Project: Novel recombinant immunotoxins for the elimination of auto-reactive B lymphocytes in multiple sclerosis (MS)
Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system that is characterized by inflammatory demyelination processes damaging nerves and resulting in chronic disabilities. Recent studies show that the disease is not completely T cell-mediated, but that also B lymphocytes play a crucial role in disease pathogenesis. These findings were confirmed by systemic B cell elimination using the anti-CD20-specific antibody rituximab that resulted in a reduction of lesions and a reduced relapse rate in ‘relapsing-remitting multiple sclerosis’ (RRMS). The clinical effect was already evident before a significant effect on the level of serum immunoglobulin was detectable. This phenomenon suggests that the role of B lymphocytes in the pathogenesis is beyond the generation of pathogenic autoantibodies. Related mechanisms and their antigen specificity are currently not yet fully understood. This project assesses the extent to which a selective elimination of defined antigen-specific B cell population leads to a positive success. The success of the treatment is examined in vitro and in the experimental autoimmune encephalomyelitis (EAE) animal model. This model reflects the most important pathological and clinical characteristics of the human disease and is used by default for the assessment of novel therapeutics.
Goal of the project
The basic findings on the mode of action were already confirmed by preliminary experiments carried out in close cooperation with the division of Clinical Neuroscience (University of Glasgow, UK) under the direction of Professor Christopher Linington. We produced a novel recombinant immunotoxin consisting of the myelin oligodendrocyte glycoprotein (MOG) fused to a truncated version of the exotoxin A of Pseudomonas aeruginosa (ETA). Using this fusion protein, we were able to selectively deplete MOG-specific B lymphocytes and reduce disease severity in a MOG-induced EAE animal model. Before this innovative approach can be developed into a therapeutic tool for treating multiple sclerosis and other autoimmune diseases with pathogenic B cell activities, we want to determine how antigen-specific immunotoxins can influence the disease development in the EAE animal model.
