Verfügbarkeit: Functional roles of PD-L1 and PD-L2 in the pathogenesis of chronic lymphocytic leukaemia

Functional roles of PD-L1 and PD-L2 in the pathogenesis of chronic lymphocytic leukaemia – an in vivo Analysis:

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Bibliographische Detailangaben
1. Verfasser:	Reinartz, Sebastian (VerfasserIn)
Format:	Abschlussarbeit Buch
Sprache:	English
Veröffentlicht:	Köln 2022
Schlagworte:	ddc:570 ddc:610 doc-type:other Text Hochschulschrift
Online-Zugang:	https://kups.ub.uni-koeln.de/56127/2/Abstract_PhD%20Thesis_Druckversion_Sebastian%20Reinartz_englisch.pdf=x This 856 field was generated using the WorldCat Digital Collection Gateway Inhaltsverzeichnis Inhaltsverzeichnis
Beschreibung:	IV, 172, xv Seiten Illustrationen 21 cm

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Datensatz im Suchindex

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adam_text	TABLE OF CONTENTS I. GRAPHICAL SUMMARY ............................................................................................... 1 II. ABSTRACT ................................................................................................................. 2 III. INTRODUCTION .................................................................... 4 111.1 IMMUNE CHECKPOINT MOLECULES ......................................................................... 4 111.2 THE PD-1 - PD-1 LIGAND IMMUNE CHECKPOINT AXIS ............................................. 7 UL.2.1 PROGRAMMED CELL DEATH 1 LIGAND 1 (PD-L1) .................................................. 7 111.2.2 PROGRAMMED CELL DEATH 1 LIGAND 2 (PD-L2) ................................................ 8 III .2.3 EXPRESSION AND REGULATION OF PD-1 , PD-L1 , AND PD-L2 .............................. 9 III .2.3.1 REGULATION OF THE PD-1 RECEPTOR .............................................................. 9 III.2.3.2 REGULATION OF THE PD-1 LIGANDS .............................................................. 10 III.2.3.3 REGULATION OF THE PD-1 LIGANDS IN CANCER ............................................... 11 111.2.4 MECHANISMS OF PD-1-MEDIATED SIGNALLING IN T CELLS ................................. 12 111.2.5 THE PHENOTYPE OF PD-1, PD-L1, AND PD-L2 KNOCKOUT MOUSE MODELS ...... 15 111.3 T CELLS ............................................................................................................. 15 11.3.1 T CELL MATURATION ....................................................................................... 15 111.3.2 FUNCTIONS OF THE DIFFERENT T CELL SUBSETS .................................................. 16 111.3.3 T CELL RECEPTOR SIGNALLING .......................................................................... 19 III. 3.4 T CELL EXHAUSTION ....................................................................................... 111.3.5 T CELL-BASED IMMUNOTHERAPY .................................................................... 22 111.4 IMMUNE CHECKPOINT BLOCKADE (ICB) THERAPY ................................................... 24 III. 5 CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) ............................................................ 27 111.5.1 B CELL RECEPTOR SIGNALLING ......................................................................... 