Verfügbarkeit: Type I Interferon and IL-10 supress T-cell mediated immunity against viral infections during liver fibrosis

Type I Interferon and IL-10 supress T-cell mediated immunity against viral infections during liver fibrosis:

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Bibliographische Detailangaben
Beteilige Person:	Hackstein, Carl-Philipp (VerfasserIn)
Format:	Hochschulschrift/Dissertation Buch
Sprache:	Englisch
Veröffentlicht:	Bonn 2018
Schlagwörter:	Hochschulschrift
Links:	http://d-nb.info/1154442470/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030488219&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
Umfang:	94 Seiten 31 Illustrationen 29 cm

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Datensatz im Suchindex

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adam_text	TABLE OF CONTENTS ZUSAMMENFASSUNG..................................................................... 1 ABSTRACT................................................................................................................. 2 1. INTRODUCTION.................................................................................................. 3 1.1. CONTRIBUTION OF THE IMMUNE SYSTEM TO THE DEVELOPMENT OF LIVER FIBROSIS AND CIRRHOSIS.................................................................................................................. 3 1.2. IMPACT OF LIVER FIBROSIS ON IMMUNE RESPONSES AND THE SUSCEPTIBILITY TOWARDS VIRAL INFECTIONS................................................................................................5 1.3. MOUSE MODELS OF LIVER FIBROSIS AND CIRRHOSIS ................................................. 6 1.4. THE LYMPHOCYTIC CHORIOMENIGITIS VIRUS (LCMV).............................................8 1.5. ANTI VIRAL IMMUNE RESPONSES .............................................. 9 1.5.1. CD8+ T-CELLS-MEDIATED IM M UN ITY..................................................................... 11 1.5.2. CD4+ T-CELLS IMMUNE RESPONSE ........................................................................ 11 1.6. PERSISTENT VIRAL INFECTIONS RENDER T CELLS EXHAUSTED ................................... 13 1.6.1. INHIBITORY RECEPTORS IM PAIR THE FUNCTION OF EXHAUSTED T-CELLS.....................14 1.6.2. TRANSCRIPTIONAL AND EPIGENETIC CONTROL OF EXHAUSTION...................................15 1.6.3. IMMUNE REGULATORY AND INFLAMMATORY SOLUBLE FACTOR CONTRIBUTING TO T-CELL EXHAUSTION........................................................................................................................16 2. AIMS OF THIS STUDY ....................................................................................... 18 3. MATERIALS AND METHODS .......................................................... 19 3.1. MATERIAL.............................................................................................................. 19 3.1.1. EQUIPMENT...........................................................................................................19 3.1.2. CONSUMABLES...................................................................................................... 20 3.1.3. CHEMICALS AND REAGENTS.....................................................................................20 3.1.4. BUFFERS, MEDIA AND SOLUTIONS ............................................................................ 23 3.1.5. ANTIBODIES AND TETRAMERS ................................................................................. 24 3.1.5.1. ANTIBODIES USED FOR IN VIVO BLOCKADE OF INTERACTIONS .......................................... 24 3.1.5.2. ANTIBODIES USED FOR IN VITRO STIMULATION.............................................................24 3.1.5.3. TETRAMERS AND DEXTRAMERS.................................................................................24 3.1.5.4. ANTIBODIES FOR IMMUNOFLUORESCENCE .................................................................. 25 3.1.5.5. ANTIBODIES FOR FLOW CYTOMETRIC ANALYSIS..............................................................25 3.1.6. RT-PCR PRIMERS AND PROBES...............................................................................27 3.1.7. CELLS AND VIRUSES ................................................................................................ 