Presenter of 1 Presentation
O070 - ANTIGEN-SPECIFIC TOLERANCE INDUCTION AS A THERAPY FOR MYASTHENIA GRAVIS (ID 135)
Abstract
Background and Aims
Myasthenia gravis (MG), is an antibody-mediated, T-cell dependent autoimmune disease. In MG autoantibodies target mostly the muscle nicotinic acetylcholine receptor (nAChR), located at the neuromuscular junction. Currently, MG is usually treated with non-specific immunomodulatory agents, which may have several side effects. Therefore, there is a need for the development of novel, more specific therapies. Reprogramming the specific autoreactive immune cells in order to restore the immune tolerance is a compelling antigen specific approach.
Methods
We investigated the therapeutic potency of the human nAChR α1 subunit extracellular domain (α1-ECD), which contains several MG T and B cell epitopes, using a mutated form of α1-ECD with increased solubility. The in vivo studies were performed in a rat experimental autoimmune MG (EAMG) animal model, induced by immunisation with the α1-ECD and thus well suited for testing antigen-specific treatments. The animal clinical score, body weight, compound muscle action potential decrement and muscle AChR content were measured. Sera samples taken at various time points after induction were used for autoantibody characterization.
Results
We assessed therapeutic efficacy with different administration routes, doses and time points during disease progression. Our results showed that intravenous treatment with α1-ECD resulted in significantly reduced EAMG symptoms in a dose and time dependent manner. Changes in autoantibody levels and subclasses were detected. Importantly, the effect was long-lasting, in contrast to drugs representing current standard of care for MG.
Conclusions
Restoring immunological tolerance against specific autoantigens by intravenous administration is, therefore, a promising therapeutic approach for MG. Further investigations are underway to elucidate immune mechanisms involved.