29 III.5.2 THE EFJ-TCL1 TRANSGENIC MOUSE MODEL ..................................................... 31 III. 5.3 PD-1/ PD-1 LIGAND IMMUNE CHECKPOINT BLOCKADE IN CLL ............................ 32 IV. RESEARCH AIM ....................................................................................................... 34 V. MATERIAL AND METHODS ........................................................................................... 35 V .1 EXPERIMENTAL DEVICES............................................................................. 35 V .2 DISPOSABLE MATERIALS .............................................................................. 36 V .3 CHEMICALS AND REAGENTS ........................................................................ 37 V .4 BUFFERS, MEDIA, AND SOLUTIONS ................................................................. 38 V .5 KITS ......................................................................................................... 39 V .6 CELL LINES ................................................................................................ 39 V .7 MOUSE STRAINS ......................................................................................... 40 V .8 SOFTWARE ................................................................................................. 40 V .9 ANIMAL EXPERIMENTS ................................................................................... 41 V .9.1 EXPERIMENTAL MICE AND HUSBANDRY ................................................ 41 V .9.2 GENERATION OF PD-I1 AND PD-I2 KNOCK-OUT MICE ............................... 41 V .9.4 BLOOD SAMPLE COLLECTION ................................................................ 49 V .9.5 CELL ISOLATION FROM MURINE LYMPHOID TISSUES ................................. 49 V .9.6 PHENOTYPING OF EP-TCLI^PD-IT 7 AND EFJ-TCLR^PD-IZ 7 MICE .... 50 V .9.7 TRANSCRIPTOME ANALYSIS ................................................................ 50 V .9.8 ADOPTIVE TRANSFER OF MURINE CLL CELLS ........................................... 52 V .9.9 T CELL DEPLETION IN ALLOGRAFT RECIPIENT MICE ..................................... 53 V .10 CELL CULTURE EXPERIMENTS ............................................................................. 53 V .10.1 CELL LINE CULTURE ............................................................................. 53 V .10.2 CELL LYSIS ........................................................................................ 54 V .10.3 BCR-INHIBITOR TREATMENT ................................................................ 54 V .1 0.4 ISOLATION OF CLL CELLS FROM PERIPHERAL PATIENT BLOOD ..................... 55 V .1 0.5 CO-CULTURE EXPERIMENTS ................................................................ 57 V .1 1 PROTEIN BIOCHEMISTRY ................................................................................... 58 V .1 1.1 WESTERN-BLOT ANALYSIS ................................................................... 58 V .1 2 CELL ANALYSIS ................................................................................................ 60 V .1 2.1 FLOW CYTOMETRY .............................................................................. 