Dokument

Zusammenfassung:
Als ursächlich für in den letzten Jahrzehnten stetig steigenden Prävalenzen von Asthma bronchiale in industrialisierten Ländern werden neben einer genetischen Prädisposition vor allem Umweltfaktoren verantwortlich gemacht. Die Hygiene-Hypothese bestätigend konnten epidemiologische Studien eine Reduktion allergischer Erkrankungen durch Exposition gegenüber mikrobiellen Komponenten im bäuerlichen Umfeld belegen. In Folge wurde das apathogene, Gram-positive Bakterium Lactococcus lactis (L. lactis) aus dem Stallstaub traditioneller Kuhställe isoliert. Im Tiermodell führte die intranasale Applikation von L. lactis an Ovalbumin (OVA)-sensibilisierte und -provozierte BALB/c-Mäuse zur signifikanten Reduktion des asthmatischen Phänotyps. In der vorliegenden Arbeit konnte dieser Effekt bestätigt werden. Des Weiteren wurden die zugrunde liegenden molekularen Mechanismen untersucht. Aus immunologischer Sicht geht Asthma mit einer Dominanz T-Helfer (Th)2-spezifischer Zytokine einher, bei Reduktion Th1- und Treg-spezifischer Zytokine. Daher wurden die Zytokinsekretionsmuster in mononukleären Zellen (MNCs), isoliert aus bronchialen Lymphknoten (lokale Reaktion) und der Milz (systemische Reaktion), untersucht. Dabei führte die L. lactis-Applikation lokal zu einer signifikante Reduktion der Th2-Antwort (Interleukin (IL)-5, IL-13). In der Milz waren die Th2-Zytokine tendenziell reduziert. Bei bestehenden immunologischen Konzepten einer Th1/Th2-Dysbalance oder einer Treg-Suppression als kausale Faktoren der Asthmaentstehung, konnte die protektive L. lactis-Wirkung mit keinem der beiden Modelle erklärt werden, da sich neben der reduzierten Th2-Antwort auch eine tendenzielle Reduktion Th1- (Interferon gamma (IFNy)) und Treg-spezifischer Zytokine (IL-10) fand. Im Rahmen der Pathogenese von Asthma bronchiale werden epigenetische Veränderungen als klärendes Bindeglied zwischen Gen-Umweltinteraktionen und der Fehlfunktion des Immunsystems vermutet. Für den epigenetischen Mechanismus der DNA-Methylierung konnte eine Assoziation mit der T-Zell-Differenzierung gezeigt werden. Daher wurde in der vorliegenden Arbeit bei nachgewiesenen Differenzen der Zytokinkonzentration durch L. lactis-Behandlung in weiteren Experimenten die DNA-Methylierung von CpGs CD4+CD25+- und CD4+CD25--T-Zellen in Promotorregionen Th1-, Th2- und Treg-typischer Zytokine analysiert. Hier konnten in den untersuchten DNA-Abschnitten für IL-5, IL-10 und IFNy keine signifikanten Unterschiede gefunden werden. Weitere Untersuchungen könnten klären, ob stattdessen Methylierungsunterschiede in weiter distal des Transkriptionsstarts gelegenen regulativen DNA-Regionen oder der epigenetische Mechanismus der Histonmodifikation mit dem Asthma-protektiven L. lactis-Effekt assoziiert sind. Schließlich deuten in der vorliegenden Arbeit gefundene signifikante Unterschiede der Methylierung des IFNγ-Promotors zwischen OVA-sensibilisierten Tieren und PBS (Phosphate Buffered Saline)-pseudosensibilisierten Tieren darauf hin, dass der epigenetische Mechanismus der DNA-Methylierung im Rahmen von Immunisierungsprozessen ein Rolle spielt. Signifikante Differenzen der Grund-Methylierung des IFNγ-Promotors zwischen T-Zellen bronchialer Lymphknoten und der Milz zeigen, dass eine separate Analyse lokaler und systemischer Effekte in diesem Modell erforderlich ist.

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