| dc.contributor.advisor | Flügel, Alexander Prof. Dr. | |
| dc.contributor.author | Chiappetta, Giuseppe | |
| dc.date.accessioned | 2019-10-11T09:54:15Z | |
| dc.date.available | 2019-10-11T09:54:15Z | |
| dc.date.issued | 2019-10-11 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0005-1271-7 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7670 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 610 | |
| dc.title | The Role of Glycolysis in shaping the Autoimmune Potential of Myelin-Reactive T Cells in the Course of Experimental Autoimmune Encephalomyelitis | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Simons, Mikael Prof. Dr. | |
| dc.date.examination | 2018-11-07 | |
| dc.description.abstracteng | Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), where myelin-reactive T cells play a key role in the inflammatory events responsible for the formation of demyelinated lesions. Auto-reactive T cells are present in the immune repertoire of healthy people, but they only rarely cause autoimmunity. Exact mechanisms by which autoreactive T cells become pathogenic are still unclear.
In order to investigate these mechanisms, we used a transgenic Lewis rat model containing endogenous myelin basic protein (MBP)-reactive CD4 T cells and we analyzed these cells in naïve state or during experimental autoimmune encephalomyelitis (EAE) conditions. Further, we analyzed another experimental model, namely “memory” Lewis rats, which contain lifelong-persisting myelin-reactive memory CD4 T cells in their immune repertoire. Neither of these models develop spontaneous autoimmunity, however active immunization can readily induce disease with accelerated onset. We found that T cells of the memory but not of the naïve phenotype are capable of entering spinal cord tissue. Using intrathecal transfer of different T cells populations we were able to show that only freshly activated effector T cells are able to induce clinical disease after bypassing the blood brain barrier (BBB). After analysis of activation levels for different T cell subsets in active and transfer EAE, we hypothesized that the functional state of recently activated effector and not of resting memory MBP-specific T cells supports their pathogenicity and that such a state might be related to glycolytic activity. We studied glycolysis and factors regulating the metabolic switch after activation of MBP-specific T cells in vitro and after transfer in vivo during the course of transfer EAE. Of note, the inhibition of glycolysis by drug treatment in vivo delayed the onset of transfer EAE. This effect was associated with reduced inflammatory infiltration of the CNS tissue at the onset of disease. To confirm that the effect of in vivo glycolysis inhibition modulates the function of T cells, we tested a similar pharmacological approach in vitro and could show that inhibition of glycolysis in T cells prior to antigenic stimulation reduces the production of pro-inflammatory cytokines.
Our results suggest that a high glycolytic rate enables CD4 T cells to perceive weak antigenic signals in the immune privileged tissue of the CNS and to become re-activated, triggering inflammatory processes. A therapy lowering the glycolytic rate in auto-reactive T cells may be a relevant approach for the treatment of T cell mediated autoimmunity. | de |
| dc.contributor.coReferee | Reichardt, Holger Prof. Dr. | |
| dc.subject.eng | Glycolysis | de |
| dc.subject.eng | Immunology | de |
| dc.subject.eng | T cells | de |
| dc.subject.eng | EAE | de |
| dc.subject.eng | T cell activation | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0005-1271-7-7 | |
| dc.affiliation.institute | Medizinische Fakultät | |
| dc.subject.gokfull | GOK-MEDIZIN | de |
| dc.identifier.ppn | 1678787612 | |