60 V .1 3 DATA ILLUSTRATION AND STORAGE ....................................................................... 62 V .1 4 STATISTICAL ANALYSIS ...................................................................................... 62 VI . RESULTS............................................................................................................. 63 AIM 1: DETERMINING THE ROLE OF PD-11 AND PD-I2 IN THE PATHOGENESIS OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IN VIVO ......................................................................................... 63 V I. 1 PD-1 LIGAND EXPRESSION IN EFJ-TCL1 T9/WT MICE ..................................... 63 V I.2 GENERATION OF PD-11 AND PD-I2 KNOCK-OUT MICE .................................. 65 V I.3 CONFIRMATION OF PD-11 AND PD-12 KNOCK-OUT ON PROTEIN LEVEL ............. 69 V I.4 BREEDING OF EP-TCLI^PD-IT 7 AND EP-TCLI^PD-IZ 7 MICE ............ 71 V I.5 CLL PATHOGENESIS IN EP-TCLI^PD-IT 7 - AND EP-TCLI^PD-IZ 7 - MICE 72 V I.6 HEALTHY B CELL AND CD11B + MONOCYTE POPULATIONS IN LYMPHOID TISSUE OF EP-TCL1 TG/WT PD-H - AND EP-TCLR^PD-IZ 7 MICE .................................................... 78 V I.7 LONGITUDINAL CHARACTERIZATION OF THE PD-11 LIGAND EXPRESSION IN EP-TCLI^PD-IT 7 AND EP-TCLI^PD-IZ 7 MICE DURING CLL PATHOGENESIS........... 79 V I.8 LONGITUDINAL CHARACTERIZATION OF MAJOR T CELL POPULATIONS IN EP-TCLI^PD-IT 7 AND EP-TCLI^PD-IZ 7 MICE DURING CLL PATHOGENESIS.......... 86 V I.9 CD4/CD8 RATIO IN EP-TCLI^PD-H 7 - AND EP-TCLR^PD-IZ 7 MICE DURING CLL PATHOGENESIS ....................................................................................................... 92 LL V I. 10 LONGITUDINAL CHARACTERIZATION OF THE PD-1 EXPRESSION IN EP-TCLI^PD-IT 7 - AND EP-TCLI^PD-L^ MICE DURING CLL PATHOGENESIS ...................................... 95 VI. 11 MRNA SEQUENCING OF MAJOR SPLENOCYTES FROM EP-TCLI^PD-H^ MICE VS EFJ~TCL1 T9/WT CONTROLS 101 VI. 11.1 DIFFERENTIALLY EXPRESSED GENES IN SPLENIC HEALTHY B CELLS .................... 103 VI.1 1.2 GO TERM ANALYSIS FOR SPLENIC HEALTHY B CELLS ........................................ 106 VI. 11.3 DIFFERENTIAL GENE EXPRESSION IN SPLENIC CLL CELLS ................................ 108 VI.1 1.4 GO TERM ANALYSIS FOR SPLENIC CLL CELLS ................................................ ILL VI.1 1.6 GO TERM ANALYSIS FOR SPLENIC CD3 + CD4 + T CELLS .................................... 115 VI.1 1.7 DIFFERENTIAL GENE EXPRESSION IN SPLENIC CD3 + CD8 + T CELLS .................... 116 VI.1 1.8 GO TERM ANALYSIS FOR SPLENIC CD3 + CD8 + T CELLS .................................... 121 VI. 11.9 DIFFERENTIAL GENE EXPRESSION BETWEEN HEALTHY B CELLS AND CLL CELLS .. 123 AIM 2: EXAMINING THE ROLE OF PD-11 AND PD-I2 EXPRESSION IN THE TUMOR MICROENVIRONMENT (TME) OF CLL ............................................................................ 125 VI . 12 ADOPTIVE TRANSFER OF MURINE EP-TCL1 T9/WT CLL CELLS INTO PD-1 LIGAND DEFICIENT RECIPIENT MICE ....................................................................................... 125 VI .1 3 PERIPHERAL T CELL POPULATIONS IN ENGRAFTMENT-RESISTANT AND NON-RESISTANT PD-11 A RECIPIENT MICE .......................................................................................... 