Myeloid derived suppressor cell activation by combined lipopolysaccharide plus interferon-γ [interferon-gamma] treatment impairs dendritic cell development [Elektronische Ressource] / vorgelegt von Verena Greifenberg

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Aus der Hautklinik der Friedrich- Alexander- Universität Erlangen-Nürnberg Direktor: Prof. Dr. med. Univ. Gerold Schuler Myeloid-derived suppressor cell activation by combined lipopolysaccharide plus interferon-γ treatment impairs dendritic cell development Inaugural-Dissertation zur Erlangung der Doktorwürde der Medizinischen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg vorgelegt von Verena Greifenberg aus Bamberg Gedruckt mit Erlaubnis der Medizinischen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg Dekan: Prof. Dr. J. Schüttler Referent: Prof. Dr. M. Lutz Korreferenten: Prof. Dr. Dr. A. Gessner Prof. Dr. N. Romani Prof. Dr. A. Steinkasserer Tag der mündlichen Prüfung: 26. November 2009 Für einen lieben Menschen Für eine Diva Für eine liebe Diva 1 ............................................................................................................... SUMMARY 1 1.1...................
Publié le : jeudi 1 janvier 2009
Lecture(s) : 127
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Source : WWW.OPUS.UB.UNI-ERLANGEN.DE/OPUS/VOLLTEXTE/2009/1504/PDF/VERENA_GREIFENBERG_DISSERTATION.PDF
Nombre de pages : 74
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    Aus der Hautklinik der Friedrich- Alexander- Universität Erlangen-Nürnberg Direktor: Prof. Dr. med. Univ. Gerold Schuler            Myeloid-derived suppressor cell activation by combined lipopolysaccharide plus interferon-γtreatment impairs dendritic cell development        Inaugural-Dissertation zur Erlangung der Doktorwürde der Medizinischen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg        vorgelegt von  Verena Greifenberg  aus  Bamberg
  
 
    Gedruckt mit Erlaubnis der Medizinischen Fakultät der Friedrich-Alexander-Universität  Erlangen-Nürnberg                  
      Dekan: Dr. J. Schüttler Prof.  Referent:                                                     Prof. Dr. M. Lutz  Korreferenten: Prof. Dr. Dr. A. Gessner  Prof. Dr. N. Romani  Prof. Dr. A. Steinkasserer   Tag der mündlichen Prüfung: 26. November 2009 
üFr eFinrüe nie ne M nesch
               lieben  Für eineDiva  liebe Diva                          
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 1...............................................................................................................SUMMARY 1 1.1..........................................................................................BACKGROUND AND AIMS 1 1.2...............................................................................................................METHODS 1 1.3................................................................................................................ RESULTS 1 1.4....................................................................................... PRACTICAL CONCLUSIONS 2 2............................................................................................ZUSAMMENFASSUNG 3 2.1........................................................................................HINTERGRUND UNDZIELE 3 2.2.............................................................................................................METHODEN 3 2.3........................................................................ ERGEBNISSE UNDBEOBACHTUNGEN 3 2.4......................................................................PRAKTISCHESCHLUSSFOLGERUNGEN 4 3.......................................................................................................INTRODUCTION 5 3.1.............................................. STRUCTURE AND FUNCTIONS OF THE IMMUNE SYSTEM 5 3.1.1......................................... 5Common introduction into the immune system 3.1.2............................................................... 6Regulation of immune response 3.2................................................................... MYELOID-DERIVED SUPPRESSOR CELLS 8 3.2.1..................................................................................................Overview 8 3.2.2................................................................................... 9Plasticity of MDSC 3.2.3....................................................MDSC in homeostasis and in diesease 9 3.2.3.1 ....................................................................................... Murine MDSC 10 3.2.3.2 ....................................................................................... Human MDSC 11 3.2.4..........................................................................In vitro generated MDSC 12 3.2.5.............................................................Induction of generation of MDSC 12 3.2.5.1 ......................................Factors for expansion and activation of MDSC 12 3.2.5.2 ................................................................ Signal transduction in MDSC 14 3.2.6............................................... 14Strategies of MDSC for T-cell suppression 3.2.6.1 .................................................. Mechanisms of suppression by MDSC 15 3.2.6.1.1 ....................................................................... Nitrogen monoxide 15 3.2.6.1.2 ................................................................L-arginine and arginase 15 3.2.6.1.3 ..............................................................Reactive oxygen species 16 3.2.6.1.4 ........................................................Transforming growth factorβ 16 3.2.6.2 ............................. Mechanisms of suppression of both subpopulations 16 3.2.6.3 ..................................... Role of antigen-specific suppression by MDSC 17 3.2.7..................................................Integration of MDSC in cellular networks 17 3.2.8....................................................................................................Outlook 18 
 3.2.9...............................................................................................Hypothesis 19 4............................................................................................................EINLEITUNG 20 4.1....................................................... AUFBAU UNDFUNKTIONEN DESIMMUNSYSTEMS 20 4.1.1............................................Allgemeine Einführung in das Immunsystem 20 4.1.2..................................................................Regulation der Immunantwort 22 4.2....................................................... SUPPRESSORZELLEN DER MYELOISCHENREIHE 23 4.2.1.............................................................................Allgemeine Einführung 24 4.2.2................................................................................ 25Plastizität der MDSC 4.2.3....................................MDSC in der Homöostase und bei Erkrankungen 26 4.2.3.1 ....................................................................................... Murine MDSC 26 4.2.3.2 ......................................................................... MDSC beim Menschen 27 4.2.4.......................................................................... 28In vitro generierte MDSC 4.2.5.............................................................Induktion der Bildung von MDSC 29 4.2.5.1 ............................. Faktoren zur Expansion und Aktivierung von MDSC 29 4.2.5.2 ................................................................. Signaltransduktion in MDSC 31 4.2.6.......................................... 31Strategien der MDSC zur T-Zell-Suppression 4.2.6.1 ........................................ Mechanismen der Suppression durch MDSC 32 4.2.6.1.1 ......................................................................... Stickstoffmonoxid 32 4.2.6.1.2 .................................................................L-Arginin und Arginase 32 4.2.6.1.3 .......................................................... Reaktive Sauerstoffspezies 33 4.2.6.1.4 ........................................................Transforming growth factorβ 33 4.2.6.2 ..................... Suppressionsmechanismen der beiden Subpopulationen 34 4.2.6.3 ............Bedeutung der Antigenspezifität der Suppression durch MDSC 34 4.2.7............................... 35Integration der MDSC in weitere zelluläre Netzwerke 4.2.8...................................................................................................Ausblick 35 4.2.9................................................................................................Hypothese 36 5....................................................................................VORVERÖFFENTLICHUNG 37 6......................................................................................LITERATURVERZEICHNIS 38 7.................................................................................ABKÜRZUNGSVERZEICHNIS 52 8........................................................................................................DANKSAGUNG 55 9..........................................................................................................LEBENSLAUF 57  
 
