3 Material und Methoden
5.6 Einfluß von Cilomilast, Rapamycin und Takrolimus auf die Expression von CD80 und CD86
5.7.1 Einfluß auf IL-12
In eigenen Untersuchungen kann ein inhibitorischer Effekt von Cilomilast und Takrolimus auf die LPS-induzierte IL-12-Produktion von DCs gezeigt werden.
Rapamycin zeigte dagegen keinen Effekt. Dies bestätigt die Ergebnisse von BILLAH et al. (2002), TIEFENTHALER et al. (2004) und CHIANG et al. (2004).
Die Funktion des IL-12 besteht Vermittlung einer Th1-mediierten Immunantwort;
so werden natürliche Killerzellen durch IL-12 aktiviert und naive T-Zellen im Lymphknoten durch IL-12 sezernierende DCs so geprimt, daß sie sich im weiteren Verlauf zu CD8+ T-Zellen differenzieren (CARTER und DUTTON 1996). Es ist denkbar, daß die hier gezeigte IL-12-Inhibition durch Cilomilast und Takrolimus durch eine Beeinflussung der PDE4 bzw. des FKBP-12 vermittelt wird.
Das hier gezeigte Ergebnis verdeutlicht, daß Cilomilast und Takrolimus sowohl in Th1- als auch Th2-vermittelten Kontaktallergiemodellen wirksam sind (SALERNO et al. 1998, EHINGER et al. 2000) und die Funktion dendritischer Zellen direkt beeinflussen.
6 Zusammenfassung
Boris Sülzle
Untersuchungen zur pharmakologischen Beeinflussung dendritischer Zellen
In der vorliegenden Arbeit ist die pharmakologische Beeinflussung dendritischer Zellen in In-vivo- und In-vitro-Modellen untersucht worden. Als Testsubstanzen wurden der PDE4-Inhibitor Cilomilast sowie die Immunsuppressiva Rapamycin und Takrolimus verwendet.
In vivo wurde die Wirkung der Pharmaka im TDI-Kontaktallergiemodell an BALB/c-Mäusen untersucht. Als funktionelle Parameter wurden die Ohrschwellung (Mouse-Ear-Swelling-Test, MEST) und post mortem die DC-Migration (Skin-Migration-Assay) sowie die DC-induzierte T-Zell-Proliferation, gemessen am Gewicht des regionalen Lymphknotens (Local-Lymphnode-Assay, LLNA), verwendet.
Weiterhin erfolgte post mortem die Untersuchung der MMP-9-Aktivität in Ohrexplantaten der Tiere mit Hilfe der Zymographie.
Die Ergebnisse der In-vivo-Untersuchungen verdeutlichen die Funktion der DCs bei der Initiierung einer adaptiv-zellvermittelten Immunantwort. Im TDI-Modell konnte für Rapamycin, unabhängig von der Applikationsart, keine Wirkung zur Inhibition der Kontaktallergie gezeigt werden. Durch Cilomilast (topisch) und Takrolimus (systemisch und topisch) konnte die Induktion der Kontaktallergie dagegen verhindert werden, wie signifikante Unterschiede im Vergleich zur Kontrollgruppe im MEST, Skin-Migration-Assay, Zymographie und LLNA dies belegen. Für Cilomilast ist ein direkter Einfluß auf DCs zu erkennen (Migrationshemmung), während dies bei Takrolimus nicht der Fall ist. Hier ist als Effektormechanismus zur Inhibition der Kontaktallergie eine direkte Wirkung auf T-Lymphozyten bzw. die Interaktion zwischen DCs und T-Zellen in Betracht zu ziehen.
Für die In-vitro-Untersuchungen wurden dendritische Zellen aus murinem Knochenmark gewonnen. Untersucht wurde die T-Zell-Allostimulationsfähigkeit dendritischer Zellen und deren Suppression durch Cilomilast, Rapamycin und
Takrolimus in der Mixed-Leukocyte-Reaction (MLR); dabei ergab sich eine signifikante Suppression der T-Zell-Proliferation durch den Einsatz der Testsubstanzen, die auch in unterschiedlichen Konzentrationen in der MLR getestet wurden. Hierbei zeigte Cilomilast lediglich in der höchsten Konzentration (10 µmol/l) eine schwach signifikante Hemmung, während Rapamycin (10-4 µmol/l - 1 µmol/l) und Takrolimus (10-2 nmol/l – 100 nmol/l) in allen verwendeten Konzentrationen die DC-induzierte T-Zell-Proliferation inhibierten. Zusätzlich wurden in der MLR DCs und T-Zellen mit Cilomilast prä-inkubiert, um Unterschiede hinsichtlich des Effektormechanismus von Cilomilast abzuleiten. In diesen Ansätzen zeigte sich ein direkter Einfluß von Cilomilast auf DCs und T-Zellen.
