Medizin adjuvant 2014-07-31 https://archiv.ub.uni-marburg.de/diss/z2014/0564/cover.png monograph RNA/DNA-hybrids in innate immunity and cholesterol-coupled RNA as adjuvant retrovirale Infektion Interferon https://doi.org/10.17192/z2014.0564 Medical sciences Medicine Medizin Obermann, Hannah-Lena Obermann Hannah-Lena retroviral infection cholesterol Adjuvans application/pdf Immunologie RNA/DNA-hybrids in innate immunity The innate immune system senses viral and bacterial nucleic acids in the cytoplasm or in endosomal compartments via different pattern recognition receptors (PRR) such as Toll-like receptors (TLR). The repertoire of pathogen-associated molecular patterns (PAMP) is still not exhausted. Since RNA/DNA-hybrids are formed transiently during viral infection, cell endogenous processes and may lead to autoimmune diseases, the immunstimulatory capacity of RNA/DNA-hybrids needs to be further investigated. Analysis of HCMV- and HIV-derived synthetic RNA/DNA-hybrids showed an efficient induction of IFNα-secretion in human PBMC as well as in murine Flt3L-DC. Additionally, murine Flt3L-DC produced TNFα, IL-6 and IP-10 upon RNA/DNA-hybrid stimulation. Cytokine induction occured in a TLR9-dependent manner since TLR9-deficient Flt3L-DC did not respond with cytokine production to RNA/DNA-hybrids. Direct interaction of RNA/DNA-hybrids with TLR9 was demonstrated by an ELISA-based binding assay. Furthermore, intact RNA/DNA-hybrids could be detected within transfected Flt3L-DC with the RNA/DNA-hybrid-specific antibody S9.6. The influence of RNA/DNA-hybrids within viral, bacterial or mitochondrial ge-nomes could not be analysed in detail, because their immunostimulatory potential was probably masked by high amounts of genomic DNA. Infection of Flt3L-DC with Mo-MuLV lead to RNA/DNA-hybrid formation and accumulation within the cells cytoplasm and in vesicular structures. However, Mo-MuLV negatively influenced CpG2216-mediated IFN-signalling independent of Siglec-H or DAP12 in Flt3L-DC and therefore avoided antiviral immune responses. Cholesterol-coupled dsRNA40 serves as a potent adjuvant delivery system Vaccination is indispensable to prevent infectious diseases and therefore development of safe and potent vaccine adjuvants is still highly important. Adjuvants are included in vaccines to enhance immune responses to an antigen. In general, TLR-ligands possess the potential to be utilized as adjuvants. Different TLR are expressed within diverse subtypes of immune cells and induce various cytokines. The cytokine milieu mainly influences the characteristics of an vaccine. RNA40, which is a well established HIV-derived TLR7-ligand, has to be complexed to a transfection reagent for cellular uptake and for preventing enzymatic degradation. In this study a very potent adjuvant delivery system for TLR7 has been developed. Double-stranded RNA40 was coupled to cholesterol to force cellular uptake. Cholesterol occurs naturally within cell membranes for which reason undesired side-effect should be prevented. Cellular uptake of cholesterol coupled dsRNA40 by Flt3L-DC was analyzed by flow cytometry and was as effective as uptake of dsRNA40 complexed to Dotap. Interestingly, stimulation of Flt3L-DC with dsRNA40 coupled to cholesterol lead to an increased secretion of IFNα, TNFα, IL-6 and IL-10 in comparison to complexation of dsRNA40 to Dotap. Immune stimulation by cholesterol itself could be excluded. Overall, these in vitro experiments showed an effective activation of murine Flt3L-DC by dsRNA40-Chol in a TLR7-dependent manner. 