Publikationsserver der Universitätsbibliothek Marburg
Titel:Untersuchung genetisch modifizierter Mäuse bezüglich IgE vermittelter allergischer Reaktionen, T-Zellentwicklung und der Abwehr endogener Retroviren
Autor:Lübben, Wolger
Weitere Beteiligte: Bauer, Stefan (Prof. Dr.)
Veröffentlicht:2012
URI:https://archiv.ub.uni-marburg.de/diss/z2012/0892
URN: urn:nbn:de:hebis:04-z2012-08926
DOI: https://doi.org/10.17192/z2012.0892
DDC: Medizin
Titel (trans.):Analysis of genetically modified mice with regard to IgE mediated allergic reactions, T cell development and the resistance of endogenous retroviruses
Publikationsdatum:2012-11-14
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Basophile Zelle, T-cell acute lymphoblastic lymphoma, immunoglobulin E, Immunglobulin E, Akute lymphatische Leukämie, Endogene Retroviren, Toll-like-Rezeptoren, basophils, anaphylaxis, Anaphylaxie, toll like receptors, endogenous retroviruses

Zusammenfassung:
Die vorliegende Arbeit setzt sich aus vier verschiedenen Teilprojekten zusammen: der Untersuchung einer aktiven systemischen Anaphylaxie in IgE-knock-in-Mäusen, der Generierung transgener Knock-in-Mäuse mit Überexpression von humanem IgE, der Erzeugung von Mäusen mit induzierbarem Knock-out von PLCγ1 und der Bedeutung von TLR3, TLR7 und TLR9 bei der Abwehr endogener Retroviren (ERV) und der durch ERVs verursachten Tumorerkrankungen. Im 1. Projekt wurden IgE-knock-in-Mäuse untersucht, bei denen IgE in den IgG1 Lokus insertiert wurde und IgE damit wie IgG1 reguliert wird. In diesen Mäusen konnte, bei normaler B- und T-Zellentwicklung, in vivo und in vitro eine starke Überexpression von IgE festgestellt werden. In vitro Analysen bestätigten eine Expression von membrangebundenem IgE auf der Oberfläche ihrer B-Zellen. Außerdem war die Menge passiv an den FcεRI gebundenen IgEs etwa doppelt so hoch wie bei Wildtyp-Mäusen. Die mit dem Modellantigen TNP-OVA immunisierten Tiere zeigten darüber hinaus eine drastische Erhöhung von antigenspezifischem IgE. Durch eine i.v. Injektion von TNP-OVA wurde dann eine aktive systemische Anaphylaxie (ASA) ausgelöst, die in den IgE-knock-in-Mäusen deutlich stärker ausfiel, als in den Kontrollen. Somit konnte festgestellt werden, dass eine ASA in IgE-knock-in-Mäusen durch IgE und nicht durch IgG1 vermittelt wird. Eine Basophilendepletion mittels Ba103-Antikörpern ergab des Weiteren, dass eine IgE- vermittelte ASA, bei einem stark erhöhten Spiegel von spezifischem IgE, in erster Linie durch Basophile und weniger durch Mastzellen aktiviert wird. Ziel des 2. Projekts war die Generierung einer knock-in-Maus, die eine starke Überexpression von humanem IgE zeigen sollte, um ein besseren Verständnis für IgE vermittelte Reaktionen im Menschen zu erhalten. Aufgabe des 3. Teilprojekts war es eine Maus mit einem induzierbaren Knock-out der Phospholipase-Cγ1 (PLCγ1) zu generieren. Hierzu wurden zwei loxP-Stellen ins Gen von PLCγ1 eingeführt. Aus einer solchen gefloxten PLCγ1-iko-Maus lassen sich, durch eine Deletion der von den loxP-Stellen eingerahmten Exons, gewebsspezifische PLCγ1-ko-Mäuse erzeugen. Auf diese Weise können z.B. Mäuse konstruiert werden, bei denen PLCγ1 ausschließlich in T-Zellen deletiert ist, um die Bedeutung von PLCγ1 für die T-Zellentwicklung, insbesondere der regulatorischen T-Zellen, aufzuklären. Es konnten erfolgreich entsprechende Targetvektoren und ES-Zellen generiert werden. Allerdings fand nach der Blastozysteninjektion, trotz einer hoher Chimerität der Nachkommen, keine Keimbahntransmission statt. Im letzten Teil wurde die Bedeutung der endosomalen, nukleinsäureerkennenden Toll-like Rezeptoren 3, 7 und 9 für die Abwehr endogener Retroviren und der von ihnen ausgelösten Tumorerkrankungen mit Hilfe entsprechender Knock-out-Mäuse untersucht. Dabei konnte eine spontane, unkontrollierte Virämie des Murinen Leukämievirus (MuLV) in TLR7 defizienten Mäusen festgestellt werden. Allerdings entwickelten nur TLR3, TLR7 und TLR9 tripel defiziente Tiere eine durch das Virus ausgelöste prä-T-Zell akute lymphatische Leukämie (T-ALL). Die Insertion des MuLV-Provirus in die Onkogene Nup214 und Notch-1 führte dabei zu einer Deregulierung der Proteinexpression, die zur Entstehung der T-ALL beigetragen haben könnte. Auch konnte gezeigt werden, dass TLR379-/--Mäuse erhöhte Autoimmunreaktionen aufweisen.

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