Regulatory T cells (Tregs) are a key player in mediating self-tolerance and immune homeostasis by modulating the effector function of T helper cells. Our group recently demonstrated that Tregs are also capable of inhibiting and modulating B cells in an antigen-specific manner, suggesting a role for regulatory T cells in regulating the long-live humoral immunity (Gotot et al., PNAS 2012; Gotot et al., Immunol Cell Biol 2018).
Hemophilia A is a bleeding disorder in which a key player of the coagulation cascade, factor VIII, is missing resulting in prolonged bleeding episodes and spontaneous bleedings into joints and muscles. Until today, the protein replacement therapy is the common approach to substitute the missing full-length clotting factor FVIII. However, a main complication of this therapy is the formation of neutralizing anti-FVIII antibodies (inhibitors), which abrogate coagulation and can be life threatening. Inhibitors occur in 30% of all patients. To eradicate these antibodies an immune tolerance induction therapy (ITI) was established. ITI is based on repetitive injections of high dose of plasma-derived or recombinant FVIII, which leads to the restoration of immune tolerance in up to 70% of the patients. Nevertheless, ITI success and duration are difficult to predict and the underlying immune tolerance mechanisms are still unknown.
Therefore, in a translational manner our lab is interested in
• identifying the cellular and molecular mechanisms promoting tolerance induction during ITI in order to elucidate new biomarkers
• develop genetically modified T cell-based therapies to improve B cell inhibition
• Investigate the effects of different nutrient diets and fusion proteins during the course of ITI in order to increase tolerance efficiency.
The overall goal is to answer the outstanding question: How is high-zone tolerance established and can that be optimized for other autoimmune diseases?