127 VI . 14 ADOPTIVE TRANSFER OF MURINE EP-TCL1 T9 CLL CELLS IN T CELL-DEPLETED RECIPIENT MICE ..................................................................................................... 129 VI .1 5 CO-CULTURE OF PD-1 LIGAND DEFICIENT MBMDMS AND PRIMARY HUMAN CLL CELLS 133 AIM 3: INVESTIGATING THE IMPACT OF B CELL RECEPTOR (BCR) SIGNALLING ON THE REGULATION OF PD-L1 AND PD-L2 SURFACE EXPRESSION .................................................................. 136 VI .1 6 PD-1 LIGAND EXPRESSION ON HUMAN B CELL LINES AFTER BCR-INHIBITOR TREATMENT ............................................................................................................. 136 VI .1 7 PD-1 LIGAND EXPRESSION ON PRIMARY HUMAN CLL CELLS AFTER BCR-INHIBITOR TREATMENT ............................................................................................................. 138 VI .1 8 PD-1 LIGAND EXPRESSION ON PRIMARY MURINE CLL CELLS AFTER BCR-INHIBITOR TREATMENT ............................................................................................................. 139 VI .1 9 SUMMARY OF IN VITRO BCR-INHIBITOR TREATMENTS .................................... 139 VII . DISCUSSION ........................................................................................................ 141 VII .1 AIM 1: DETERMINING THE ROLE OF PD-11 AND PD-I2 IN THE PATHOGENESIS OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IN VIVO ......................................................................... 141 VII . 1.1 EFFECT OF GLOBAL PD-11 AND PD-12 KNOCKOUT ON CLL PROGRESSION IN THE EU TCL1 T9 141 VII . 1.2 TRANSCRIPTIONAL CHANGES IN MAJOR SPLENIC IMMUNE CELL TYPES OF 8 MONTHS OLD 145 VII .1. 2.1 PD-11 DEFICIENT SPLENIC HEALTHY B CELLS 145 III VII .1 .2.2 PD-11 DEFICIENT SPLENIC CLL CELLS .............................................. 146 VII .1. 2.3 SPLENIC CD4 + AND CD8 + T CELLS IN EP-TCLI^PD-IT^ MICE ........ 148 VII .2 AIM 2: EXAMINING THE ROLE OF PD-11 AND PD-I2 EXPRESSION IN THE TUMOUR MICROENVIRONMENT (TME) OF CLL ............................................................................ 151 VII . 2.1 CLL DEVELOPMENT AND PROGRESSION IN MURINE ADOPTIVE TRANSFER MODELS EITHER LACKING PD-11 OR PD-I2 IN THE TUMOUR MICROENVIRONMENT (TME) .................. 151 VII .2.2 IMPACT OF PD-1 LIGAND EXPRESSION ON THE FEEDER CAPACITY OF MBMDMS IN A 154 VII .3 AIM 3: INVESTIGATING THE IMPACT OF B CELL RECEPTOR (BCR) SIGNALLING ON THE REGULATION OF PD-L1 AND PD-L2 EXPRESSION............................................................. 155 VII .3.1 IMPACT OF SMALL MOLECULE BCR-INHIBITORS ON THE SURFACE EXPRESSION OF PD 1 155 VIII . OUTLOOK ........................................................................................................... 157 VIII .1 FUNCTIONAL CHARACTERISATION OF CYTOTOXIC T CELLS IN EFJ-TCLI^PD-H^ MICE 157 VIII . 2 INVESTIGATING THE FUNCTIONAL ROLE OF TIM3 UPREGULATION ON CD8 + T CELLS IN EU-TCL1TG/*PD-11 MICE AND ITS SUITABILITY AS A POTENTIAL TARGET TO RESTORE CYTOLYTIC T CELL FUNCTION 158 VIII . 3 ADOPTIVE TRANSFER OF EU-TCL1TG/W PD-11 CLL CELLS INTO WT RECIPIENT MICE . 