Einfluss von Fumarsäureestern auf T-Zellsubpopulationen bei Patienten mit Psoriasis

Bei Psoriasis handelt es sich um eine häufige, typischerweise chronisch verlaufende, entzündliche Hauterkrankung, die circa 2% der Gesamtbevölkerung betrifft. Die Hautveränderungen sind durch erythematöse, scharf begrenzte Plaques oder Papeln gekennzeichnet, die von silbrig-weißen Schuppen bedeckt s...

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Bibliographic Details
Main Author: Riemann, Stella
Contributors: Eming, R. (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2021
Online Access:PDF Full Text
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Psoriasis is a common, chronic inflammatory skin disease typically appearing as erythematous plaques or papules covered with silvery-white scales. Skin changes are normally not life-threatening, nevertheless they are stigmatizing and can put a heavy burden on the patients’ lives. Since sole topical treatment is often not successful, systemic medication is increasingly applied. In Germany, fumaric acid esters (FAE) are the most commonly prescribed first-line systemic treatment for moderate to severe psoriasis. The development of psoriasis appears to be of an immunological origin. Distinct changes on the T-cellular level have been reported for psoriasis. Although the licenced FAE formulation Fumaderm is approved since 1994, the impact of the main active substance dimethyl fumarate (DMF) and its metabolite monomethyl fumarate (MMF) is still not fully elucidated. Thus, the aim of the present study was to investigate the effects of FAE on distinct T cell subsets in patients with psoriasis using the highly sensitive ELISPOT analysis. For this purpose, 15 patients were treated with FAE and based on the secretion of their marker cytokines IFN-γ-, IL-17-, IL-5- and IL-10 after ex vivo activation of peripheral blood mononuclear cells, T helper (Th1), Th17, Th2 and regulatory T cells were followed over a period of up to 12 weeks. FAE-therapy led to an improvement of clinical symptoms in most patients based on the Physician Global Assessment (PGA). The early treatment process was accompanied by a decrease of T cells. A significant reduction was determined for all T cell subsets after stimulation of PBMC with T cell-specific anti-CD3/CD28 beads and the mitogen phytohemagglutinin (PHA), except for PHA-stimulated IL-10-secreting cells. Interestingly, especially IFN-γ-secreting Th1 cells were reduced, while FAE did not seem to induce immunosuppressive IL-10-secreting T cells in vivo. In addition to the ex vivo data during the early course of treatment, in vitro experiments with DMF, MMF and fumaric acid (FA) were performed with PBMC of patients and healthy controls. Here, DMF, but neither MMF nor FA, led to a significant, dose-dependent reduction of all examined T cell frequencies. The discrepancy between the rapid metabolism of DMF in vivo and its distinct effects in vitro, which exceed those of the in vivo active MMF, underlines the need for further research. Another aim of the study was to compare the frequencies of cytokine-secreting cells in patients and healthy controls. Whereas no differences were detected after non-specific cell stimulation (anti-CD3, PHA und anti-CD3/CD28-beads), stimulation with the putative psoriasis-specific autoantigen LL37 induced proinflammatory T cells exclusively in the patient cohort. Performing the ELISPOT assay, LL37-specific T cells were found in 37.5% of the examined patients with psoriasis (LL37-responders). In the control cohort only an anti-inflammatory IL-10-response to LL37 was observed. Furthermore, a tendency towards more severe psoriasis was found in the LL37-responders in comparison to the non-responders, thus confirming the role of LL37 as an autoantigen at least in a subset of patients with psoriasis. Taken together, the results of this study indicate an early reduction of T cells during FAE-treatment. Moreover, the data suggest that the clinical efficacy of FAE in the treatment of psoriasis is mediated by a decrease in Th1- and Th17 cells, and not by an induction of IL-5- and IL-10-secreting T cells. Based on the in vitro data, the observed reduction in T cell frequencies might rather be caused by DMF than its metabolite MMF.