27 3.1.8. MOUSE STRAINS..................................................................................................... 27 3.1.9. SOFTWARE..............................................................................................................29 3.2. METHODS............................................................................................................. 30 3.2.1. EXPERIMENTAL TREATMENT OF MICE.......................................................................30 3.2.1.1. INDUCTION OF LIVER FIBROSIS BY BILE-DUCT LIGATION (BDL) ........................................ 30 3.2.1.2. INDUCTION OF LIVER FIBROSIS BY CCU-TREATMENT ...................................................... 30 3.2.1.3. INFECTION WITH LCMV WE.....................................................................................31 3.2.1.4. TREATMENT WITH BLOCKING ANTIBODIES................................................................... 31 3.2.1.5. IRRADIATION AND ADOPTIVE CELL TRANSFER.................................................................31 3.2.2. ISOLATION OF CELLS FROM ORGANS.............................................................................. 31 3.2.2.1. ISOLATION OF SPLENOCYTES...................................................................................... 31 3.2.2.2. ISOLATION OF LIVER-ASSOCIATED LYMPHOCYTES...........................................................32 3.2.2.3. ISOLATION OF HEPATIC NON-PARENCHYMAL CELLS ........................................................ 32 3.2.2.3. DETERMINATION OF CELL NUMBERS BY MICROSCOPY ................................................... 33 3.2.3. CELL CULTURE..........................................................................................................33 3.2.3.1. L929 CULTURE.......................................................................................................33 3.2.3.2. GENERATION OF LCMV STOCKS.................................................................................33 3.2.3.3. LCMV PLAQUE ASSAY.............................................................................................33 3.2.4. FLOW CYTOM ETRY.................................................................................................. 34 3.2.4.1. STAINING OF SURFACE MOLECULES............................................................................. 34 3.2.4.2. STAINING OF TRANSCRIPTION FACTORS AND CTLA-4.....................................................35 3.2.4.3. STAINING OF CYTOKINES.......................................................................................... 35 3.2.4.4. IN VITRO PROLIFERATION ASSAY................................................................................ 35 3.2.5. CONFOCAL MICROSCOPY.......................................................................................... 36 3.2.5.1. FIXATION OF LIVER SAMPLES.................................................................................... 36 3.2.5.2. STAINING OF LIVER SECTIONS FOR CONFOCAL MICROSCOPY ............................................. 36 3.2.5.3. CALCULATION OF THE NUMBER OF MXL-POSITIVE CELLS ON IMMUNOFLUORESCENT SLIDES... 36 3.2.6. RNA EXTRACTION, CDNA-SYNTHESIS AND RT-PCR ................................................ 37 3.2.7. LEGENDPLEX CYTOKINE ASSAY..............................................................................37 3.2.8. STATISTICAL ANALYSIS...............................................................................................37 4. RESULTS...................................................................................................................... 38 4.1. CIRRHOTIC LIVER DISEASE IMPAIRS THE ABILITY OF THE IMMUNE SYSTEM TO RESPOND TO INFECTION..................................................................................... 38 4.1.1. LIVER FIBROSIS IS ASSOCIATED W ITH LCMV-PERSISTENCE IN M ICE ....................... 36 4.1.2. IMPAIRED T-CELL IMMUNE RESPONSES IN MICE SUFFERING FROM LIVER FIBROSIS... 39 4.1.3. VIRUS-SPECIFIC T-CELLS SHOW SIGNS OF T-CELL EXHAUSTION DURING LIVER FIBROSIS43 4.2. LIVER FIBROSIS AND CIRRHOSIS ARE ASSOCIATED WITH CHANGES IN THE EXPRESSION OF INFLAMMATORY AND IMMUNE REGULATORY CYTOKINES ....... . ...................................... 