Kurzfassung

In autoimmune diseases, Th1 and Th17 cells were shown to play an important role. Th17 cells secrete IL-17A and IL-17F and are controlled by the transcription factor RORgt. Experimental autoimmune encephalomyelitis (EAE) is the animal model for multiple sclerosis, which can be induced in C57BL/6 mice. Many of the original observations on the pathogenic role of T cells in CNS autoimmunity were performed with Th1 cells, but more recently a pathogenic role of Th17 cells was shown for this...In autoimmune diseases, Th1 and Th17 cells were shown to play an important role. Th17 cells secrete IL-17A and IL-17F and are controlled by the transcription factor RORgt. Experimental autoimmune encephalomyelitis (EAE) is the animal model for multiple sclerosis, which can be induced in C57BL/6 mice. Many of the original observations on the pathogenic role of T cells in CNS autoimmunity were performed with Th1 cells, but more recently a pathogenic role of Th17 cells was shown for this disease.
Thereby, increasing evidence point to a pathogenic role for their signature cytokine, IL-17 itself; a view that is further supported by a recent clinical trial with an IL-17A-neutralizing antibody (Secukinumab).
IL-17A and IL-17F bind the same receptor complex (IL-17RA/IL-17RC heterodimer) and have very similar biological functions. We could show that although IL-17A-deficient animals can develop EAE, it was to a lesser extent compared to wild type animals. The disease severity is further reduced if the mice lack both IL-17A and IL-17F. We have recently generated mice with a loxP-flanked allele of IL-17RA. Deletion of this receptor results in cells that are unable to respond to IL-17A, IL-17F but also to IL-17C and IL-17E, other members of the family. This new IL-17RAFL/FL mouse strain allows us to understand exactly how IL-17 exerts its function. For that, we plan to use a series of mice expressing the Cre-recombinase in particular cells of the CNS. We have obtained mice that allow for the deletion of IL-17RA specifically in the endothelial cells of the blood-brain barrier (BBB), in astrocytes, NG2+ cells or neurons. These different conditional mutants will be subjected to active MOG induced EAE, or passive disease using T cell transfer with Th1 or Th17 cells, to determine whether the tissue-specific response to IL-17 differs when the encephalitogenic cells express this cytokine or not. Further, we have recently established a system that
allows us to isolate tagged RNA from specific cell types of the CNS. We will use this approach in combination with Next Generation Sequencing (NGS) to identify how the lack of IL-17 responsiveness affects gene expression of CNS cells during inflammation. Furthermore, we will also characterize the response of the different glial and neuronal cells to CNS inflammation, by comparison of gene expression profiles of naïve mice and mice afflicted with EAE. Finally, we plan to translate our findings from the animal model to the human disease by comparing the results to existing human NGS data sets as well as validating candidates with tissue samples derived from MS patients. Moreover, our findings from the mouse BBB will be validated with cultured human endothelial cells, including the manipulation of target candidates by genetic and pharmacological means. Taken together, the proposed experiments will enable us to determine the tissue-specific response of the CNS to IL-17, and understand how this cytokine contributes to the damage seen in CNS autoimmunity.» weiterlesen» einklappen