Dokument: Mechanistical and therapeutical aspects of preventing diabetes
| Titel: | Mechanistical and therapeutical aspects of preventing diabetes | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=32993 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20141218-111248-6 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | master Shaabani, Namir [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof.Dr Lang, Karl Sebastian [Gutachter] Prof. Dr. Proksch, Peter [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | Diabetes mellitus type I is an autoimmune disease, which is associated with virus infections. Understanding different mechanisms involved in the induction of autoimmune diabetes can give new potential targets for therapy. In this thesis we investigated different immunological mechanisms, which can contribute to the induction of autoimmune diabetes.
We analyzed the role of the interferon-inhibitor Ubiquitine Specific Peptidase 18(Usp18)in the induction of autoimmune diabetes. We found that expression of Usp18 in bone marrow derived cells was essential to breakimmunological tolerance and to induce autoimmune diabetes. Expression of Usp18 in antigen presenting cells enforced viral replication in those cell types which was essential to induce auto-reactive immune response. We showed that enforced viral replication is involved in breaking immunological tolerance and was essential to induce autoimmune diabetes. Using the vesicular stomatitis virus (VSV) as a virus model system, we found that Usp18 dependent viral replication was associated with efficient, anatomically highly selective VSV replication. This replication was essential to activate an efficient antiviral immune response. Together these data clearly point to the importance of Usp18 dependent enforced viral replication in the pathogenesis of diabetes. In another series of experiments we analyzed the impact of the Wiskott-Aldrich syndrome protein (WASP) in the induction of autoimmune diabetes. We found that expression of WASP in bone marrow derived cells was efficient to induce diabetes. Lack of WASP was linked to a reduced ability of dendritic cells to produce type I interferon and to prime auto-reactive virus-specific CD8+ T cells. Moreover, we found that endoplasmic reticulum stress induced by Tunicamycin reduced the incidence of diabetes. Tunicamycin did not affect beta islet cells directly. However, activated beta-cell specific CD8+ T cells were highly sensitive to Tunicamycin and underwent apoptosis upon activation. The exact mechanism of action remains to be determined. Furthermore, we analyzed the role of ATP receptor signaling and ER stress signaling in the role in the induction autoimmune diabetes. Therefore, we used a general inhibitor of ATP receptors oxidized ATP (oxATP) and the ER stress inducer Tunicamycin in the autoimmune diabetes model. We found that oxATP had a strong inhibitory effect on the IFN-g production of auto-reactive CD8+ T cells in vitro and in vivo. At higher concentrations oxATP induced apoptosis. In vivo oxATP suppressed activation of T cell responses and therefore suppressed T cell mediated autoimmune diabetes. In conclusion we present several mechanisms, which participate in induction of autoimmune diabetes. In future work those mechanisms might be evaluated as targets for treating autoimmune diabetes in humans. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 18.12.2014 | |||||||
| Dateien geändert am: | 18.12.2014 | |||||||
| Promotionsantrag am: | 31.03.2014 | |||||||
| Datum der Promotion: | 04.11.2014 |