46 4.2.1. DISRUPTION OF TNFR SIGNALING OR NEUTRALIZATION OF TNFA DOES NOT IMPROVE ANTIVIRAL IM M UNITY DURING LIVER FIBROSIS........................................................................47 4.2.2. THERAPEUTIC BLOCKADE OF IFNAR1 SIGNALING IMPROVES T CELL IM M UNITY DURING LIVER FIBROSIS.......................................................................................................................50 4.2.3. SPECIFIC ABLATION OF IFNAR IN MYELOID CELLS RESCUES ANTIVIRAL IM M UNITY IN MICE W ITH LIVER FIBROSIS.................................................................................................... 53 4.3. THE IMMUNE REGULATORY CYTOKINE IL-10 IS UPREGULATED IN THE FIBROTIC LIVER AFTER INFECTION IN AN IFN 1-DEPENDENT MANNER........................................................57 4.3.1. ANTIGEN-EXPERIENCED T-CELLS FROM BDL-OPERATED MICE SHOW INCREASED EXPRESSION OF THE IL-10 RECEPTOR ALPHA CHAIN ............................................................. 57 4.3.2. GENETIC ABLATION OF 1110 IN IFN I RESPONSIVE CELLS PROMOTES T CELL IM M UNITY AND VIRAL CONTROL IN BDL-OPERATED M ICE........................................................................58 4.3.3. THERAPEUTIC BLOCKADE OF IL-10R SIGNALING ENHANCES ADAPTIVE IM M UNITY AND VIRAL CLEARANCE IN FIBROTIC M ICE.......................................................................................62 4.3.4. T-CELLS LACKING THE IL-10R ALPHA CHAIN SHOW SUPERIOR EXPANSION AND CYTOKINE PRODUCTION IN BDL-OPERATED MICE..................................................................65 5. DISCUSSION.................................................................................................... 68 5.1. VIRUS SPECIFIC T-CELLS ACQUIRE AN EXHAUSTION-LIKE PHENOTYPE DURING LIVER CIRRHOSIS............................................................................................... 69 5.2. INCREASED LEVELS OF IFN I DRIVE SUPPRESSION OF ANTIVIRAL IMMUNITY DURING LIVER CIRRHOSIS................................................................................................................71 5.3. IL-10 IS INDUCED DURING LIVER CIRRHOSIS IN AN IFN I DEPENDED MANNER AND DIRECTLY SUPPRESSES VIRUS-SPECIFIC T-CELLS................................................................ 74 5.4. IMPLICATIONS OF IFN I AND IL-10 MEDIATED SUPPRESSION OF ANTIVIRAL IMMUNITY IN THE CONTEXT OF LIVER CIRRHOSIS ............................................................... 75 6. REFERENCES.................................................. 77 7. ABBREVIATIONS. ............ . ................................................................................. 92 DANKSAGUNG.........................................................................................................94
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spellingShingle	Hackstein, Carl-Philipp Type I Interferon and IL-10 supress T-cell mediated immunity against viral infections during liver fibrosis
subject_GND	(DE-588)4113937-9
title	Type I Interferon and IL-10 supress T-cell mediated immunity against viral infections during liver fibrosis
title_auth	Type I Interferon and IL-10 supress T-cell mediated immunity against viral infections during liver fibrosis
title_exact_search	Type I Interferon and IL-10 supress T-cell mediated immunity against viral infections during liver fibrosis
title_full	Type I Interferon and IL-10 supress T-cell mediated immunity against viral infections during liver fibrosis vorgelegt von Carl-Philipp Hackstein, geboren in Freiburg im Breisgau
title_fullStr	Type I Interferon and IL-10 supress T-cell mediated immunity against viral infections during liver fibrosis vorgelegt von Carl-Philipp Hackstein, geboren in Freiburg im Breisgau
title_full_unstemmed	Type I Interferon and IL-10 supress T-cell mediated immunity against viral infections during liver fibrosis vorgelegt von Carl-Philipp Hackstein, geboren in Freiburg im Breisgau
title_short	Type I Interferon and IL-10 supress T-cell mediated immunity against viral infections during liver fibrosis
title_sort	type i interferon and il 10 supress t cell mediated immunity against viral infections during liver fibrosis
topic_facet	Hochschulschrift
url	http://d-nb.info/1154442470/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030488219&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
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