159 VIII .4 GENERATION AND CHARACTERISATION OF B CELL-SPECIFIC PD-11 KNOCK-OUT IN EU TCL1 T9/WT MICE ...................................................................................................................................... 159 IX . REFERENCES ..................................................................................................... 160 APPENDICES ................................................................................................................... I SUPPLEMENTAL FIGURES ................................................................................................. I ABBREVIATION ............................................................................................................. III LIST OF FIGURES .......................................................................................................... IX LIST OF TABLES ........................................................................................................... XI ACKNOWLEDGEMENTS ................................................................................................ XIII ERKLARUNG ZUR DISSERTATION ...................................................................................... XIV DECLARATION FOR THE DOCTORAL THESIS ........................................................................... XV IV
adam_txt	TABLE OF CONTENTS I. GRAPHICAL SUMMARY . 1 II. ABSTRACT . 2 III. INTRODUCTION . 4 111.1 IMMUNE CHECKPOINT MOLECULES . 4 111.2 THE PD-1 - PD-1 LIGAND IMMUNE CHECKPOINT AXIS . 7 UL.2.1 PROGRAMMED CELL DEATH 1 LIGAND 1 (PD-L1) . 7 111.2.2 PROGRAMMED CELL DEATH 1 LIGAND 2 (PD-L2) . 8 III .2.3 EXPRESSION AND REGULATION OF PD-1 , PD-L1 , AND PD-L2 . 9 III .2.3.1 REGULATION OF THE PD-1 RECEPTOR . 9 III.2.3.2 REGULATION OF THE PD-1 LIGANDS . 10 III.2.3.3 REGULATION OF THE PD-1 LIGANDS IN CANCER . 11 111.2.4 MECHANISMS OF PD-1-MEDIATED SIGNALLING IN T CELLS . 12 111.2.5 THE PHENOTYPE OF PD-1, PD-L1, AND PD-L2 KNOCKOUT MOUSE MODELS . 15 111.3 T CELLS . 15 11.3.1 T CELL MATURATION . 15 111.3.2 FUNCTIONS OF THE DIFFERENT T CELL SUBSETS . 16 111.3.3 T CELL RECEPTOR SIGNALLING . 19 III. 3.4 T CELL EXHAUSTION . 111.3.5 T CELL-BASED IMMUNOTHERAPY . 22 111.4 IMMUNE CHECKPOINT BLOCKADE (ICB) THERAPY . 24 III. 5 CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) . 27 111.5.1 B CELL RECEPTOR SIGNALLING . 29 III.5.2 THE EFJ-TCL1 TRANSGENIC MOUSE MODEL . 31 III. 5.3 PD-1/ PD-1 LIGAND IMMUNE CHECKPOINT BLOCKADE IN CLL . 32 IV. RESEARCH AIM . 34 V. MATERIAL AND METHODS . 35 V .1 EXPERIMENTAL DEVICES. 35 V .2 DISPOSABLE MATERIALS . 36 V .3 CHEMICALS AND REAGENTS . 37 V .4 BUFFERS, MEDIA, AND SOLUTIONS . 38 V .5 KITS . 39 V .6 CELL LINES . 39 V .7 MOUSE STRAINS . 40 V .8 SOFTWARE . 40 V .9 ANIMAL EXPERIMENTS . 41 V .9.1 EXPERIMENTAL MICE AND HUSBANDRY . 41 V .9.2 GENERATION OF PD-I1 AND PD-I2 KNOCK-OUT MICE . 41 V .9.4 BLOOD SAMPLE COLLECTION . 49 V .9.5 CELL ISOLATION FROM MURINE LYMPHOID TISSUES . 49 V .9.6 PHENOTYPING OF EP-TCLI^PD-IT 7 ' AND EFJ-TCLR^PD-IZ 7 ' MICE . 50 V .9.7 TRANSCRIPTOME ANALYSIS . 50 V .9.8 ADOPTIVE TRANSFER OF MURINE CLL CELLS . 52 V .9.9 T CELL DEPLETION IN ALLOGRAFT RECIPIENT MICE . 53 V .10 CELL CULTURE EXPERIMENTS . 53 V .10.1 CELL LINE CULTURE . 53 V .10.2 CELL LYSIS . 54 V .10.3 BCR-INHIBITOR TREATMENT . 54 V .1 0.4 ISOLATION OF CLL CELLS FROM PERIPHERAL PATIENT BLOOD . 