Dokument: Einfluss der Indolamin 2,3-Dioxygenase auf das Zellwachstum von T-Zellen, Tumorzellen und Staphylokokken
| Titel: | Einfluss der Indolamin 2,3-Dioxygenase auf das Zellwachstum von T-Zellen, Tumorzellen und Staphylokokken | |||||||
| Weiterer Titel: | Indolamine 2,3-Dioxygenase and its effect on the proliferation of T-Cells, Tumorcells and Staphylococcus | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=12347 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20091106-090950-1 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Siebel, Stephan [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Däubener, Walter [Gutachter] Prof. Dr. Dilloo, Dagmar [Gutachter] | |||||||
| Stichwörter: | IDO, T Zellen, Tumorzellen, Kynurenin, Hydroxykynurenin | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Indolamin 2,3-Dioxygenase ist ein ubiquitär im Körper vorkommendes Enzym, das den ersten und mengenbestimmenden Schritt im sogenannten Kynurenin-Weg vermittelt. Hierbei verstoffwechselt die IDO, stimuliert durch IFN γ, die Aminosäure Tryptophan zu Kynurenin.
Im Folgenden entstehen dann, abhängig von anderen (in dieser Arbeit nicht untersuchten) Enzymen, weitere Tryptophanabbauprodukte, wie z.B. Hydroxykynurenin, Hydroxyanthranilsäure, Anthranilsäure und Quinolinsäure. Da Tryptophan eine essentielle Aminosäure ist, hat ihr Abbau einen wesentlichen Einfluss auf den Stoffwechsel tryptophanabhängiger Organismen. Diese Erkenntnisse stellten den Ausgangspunkt meinerer Arbeit dar, in der zuerst einmal das oben beschriebene praktisch nachvollzogen wurde. Die ersten Versuche zeigten eindrücklich die Stimulierbarkeit der IDO durch INF γ, den IDO vermittelten Tryptophanabbau und die Entstehung des Kynurenins als erstes Reaktionsprodukt im Kynurenin-Weg. Bei maximaler Stimulation der IDO mit IFN γ war die Menge des Kynurenins stets abhängig von der Konzentration des in der Kultur vorhandenen Tryptophans. Bereits veröffentliche Studien beschrieben, dass der Mangel an Tryptophan einen potenten inhibitorischen Effekt auf das Wachstum von Mykobakterien, Toxoplasmen. Chlamydien und Streptokokken darstellt. In meiner Arbeit wurde dieser antiproliferative Effekt vor allem auf Staphylococcus aureus, T-Zellen sowie den Tumorzellreihen A549, 86HG39 und HBMEC untersucht. Die Depletion von Tryptophan in den entsprechenden Ansätzen zeigte sich ebenfalls als effektiver Hemmmechanismus auf die Proliferation der hier getesteten Zellreihen. Was nebenbei bestätigte, dass die hier untersuchten T-Zellen, Tumorzellen und Staphylokokken zu den auxotrophen Organismen gehören, die auf die Zufuhr von Tryptophan für ihren Stoffwechsel angewiesen sind. Der antiproliferative Effekt des Tryptophanabbaus, war aber stets nur ein zytostatischer und kein zytotoxischer, der durch erneute Supplementation der tryptophanarmen Ansätze mit Tryptophan antagonisiert werden konnte. Mithilfe der sogenannten WRS (tryptophanyl-transfer RNA synthetase) war es den Zellen möglich einen intrazellulären Tryptophanspeicher zu schaffen und somit zumindest zeitweise in den tryptophanarmen Medien zu überleben. Nach Zufuhr supra-physiologischer Mengen an Tryptophan konnten die Zellen ihre Stoffwechselaktivität wieder aufnehmen und erneut proliferieren. Da aber in vivo nicht nur Tryptophan mithilfe der IDO abgebaut wird, sondern –wie bereits oben erläutert- Tryptophanmetabolite entstehen, wurde in folgenden Ansätzen untersucht, welche Rolle die Metabolite Kynurenin, Hydroxykynurenin, Hydroxyanthranilsäure, Anthranilsäure und Quinolinsäure auf das Wachstum der genannten Zellen haben. Hierbei zeigte sich deutlich, dass die Tumorzellen und Staphylokokken nur mässig bis gar nicht in ihrer Proliferation gehemmt werden, dass das T-Zellwachstum jedoch deutlich inhibiert wird. Die Metabolite Kynurenin, Hydroxykynurenin und Hydroxyanthranilsäure übten vor allem in der frühen Proliferationsphase stimulierter T-Zellen einen starken antiproliferativen Effekt auf das