Inhaltszusammenfassung

The ideal treatment of autoimmune diseases, such as Multiple Sclerosis, would be to specifically target the disease-causing immune cells without compromising the broader function of the immune system. This could be achieved by either deleting these cells or transform them into regulatory cells able to ameliorate disease. In the TCR-transgenic TG4 mouse model, where CD4+ T cells are specific for the myelin basic protein (MBP) Ac1-9 peptide, immunotherapy based on the administration of cognate ...The ideal treatment of autoimmune diseases, such as Multiple Sclerosis, would be to specifically target the disease-causing immune cells without compromising the broader function of the immune system. This could be achieved by either deleting these cells or transform them into regulatory cells able to ameliorate disease. In the TCR-transgenic TG4 mouse model, where CD4+ T cells are specific for the myelin basic protein (MBP) Ac1-9 peptide, immunotherapy based on the administration of cognate peptide in escalating dose immunotherapy (EDI), induces tolerance in these myelin-specific CD4+ T cells and protects the animals from experimental autoimmune encephalomyelitis (EAE). In this thesis, three aspects of this method of tolerance induction are addressed. First, we demonstrate that antigen-specific peptide immunotherapy leads to an increase in the number of CD4+ Foxp3+ Treg cells and IL-10-secreting CD4+ T cells not just in secondary lymphoid structures, but in organs throughout the whole body. In addition to an increase in the number of CD4+ T cells with regulatory properties, effector T cells were prevented from entering the central nervous system (CNS). Analysis of changes to the phenotype of CD4+ T cells during EDI demonstrated that the inhibitory receptors TIM-3, TIGIT and PD-1 were significantly upregulated on both IL-10-secreting cells and Foxp3+ cells but no single receptor or a combination could be regarded as a biomarker for tolerised CD4+ T cells. In the second part, we demonstrate the important principle that tolerised CD4+ T cells can mediate regulation of not only T cells specific for the treatment peptide, but also CD4+ T cells that recognise immunodominant peptides from related proteins. We found that tolerised MBP-specific CD4+ T cells were able to exert linked bystander suppression of MOG35-55-reactive T cells in vivo, most successfully so when both peptides where presented by the same antigen-presenting cell. Finally, we reveal a previously unknown role for a subset of antigen-presenting cells with regulatory properties, known as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in limiting immune responses after EDI. Although best known for their detrimental role as immunosuppressors in cancer, PMN-MDSCs could play a beneficial role in the treatment of autoimmune disease. We discovered that the number of PMN-MDSCs increases over the course of EDI. In vitro, these PMN-MDSCs inhibited CD4+ T cell proliferation in a cell contact-dependent manner, mediated by arginase-1. Upon adoptive transfer into untreated mice, PMN-MDSCs suppressed CD4+ T cell activation. The spleen might be a particularly important site for the function of PMN-MDSCs as the removal of the spleen abrogated not only the increase of PMN-MDSCs in other organs, but also reneged tolerance induction. Overall, this body of work not only contributes new insights into the changes in CD4+ T cell phenotype during EDI, it also reveals a new aspect of bystander suppression in autoimmune disease and, most importantly, unveils the discovery of an as-yet undescribed role for PMN-MDSCs in antigen-specific tolerance induction.» weiterlesen» einklappen

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Klassifikation

DDC Sachgruppe:
Biowissenschaften, Biologie