Publikationsserver der Universitätsbibliothek Marburg

Titel:Epigenetische Regulation Th1/Th2-relevanter Gene in CD4+-T-Zellen als Mechanismus der Allergie-Prävention bei experimentellem Asthma
Autor:Brand, Stephanie
Weitere Beteiligte: Garn, Holger (Dr.)
Veröffentlicht:2010
URI:https://archiv.ub.uni-marburg.de/diss/z2010/0358
URN: urn:nbn:de:hebis:04-z2010-03580
DOI: https://doi.org/10.17192/z2010.0358
DDC:610 Medizin
Titel (trans.):Epigenetic regulation of Th1/Th2 relevant genes in CD4+ T-cells as a mechanism of allergy prevention in experimental asthma
Publikationsdatum:2010-07-08
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Epigenetik, Asthma, T-Zellen, Epigenetics, T-cells, allergisches Asthma, Epigenetik, Allergisches Asthma, Hygiene Hypothese, Hygiene Hypothesis

Zusammenfassung:
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 untersucht, ob eine veränderte epigenetische Signatur in CD4+-T-Zellen den asthmatischen Phänotyp in einem Tiermodell des experimentellen Asthmas beeinflussen kann. Dazu wurde ein adoptiver Transfer von CD4+-T-Zellen aus 5Aza- oder PBS-behandelten sensibilisierten Ovalbumin (OVA)-T-Zell-Rezeptor transgenen (DO11.10)-Donormäusen durchgeführt und der asthmatische Phänotyp in OVA-provozierten Wildtyp-Balb/c-Rezipienten analysiert. Hier resultierte die Behandlung der Donoren mit 5Aza in einer signifikanten Reduktion des asthmatischen Phänotyps in den Rezipienten. Diese Ergebnisse zeigen, dass der DNA-Methylierungsgrad in CD4+-T-Zellen einen Einfluss auf die Entwicklung des asthmatischen Phänotyps in diesem Modell hat. Da bekannt ist, dass epigenetische Regulation durch komplexe Gen-Umwelt-Interaktionen moduliert werden kann, wurde im zweiten Teil dieser Arbeit die Rolle epigenetischer Regulation bei der mikrobiell-vermittelten transmaternalen Asthma-Protektion untersucht. Dazu wurden Balb/c-Mäuse während der Schwangerschaft mit dem apathogenen, gram-negativen Bakterium Acinetobacter lwoffii F78 (A. lwoffii F78) exponiert und die Nachkommen dieser Tiere anschließend mit OVA sensibilisiert und provoziert. Die pränatale A. lwoffii F78-Exposition führte zu einer Veränderung der Th1/Th2-Balance, da die Interferon gamma (IFNg)-Produktion von mononukleären Zellen (MNCs) aus der Milz erhöht und die Produktion der Interleukine (IL)-4, IL-5 und IL-13 erniedrigt war, einhergehend mit einer signifikanten Reduktion des asthmatischen Phänotyps in diesen Tieren. Dieser Effekt scheint von der erhöhten IFNg-Produktion und damit der verschobenen Th1/Th2-Balance abhängig zu sein, da die funktionelle Inhibition von IFNg mit einem neutralisierenden Antikörper zur Wiederherstellung des asthmatischen Phänotyps führte. Daher wurden DNA-Methylierung und posttranslationale Histonmodifikationen in Th1- und Th2-regulatorischen Genregionen von CD4+CD25--T-Zellen aus der Milz von Nachkommen A. lwoffii F78-exponierter Mütter nach OVA-Sensibilisierung und -Provokation analysiert. Hier zeigte sich am IFNg-Promotor eine signifikante Erhöhung der Histon H4-Acetylierung. Um die Relevanz der veränderten H4-Acetylierung am IFNg-Promotor weiter zu untersuchen, wurden die Nachkommen während der OVA-Provokation zusätzlich mit einem Histonacetyltransferase-Inhibitor behandelt. Diese Behandlung resultierte in der Aufhebung der Asthma-Protektion einhergehend mit der Inhibierung der H4-Acetylierung am IFNg-Promotor. Die hier erhaltenen Daten liefern somit einen ersten Hinweis, das epigenetische Regulation innerhalb von Th1/Th2-Zytokin-Genen von CD4+-T-Zellen, insbesondere am IFNg-Promotor, eine wichtige Rolle bei der Asthmaprotektion spielt, welche vermittelt wird durch die pränatale Exposition mit dem Modellkeim A. lwoffii F78.

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  26. Abb. 3.12 Migration der transferierten CD4 + -T-Zellen in die Lymphknoten der Lunge wird nicht durch 5Aza beeinflusst _________________________________________________ 76
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  32. Abb. 3.20 Unveränderte CpG-Methylierung am IFNγ-Promotor nach pränataler A. lwoffii F78- Exposition ___________________________________________________________ 86
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