In FACS-Analysen wurde schließlich der Einfluß der Testsubstanzen auf die LPS-induzierte Heraufregulation der kostimulatorischen Oberflächenmoleküle CD80 und CD86 untersucht. Es zeigte sich jedoch bis auf einen schwachen Einfluß von Takrolimus auf die CD86 Regulation keine Modulation der untersuchten Oberflächenmoleküle durch den Einsatz der Testsubstanzen.
Weiterhin erfolgten Messungen der Zytokine TNF-α und IL-12 nach LPS-Stimulation der DCs mittels ELISA. Dabei konnte die LPS-induzierte Produktion von TNF-α durch Cilomilast und Rapamycin signifikant gehemmt werden; Takrolimus zeigte hier keinen Effekt. Die LPS-induzierte IL-12-Produktion der DCs wurde dagegen durch Takrolimus und Cilomilast signifikant gehemmt; Rapamycin zeigte hier keinen Effekt.
Abschließend läßt sich sagen, daß sich Cilomilast und Takrolimus durch Beeinflussung der Funktion dendritischer Zellen und T-Zellen in den durchgeführten Untersuchungen zur Prävention einer dermalen Kontaktallergie bei Mäusen wirksam erwiesen.
7 Summary
Boris Sülzle
Studies on pharmacological influence on dendritic cells
In the presented study pharmacological influence on dendritic cells was examined using in vivo and in vitro models. Test substances were the PDE4-inhibitor cilomilast, and the immunosuppressive compounds rapamycin and tacrolimus.
In vivo efficacy of the adopted pharmaca was analysed in TDI-induced contact allergy in mice (balb/c). Allergen induced ear-swelling were used as functional parameter (Mouse-Ear-Swelling-Test, MEST). Additionally, post mortem DC-migration (Skin-Migration-Assay) as well as DC-induced T cell proliferation, as measured by lymphnode weights (Local-Lymphnode-Assay, LLNA). Furthermore, MMP-9 activity was determined in mouse ear explants by zymography.
The results of the in vivo studies point up the role of dendritic cells in initiating adaptive cell-mediated immunity. Adopted pharmaceuticals in the TDI-model showed differences regarding the efficacy and its intervention. Rapamycin did not impair the induction of contact allergy, independent of any administration route, while application of cilomilast (topical) and tacrolimus (systemical and topical) inhibited the induction of contact allergy. This is clarified by significant differences in MEST, Skin-Migration-Assay and LLNA by comparison to control groups. In term to effect mechanism differences between cilomilast and tacrolimus became apparent. In contrast to tacrolimus, a direct influence on dendritic cells by cilomilast (inhibition of migration) is evident. For tacrolimus, a direct influence on T cell function respectively DC/T cell interaction is contemplable for inhibition of contact allergy.
For in vitro studies murine bone marrow-derived dendritic cells were used. DCs T cell allostimulatory capacity and its suppression by cilomilast, rapamycin and tacrolimus was tested in the Mixed-Leukocyte-Reaction (MLR). MLR performed with different drug concentrations indicated differences among the used test substances.
Only in highest exerted concentration cilomilast (10 µmol/l) inhibited T cell
proliferation weak but significantly, while rapamycin (10-4 µmol/l - 1 µmol/l) and tacrolimus (10-2 nmol/l – 100 nmol/l) did so in all tested concentrations. A direct influence on the function of DCs as well as T cells by cilomilast was found by pre-incubation of DCs and T cells with cilomilast.
Test substances influence` on LPS upregulated costimulatory surface molecules (CD80, CD86) on DCs was examined by FACS analyses. There was no alteration of surface molecule expression by adopted pharmaceuticals except weak CD86 alteration by tacrolimus.
At last ELISA measurements of TNF-α und IL-12 in supernatants of LPS stimulated DCs were performed beyond. Thereby cilomilast and rapamycin but not tacrolimus inhibited significantly LPS induced TNF-α production. IL-12 production of LPS stimulated DCs was significantly inhibited by cilomilast and tacrolimus, rapamycin did not influence IL-12 production.
In conclusion, cilomilast and tacrolimus are effective in prevention of dermal contact allergy in mice by influencing dendritic cell respectively T cell function.
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