endogenous or synthetic) in preventing or suppressing inhibitor formation in experimental models of hemophilia. These studies proposed here might ultimately pave the way to implementing approaches in humans to either prevent the formation or downregulate the production of neutralizing antibody to FVIII. Broadly speaking, we expect to be able to elucidate mechanisms that will offer an opportunity of modulating the immune response to factor VIII administration, whether during prophylaxis, to reduce the incident rate or inhibitors, or during immune tolerance to FVIII, to increase its likelihood of success. The findings along this direction could lead to the development of new strategies to prevent or clear anti-FVIII antibodies.