2014 ths Prof. Dr. Bauer Stefan Bauer, Stefan (Prof. Dr.) opus:5631 TLR9 Die Rolle von RNA/DNA-Hybriden in der angeborenen Immunantwort Das angeborene Immunsystem detektiert RNA und DNA über verschiedene pattern recognition receptors (PRR), zu welchen unter anderem die Toll-like Rezeptoren (TLR) gehören. RNA/DNA-Hybride treten im Verlauf viraler Infektionen, während endogener Prozesse sowie im Zusammenhang mit Autoimmunerkrankungen auf. In dieser Dissertation konnte gezeigt werden, dass synthetische RNA/DNA-Hybride, welche als Bestandteil der Genome des humanen Zytomegalievirus (HCMV) und des humanen Immundefizienzvirus (HIV) vorkommen, sowohl in humanen peripheral blood mononuclear cells (PBMC) als auch in murinen Flt3L-differenzierten dendritischen Zellen (Flt3L-DC) eine durch die Sezernierung von IFNα gekennzeichnete Immunantwort induzieren. Für das murine System wurde außerdem die Sezernierung weiterer Zytokine (TNFα, IL-6, IP-10) nachgewiesen. Durch die Verwendung von TLR9-defizienten Flt3L-DC wurde TLR9 als Rezeptor für die Detektion von RNA/DNA-Hybriden identifiziert. Außerdem wurde die spezifische Bindung von RNA/DNA-Hybriden an TLR9 in einer Bindungsstudie verifiziert. Dass die Induktion der Immunantwort durch RNA/DNA-Hybride erfolgte wurde fluoreszenzmikroskopisch unter Verwendung eines RNA/DNA-Hybrid-spezifischen Antikörpers bestätigt. Während der retroviralen Infektion von Flt3L-DC mit dem Moloney murinen Leukämievirus (Mo-MuLV) wurde die intrazelluläre Bildung und Akkumulation von RNA/DNA-Hybriden verifiziert. Des Weiteren wurde gezeigt, dass Mo-MuLV einen inhibitorischen Einfluss auf die CpG2216-vermittelte Induktion der IFN-Signalkaskade in Flt3L-DC besitzt, welcher weder über den Oberflächenrezeptor Siglec-H noch über das Adaptermolekül DAP12 vermittelt wird. Das TLR9-abhängige immunstimulatorische Potential synthetischer RNA/DNA-Hybriden konnte für virale, bakterielle oder mitochondriale Genome, welche natürlicherweise vorkommende RNA/DNA-Hybrid-Strukturen beinhalten, nicht abschließend analysiert werden, da der wesentlich höhere Gehalt an immunstimulatorischer genomischer DNA zu einer Überlagerung des RNA/DNA-Hybrid-induzierten Einflusses führte. Das Potential von cholesterolkonjugierter RNA40 als Adjuvans Zur Prävention von Infektionskrankheiten ist die Entwicklung von Impfstoffen von großer Bedeutung. Adjuvantien werden als Bestandteil von Impfstoffen eingesetzt und verstärken die durch den Impfstoff induzierte Immunantwort. Sowohl natürliche als auch synthetische TLR-Liganden besitzen das Potential als Adjuvantien verwendet zu werden. Da die unterschiedlichen TLR zelltypspezifisch exprimiert und durch ihre Liganden verschiedene Zytokinprofile induziert werden, kann eine eingeleitete Immunantwort durch TLR-Liganden modelliert werden. Solche Adjuvantien dürfen keine unerwünschten Nebenwirkungen besitzen. RNA40, eine Sequenz aus dem HIV-Genom, wurde bereits als TLR7-Ligand beschrieben. Derzeit müssen jedoch Transfektionsreagenzien verwendet werden, um sowohl die zelluläre Aufnahme des TLR-Liganden zu forcieren als auch die Stabilität der Nukleinsäuren zu gewährleisten. Da Transfektionsreagenzien zelltoxische Eigenschaften besitzen, sind sie für die Zulassung als Adjuvans von humanen Impfstoffen problematisch. In dieser Arbeit konnte gezeigt werden, dass cholesterolkonjugierte dsRNA40 (dsRNA40-Chol) ohne zusätzliche Komplexierung mit einem synthetischen Transfektionsreagenz ein außerordentliches immunstimulatorisches Potential besitzt, welches sich in der Sezernierung von IFNα, TNFα, IL-6 und IP-10 durch murine Flt3L-DC äußerte. Die durch dsRNA40-Chol eingeleitete Immunreaktion war im Vergleich zu der durch dotapkomplexierte dsRNA40 induzierten deutlich stärker. 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