T-Zellwachstum aus, der nicht durch Zufuhr von Tryptophan antagonisiert werden konnte. Somit konnte von einem zytotoxischen Effekt der Metabolite auf die T-Zellen ausgegangen werden. Die Metabolite Anthralinsäure und Quinolinsäure übten keinen antiproliferativen Effekt auf das T-Zellwachstum aus. Ebenfalls unbeeinflusst, jedoch von allen fünf verwendeten Metaboliten, blieben unstimulierte T-Zellen. Die Ergebnisse dieser Versuche zeigen, dass zwar alle in dieser Arbeit verwendeten Zellreihen auf die Zufuhr von Tryptophan als essentielle Aminosäure für ihren Stoffwechsel angewiesen sind, dass aber nur die T-Zellen durch die entstehenden Metabolite gehemmt werden. Diese in vitro Beobachtungen bieten eine Vielzahl von Möglichkeiten für zukünftige Forschung und darüber hinaus Erklärungansätze für immunologische Phänomene, wie z.B. der Ausbreitung von Tumorzellen in gesunden Geweben, die mithilfe der IDO und den toxischen Abbauprodukten die körpereigene intakte T-Zellvermittelte Immunabwehr hemmen und somit ungehindert proliferieren können.Indolamine 2,3-Dioxygenase is an enzyme that mediates the first step of the kynurenine pathway. Stimulated by IFN γ IDO metabolizes the essential aminoacid Tryptophane thus producing kynurenine. Then, mediated by other enzymes of the kynurenine pathway further byproducts are produced, such as Hydroxyanthralinic acid, Anthranilic acid and Quinolinic acid. Since Tryptophane is an essential aminoacid, its depletion mediated by IDO has an significant effect on the proliferation of tryptophan dependent organism. This conclusion forms the basis of this doctoral thesis. The first experiments show that IFN γ stimulates the IDO enzymes, which depletes Tryptophan and breaks it down into Kynurenin. The amount of Kynurenin produced by IDO Is dependent from concentration of tryptophan in the cell culture. Previously published studies showed that the deficit of tryptophan has a potent inhibitory effect on the proliferation of Mycobateria, Toxoplasma, Chlamydia and Streptococci. In this thesis its antiproliferative effect on Staphylococcus aureus, T-cells, Tumorcells such as A549, 86HG39 and HBMEC was examined. The depletion of tryptophan in the all of these cultures resulted in an inhibition of proliferation of all of the abovementioned cells. Because the antiproliferative effect of the tryptophan depletion could be antagonized by supplementing the cultures with Tryptophan again its antiproliferative effect was considered cytostatic and not cytotoxic. Due to the WRS (tryptophanyl-transfer RNA synthetase) cells can store tryptophan intracellularly and temporarily survive the tryptophan depletion and resume their metabolism again after supplementing supraphysiological concentrations of tryptophan. The second aspect of the doctoral thesis was the effect Tryptophanmetabolites such as Kynurenine, Hydroxykynurenine, Hydroxyanthranilic acid, Anthranilic acid and Quinolinic acid on the proliferation of Staphylococcus aureus, T-cells, Tumorcells such as A549, 86HG39 and HBMEC. The experiments showed that these metabolites have only a little or none antiproliferative effect on tumorcells and staphylococci. While Kynurenine, Hydroxykynurenine and Hydroxyanthranilic acid showed a strong antiproliferative effect on stimulated T-cells during their early proliferationphase. This inhibitory effect could not be antagonized by supplementing the cultures. This led to the conclusion that its effect is cytotoxic. Anthranilic acid and Quinolinic acid had no effect on the T-cellgrowth. | |||||||
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| Lizenz: |  Urheberrechtsschutz | |||||||
| Bezug: | Oktober 2005-April 2007 | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät » Institute » Institut für Medizinische Mikrobiologie | |||||||
| Dokument erstellt am: | 06.11.2009 | |||||||
| Dateien geändert am: | 05.11.2009 | |||||||
| Promotionsantrag am: | 01.06.0009 | |||||||
| Datum der Promotion: | 23.06.0009 |
