Effects of dimethyl fumarate in two animal models of MS
von Sarah Traffehn
Datum der mündl. Prüfung:2017-04-21
Betreuer:PD Dr. Imke Metz
Gutachter:Prof. Dr. Wolfgang Brück
Gutachter:Prof. Dr. Eberhard Fuchs
EnglischMS is a heterogeneous disease characterized by transient and later permanent disability caused by inflammatory CNS lesions with profound axonal loss and demyelination. Although the exact pathogenesis of the disease is still unknown, it is assumed that MS is an autoimmune disease. While earlier concepts focused on the role of T cells, B cells are increasingly recognized to play an important role. The fumaric acid ester DMF is an immunomodulatory agent which is approved for the therapy of relapsing-remitting MS. In MS patients, DMF effectively reduces the relapse rate as well as the number and extent of MRI lesions. DMF shows anti-inflammatory properties by modulating immune cell functions leading to a decrease in pro-inflammatory cytokine production. Furthermore, DMF may exert neuroprotective effects in part mediated by the induction of Nrf2 resulting in the activation of antioxidant response pathways. In our study, we investigated whether DMF has neuroprotective and/or neuroregenerative function independent of its effect on the peripheral immune system. For this purpose, DMF effects were studied in a setting of toxic demyelination, namely the cuprizone model. In the second part of our study, it was also analyzed to what extent DMF influences pathogenic B cell and T cell properties in in an EAE model, in which B cells are involved in a pathogenic manner. Regarding the first part of the project, we found that DMF significantly diminished the cuprizone-induced apoptosis of oligodendrocytes and increased the number of oligodendrocytes over time during cuprizone intoxication. Upon short-term cuprizone exposure, DMF increased the number of oligodendrocyte progenitor cells (OPCs) whereas after long-term cuprizone diet higher numbers of mature oligodendrocytes could be observed. Although DMF treatment did not influence demyelination and remyelination of the corpus callosum, acute axonal damage was significantly decreased in DMF treated mice. In conclusion, DMF was found to exert moderate neuroprotective and neuroregenerative effects independent of the peripheral immune system. The observation of higher OPC numbers in conjunction with a higher number of mature oligodendrocytes after long-term cuprizone diet may suggest that DMF treatment potentially promotes the differentiation of oligodendrocytes. In the second part, preventive as well as therapeutic DMF treatment was effective in a B cell-mediated EAE model. Clinical benefit of DMF treatment in mice with established EAE was associated with decreased demyelination and inflammation of the spinal cord. The infiltration of macrophages/microglia and partially also of T cells was reduced by DMF treatment, whereas DMF had no detectable effect on the number of infiltrating B cells. In peripheral compartments, DMF led to a lower T cell frequency in the blood, while a complementary accumulation of T cells could be observed in lymph node and spleen of DMF-treated mice with EAE. Besides its effect on T cell frequencies, DMF treatment significantly reduced activation, differentiation and proliferation of peripheral T cells. In contrast, DMF-treatment exerted no inhibitory effect on peripheral B cells and caused an enhanced activation and differentiation of B cells. Most persistently, we observed an upregulation of MHC II on B cells. Functionally, these alterations were associated with an enhanced capacity of B cells to act as antigen presenting cells for activation of T cells. In conclusion, the observed clinical and pathological benefit in EAE with pathogenic B cell function thus appears to be mediated by an immunomodulatory effect of DMF directly on T cells. Contrary, we found that DMF treatment promoted antigen-presenting properties of B cells, while this study could not conclusively reveal which T cell phenotype is induced by these more potent B cells. Nevertheless, the primary observation of an enhanced B cell activation and antigen presenting function upon DMF treatment might be of significant relevance in specific therapeutic decisions, such as choosing the appropriate MS medication subsequent to therapeutic B cell depletion.
Keywords: multiple sclerosis