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1 Summary 1.1Background and aims Dendritic cells (DC) and myeloid-derived suppressor cells (MDSC) are involved in the control of the immune response within tumor diease and infections. Here, MDSC are mainly found in the spleen and bone marrow and barely in lymph nodes. Morphologically, they are divided into monocytic and polymorphonuclear cells. It is not known yet which role MDSC play in healthy, untreated mice. MDSC can be generated from murine bone marrow cells by application of granulocyte/macrophage-colony-stimulating-factor (GM-CSF) and suppress T-cell response in vitro. The cytokine interferon-γ(IFN-γ)and nitrogen monoxide (NO) are required for this process. However, further stimulation of bone marrow cells with GM-CSF generates immature DC. Both DC and MDSC stem from immature myeloid precursor cells. So far, it is not resolved which factors regulate the differentiation of these cells to either DC or MDSC. This dissertation aimed for the identification of different subpopulations of MDSC in splenocytes of healthy mice. In addition, the modes of stimulation, activation and the plasticity of MDSC should be analyzed. 1.2Methods Therefore, ex vivo isolated splenocytes were characterized with flow cytometry; based on this, different subpopulations were isolated via cell sorting. Their suppressive potential was examined with mixed lymphocyte reaction and measuring of the amount of released NO, cytospins helped to identify their morphology. In vitro generated and ex vivo isolated immature myeloid cells were also characterized with flow cytometry after stimulation of mice and/or cells with different cytokines. 1.3Results In this dissertation it was shown that the combination of IFN-γand LPS (bacterial lipopolysaccharide) inhibited further differentiation of in vitro generated MDSC in the most efficient way; in addition, their suppressive activity was induced and enhanced by this treatment. In ex vivo isolated splenocytes of healthy, untreated mice six different subpopulations could be defined regarding surface markers and size/granularity/morphology of the cell; two of them were able to suppress T-cell response: Gr-1highCD11bintermediate cells with ring-shaped nuclei and Gr-1low CD11bintermediatecells with heterogenous morphology.
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