Epigenetische Regulation Th1/Th2-relevanter Gene in CD4+-T-Zellen als Mechanismus der Allergie-Prävention bei experimentellem Asthma

Epigenetische Modulation ist assoziiert mit der Differenzierung von T-Helfer (Th)1- und Th2-Zellen, wobei letzere für die Dirigierung der allergischen Immunantwort eine bedeutende Rolle spielen. In dieser Arbeit wurde mittels des DNA-Methyltransferase-Inhibitors 5-Aza-2´-Deoxycytidin (5Aza) zunächst...

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Bibliographic Details
Main Author: Brand, Stephanie
Contributors: Garn, Holger (Dr.) (Thesis advisor)
Format: Doctoral Thesis
Language:German
Published: Philipps-Universität Marburg 2010
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Table of Contents: Epigenetic regulation has been shown to be associated with the differentiation of T-helper (Th)1- and Th2 cells, the latter are known to play an important role in the orchestration of allergic responses. Based on these findings the hypothesis was generated that an altered epigenetic signature in CD4+ T-cells may influence the asthmatic outcome in an animal model of experimental asthma. Therefore, an adoptive transfer of CD4+ T-cells from 5-Aza-2´-Deoxycytidine (5Aza, a DNA methyltransferse inhibitor)- or PBS-treated Ovalbumin (OVA)-sensitized OVA-T-cell-receptor transgenic (DO11.10) donor mice was performed and the asthmatic phenotype was assessed in OVA-aerosol challenged wildtype Balb/c recipient mice. After adoptive transfer of CD4+ T-cells, 5Aza-treatment resulted in a reduced asthmatic phenotype. In conclusion, these results suggest an impact of the DNA methylation level within CD4+ T-cells on the development of the asthmatic phenotype in the model. It is known that epigenetic mechanisms might be modulated by complex gene-environment interactions. To examine the role of epigenetic regulation in transmaternal asthma protection, pregnant mother mice were exposed to the non-pathogenic gram-negative bacterium Acinetobacter lwoffii F78 (A. lwoffii F78) and offspring mice were OVA sensitized and challenged. Prenatal A. lwoffii F78 administration led to a changed Th1/Th2 balance in the offspring as shown by an increased Interferon gamma (IFNg) production and decreased Interleukine (IL)-4, IL-5 and IL-13 production of splenic mononuclear cells (MNCs). Furthermore the development of experimental asthma in the progeny was significantly reduced. This effect seemed to be dependent on the elevated IFNg production since functional inhibition of IFNg with a neutralizing antibody restored the asthmatic phenotype. Therefore, DNA methylation and posttranslational histone modifications were analyzed in Th1 and Th2 regulatory gene regions of CD4+CD25- T-cells from OVA sensitized and challenged offspring. A significant increase in histone H4 acetylation was observed at the IFNg promoter region. To further investigate the relevance of altered H4 acetylation at the IFNg promoter, offspring mice were treated with an histone acetyltransferase inhibitor. This treatment abolished the asthma protective phenotype paralleled by inhibition of H4 acetylation at the IFNg promoter. These data provide first evidence that epigenetic regulation of Th1/Th2 cytokine genes in CD4+ T-cells, in particular of the IFNg promoter, plays an important role in asthma protection mediated by prenatal exposure to the model microbe A. lwoffii F78.