Antigen-specific suppression of EAE using immunization with MHC class II-restricted autoantigen epitopes containing an oxido-reductase motif
Antigeen-specifieke suppressie van EAE door middel van immunisatie met MHC klasse II-beperkte autoantigeen epitopen die een oxido-reductase motief bevatten
Deckers, Kato; M0321124
Multiple sclerosis is a demyelinating disease affecting young adults. Currently there is no cure for this highly debilitating disease. The activation of CD4+ T cells recognizing autoantigens in the CNS plays an important role in the pathogenesis of MS. As a consequence, switching off the activation of effector T cells is a strategic target for the cure of the disease. In our lab, a methodology was developed to polarize CD4+ T cells into a cytolytic function. These cytolytic CD4+ T cells (cCD4+ T cells) induce apoptosis in APCs presenting the cognate peptide. Polarization is achieved through activation with peptides to which a thiol oxidoreductase motif within flanking residues is added (CxxC MOG peptide).In this PhD research, the MHC class II restricted MOG peptide, an immunodominant epitope causing MS, was used to induce these cytolytic CD4+ T cells in EAE, a commonly used animal model for MS. These cCD4+ T cells induced apoptosis in APC presenting the cognate peptide and in bystander T cells located in the vicinity which recognize an epitope on the same APC. As a result, the immune reaction against myelin peptides is shut down at a very early stage since the presentation of myelin peptides by APCs is prevented.When mice were immunized with the modified MOG peptide before onset of EAE, disease symptoms were significantly lower, both in a transient EAE model and in a more complex chronic EAE model. Moreover, in a therapeutic setting, in which mice were immunized with the modified peptide well after first clinical signs were apparent, disease severity was significantly ameliorated. Histological examination further supported these findings. Mice that were immunized with the modified peptide showed less inflammation, less T cell infiltration and less demyelination in CNS. This was seen when immunotherapy was carried out in a preventive setting as well as in a therapeutic setting. The extent of demyelination in mice treated in a therapeutic setting was comparable to that in mice treated in a preventive setting, this suggested that remyelination took place.Evaluation of cytokine production showed that IL-17 was significantly decreased in mice that were treated with the modified peptide. Production of IFN-g on the other hand was the same in treated mice and control mice. Production of IL-17 could not be brought back to initial levels when cCD4+ T cells were restimulated with the wild type peptide. This suggested that the cytolytic phenotype is an end-stage phenotype.The undisputed advantage of this possible new immunotherapy includes the ease with which cytolytic CD4+ T cells can be elicited. 4 injections with 50 µg of modified peptide proved to be sufficient to achieve clinical efficacy in a preventive setting, and, more importantly, in a therapeutic setting. In this last setting, only 4 injections were required to diminish clinical symptoms for at least 200 days. Preliminary data from in vitro studies on human cells yielded promising results.Taken together, we established a proof of concept for treatment of MS by the use of MHC class II restricted epitopes to which a thiol oxidoreductase CxxC motif is added. This potential new therapy was validated in EAE, the commonly used animal model for MS. CD4+ T cells that are stimulated with these epitopes acquire a cytolytic function which leads to an early shut down of the immune reaction towards these and cognate peptides. Seen the promising results, this newly developed immunotherapy will be brought in the clinical phase in the near future.