Publikationsserver der Universitätsbibliothek Marburg
Titel:Nachweis FOXP3 positiver Zellen im Nierenzellkarzinom als Hinweis auf das Vorliegen einer Infiltration durch regulatorische T-Zellen
Autor:Sell, Katharina
Weitere Beteiligte: Schrader, A.J. (Prof. Dr.)
Veröffentlicht:2011
URI:https://archiv.ub.uni-marburg.de/diss/z2011/0729
DOI: https://doi.org/10.17192/z2011.0729
URN: urn:nbn:de:hebis:04-z2011-07297
DDC:610 Medizin
Titel (trans.):Detection of FOXP3 positive cells in renal cell cancer as indication for regulatory T cell infiltration
Publikationsdatum:2011-12-19
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Tregs, NZK, FOXP3, Hypernephrom, regulatory T cells, regulatorische T-Zellen, FOXP3, Tregs, RCC, renal cell cancer, Nierenzellkarzinom

Zusammenfassung:
Regulatorische T-Zellen tragen als aktive Immunregulatoren wesentlich zum Erhalt des immunologischen Gleichgewichts bei. Durch immunsuppressive Mechanismen induzieren sie Toleranz gegenüber Selbst-Antigenen und schützen den Organismus so vor Autoimmunität und überschießender Immunreaktion. Intensive Forschung der letzten Jahre hat jedoch zu der Vermutung geführt, dass regulatorische T-Zellen auch immunologische Vorgänge in malignen Erkrankungen supprimieren könnten. In mehreren Studien konnte ein vermehrtes Vorkommen regulatorischer T-Zellen in Karzinompatienten nachgewiesen und mit reduziertem Überleben korreliert werden. Auch in Patienten mit Nierenzellkarzinom scheinen regulatorische T-Zellen in der Anzahl erhöht zu sein. Viele Fragen hinsichtlich der Lokalisation und Verteilung, der genauen Charakterisierung und der spezifischen Funktionsmechanismen regulatorischer T-Zellen bleiben jedoch weiterhin unbeantwortet. In diesem Zusammenhang wurde in der vorliegenden Arbeit die Expression des nukleären Transkriptionsfaktors FOXP3, der derzeit als spezifischster Marker regulatorischer T-Zellen gilt, im Nierenzellkarzinom untersucht. Dabei wurde die Expression bei 32 Patienten in Tumorgewebe und angrenzendem normalen Nierengewebe derselben Niere untersucht und verglichen. Zur Anwendung kamen folgende Methoden: Hämatoxylin-Eosin-Färbung, immunhistochemische Färbung nach der ABC-Methode, RNA-Isolation und –Analytik, Reverse Transkription, konventionelle und quantitative RT-PCR. Zunächst konnte eine immunhistochemische Nachweismethode von FOXP3 in Nierenzellkarzinom- und normalem Nierengewebe erfolgreich etabliert werden. In 26 von 30 immunhistochemisch untersuchten Tumor- bzw. Nierenproben konnte ein vermehrtes Vorkommen FOXP3+ Zellen im Tumorgewebe nachgewiesen werden. Nur vier Patienten zeigten im Tumorgewebe weniger FOXP3+ Zellen als im korrespondierenden Normalgewebe. Auch die molekularbiologischen Untersuchungen konnten eine vermehrte Expression von FOXP3 im Tumor- verglichen mit normalem Nierengewebe nachweisen. Dabei bestätigte die quantitative real time PCR die Ergebnisse der konventionellen PCR. Von 23 untersuchten Tumor- bzw. Nierenproben wurde bei 20 Patienten eine stärkere Expression von FOXP3 im Tumorgewebe nachgewiesen. Sie war im Durchschnitt etwa 6-fach höher als die Expression von FOXP3 im korrespondierenden normalen Nierengewebe. Somit konnte gezeigt werden, dass FOXP3+ Zellen im Nierenzellkarzinom verglichen mit normalem Nierengewebe vermehrt vorkommen. Ferner wurde eine Akkumulation FOXP3+ Zellen im Grenzgebiet zwischen Tumor- und Normalgewebe beobachtet. 27 der 30 immunhistochemisch untersuchten Tumor- bzw. Nierenproben zeigten mehr FOXP3+ Zellen im Grenzgebiet zwischen Tumorgewebe und Normalgewebe als mitten im Gewebe. Keine Tendenz konnte jedoch bei der Unterteilung des Grenzgebietes zwischen Tumor- und Normalgewebe in ein Randgebiet im Tumor (RT) und ein Randgebiet im Normalgewebe (RN) gezeigt werden. Um die FOXP3+ Zellen genauer charakterisieren zu können, wurde in der vorliegenden Arbeit zudem eine immunhistochemische Färbemethode zum Parallelnachweis der beiden Marker FOXP3 und CD4 entwickelt. Der Parallelnachweis von CD4 und FOXP3 ermöglicht eine genauere Charakterisierung der untersuchten Zellen. Weitere Arbeiten könnten darauf aufbauend eine Doppelfärbung entwickeln, die eine definitive Koexpression beider Marker zeigen würde. Die regulatorische Funktion CD4+FOXP3+ Zellen wurde in verschiedenen Arbeiten bereits beschrieben. In weiteren Untersuchungen könnte auf der beschriebenen Methode aufbauend das Vorkommen regulatorischer T-Zellen im Nierenzellkarzinom weiter charakterisiert werden. Zusammengefasst konnte in der vorliegenden Arbeit der Treg Marker FOXP3 sowohl molekularbiologisch als auch auf Proteinebene im Nierenzellkarzinom verglichen mit normalem Nierengewebe vermehrt nachgewiesen werden. Eine deutliche Akkumulation FOXP3+ T-Zellen wurde im Grenzgebiet zwischen Tumor- und normalem Nierengewebe beschrieben. Basierend auf diesen Ergebnissen könnten weitere fokussierte Untersuchungen regulatorischer T-Zellen im Nierenzellkarzinom folgen. Diese sollten die weitergehende Bedeutung der Akkumulation FOXP3+ Zellen in der Grenzregion zwischen Tumor- und Normalgewebe im Zusammenhang mit ihrer Funktion beleuchten. Anhand funktioneller Tests sollten die regulatorischen Eigenschaften der FOXP3+ Zellen eindeutig nachgewiesen werden. Letztlich bleibt es eine der großen Herausforderungen der immunologischen Tumorforschung, regulatorische T-Zellen in den verschiednen Tumorentitäten weiter zu charakterisieren. Die bisherigen Ergebnisse vieler Autoren lassen mit der spezifischen Manipulation regulatorischer T-Zellen auf neue therapeutische Möglichkeiten hoffen.

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