55 V .1 0.5 CO-CULTURE EXPERIMENTS . 57 V .1 1 PROTEIN BIOCHEMISTRY . 58 V .1 1.1 WESTERN-BLOT ANALYSIS . 58 V .1 2 CELL ANALYSIS . 60 V .1 2.1 FLOW CYTOMETRY . 60 V .1 3 DATA ILLUSTRATION AND STORAGE . 62 V .1 4 STATISTICAL ANALYSIS . 62 VI . RESULTS. 63 AIM 1: DETERMINING THE ROLE OF PD-11 AND PD-I2 IN THE PATHOGENESIS OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IN VIVO . 63 V I. 1 PD-1 LIGAND EXPRESSION IN EFJ-TCL1 T9/WT MICE . 63 V I.2 GENERATION OF PD-11 AND PD-I2 KNOCK-OUT MICE . 65 V I.3 CONFIRMATION OF PD-11 AND PD-12 KNOCK-OUT ON PROTEIN LEVEL . 69 V I.4 BREEDING OF EP-TCLI^PD-IT 7 ' AND EP-TCLI^PD-IZ 7 ' MICE . 71 V I.5 CLL PATHOGENESIS IN EP-TCLI^PD-IT 7 - AND EP-TCLI^PD-IZ 7 - MICE 72 V I.6 HEALTHY B CELL AND CD11B + MONOCYTE POPULATIONS IN LYMPHOID TISSUE OF EP-TCL1 TG/WT PD-H - AND EP-TCLR^PD-IZ 7 MICE . 78 V I.7 LONGITUDINAL CHARACTERIZATION OF THE PD-11 LIGAND EXPRESSION IN EP-TCLI^PD-IT 7 ' AND EP-TCLI^PD-IZ 7 ' MICE DURING CLL PATHOGENESIS. 79 V I.8 LONGITUDINAL CHARACTERIZATION OF MAJOR T CELL POPULATIONS IN EP-TCLI^PD-IT 7 ' AND EP-TCLI^PD-IZ 7 MICE DURING CLL PATHOGENESIS. 86 V I.9 CD4/CD8 RATIO IN EP-TCLI^PD-H 7 - AND EP-TCLR^PD-IZ 7 MICE DURING CLL PATHOGENESIS . 92 LL V I. 10 LONGITUDINAL CHARACTERIZATION OF THE PD-1 EXPRESSION IN EP-TCLI^PD-IT 7 - AND EP-TCLI^PD-L^' MICE DURING CLL PATHOGENESIS . 95 VI. 11 MRNA SEQUENCING OF MAJOR SPLENOCYTES FROM EP-TCLI^PD-H^ MICE VS EFJ~TCL1 T9/WT CONTROLS 101 VI. 11.1 DIFFERENTIALLY EXPRESSED GENES IN SPLENIC HEALTHY B CELLS . 103 VI.1 1.2 GO TERM ANALYSIS FOR SPLENIC HEALTHY B CELLS . 106 VI. 11.3 DIFFERENTIAL GENE EXPRESSION IN SPLENIC CLL CELLS . 108 VI.1 1.4 GO TERM ANALYSIS FOR SPLENIC CLL CELLS . ILL VI.1 1.6 GO TERM ANALYSIS FOR SPLENIC CD3 + CD4 + T CELLS . 115 VI.1 1.7 DIFFERENTIAL GENE EXPRESSION IN SPLENIC CD3 + CD8 + T CELLS . 116 VI.1 1.8 GO TERM ANALYSIS FOR SPLENIC CD3 + CD8 + T CELLS . 121 VI. 11.9 DIFFERENTIAL GENE EXPRESSION BETWEEN HEALTHY B CELLS AND CLL CELLS . 123 AIM 2: EXAMINING THE ROLE OF PD-11 AND PD-I2 EXPRESSION IN THE TUMOR MICROENVIRONMENT (TME) OF CLL . 125 VI . 12 ADOPTIVE TRANSFER OF MURINE EP-TCL1 T9/WT CLL CELLS INTO PD-1 LIGAND DEFICIENT RECIPIENT MICE . 125 VI .1 3 PERIPHERAL T CELL POPULATIONS IN ENGRAFTMENT-RESISTANT AND NON-RESISTANT PD-11 A RECIPIENT MICE . 127 VI . 14 ADOPTIVE TRANSFER OF MURINE EP-TCL1 T9 CLL CELLS IN T CELL-DEPLETED RECIPIENT MICE . 129 VI .1 5 CO-CULTURE OF PD-1 LIGAND DEFICIENT MBMDMS AND PRIMARY HUMAN CLL CELLS 133 AIM 3: INVESTIGATING THE IMPACT OF B CELL RECEPTOR (BCR) SIGNALLING ON THE REGULATION OF PD-L1 AND PD-L2 SURFACE EXPRESSION . 136 VI .1 6 PD-1 LIGAND EXPRESSION ON HUMAN B CELL LINES AFTER BCR-INHIBITOR TREATMENT . 136 VI .1 7 PD-1 LIGAND EXPRESSION ON PRIMARY HUMAN CLL CELLS AFTER BCR-INHIBITOR TREATMENT . 138 VI .1 8 PD-1 LIGAND EXPRESSION ON PRIMARY MURINE CLL CELLS AFTER BCR-INHIBITOR TREATMENT . 139 VI .1 9 SUMMARY OF IN VITRO BCR-INHIBITOR TREATMENTS . 139 VII . DISCUSSION . 141 VII .1 AIM 1: DETERMINING THE ROLE OF PD-11 AND PD-I2 IN THE PATHOGENESIS OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IN VIVO . 141 VII . 1.1 EFFECT OF GLOBAL PD-11 AND PD-12 KNOCKOUT ON CLL PROGRESSION IN THE EU TCL1 T9 141 VII . 1.2 TRANSCRIPTIONAL CHANGES IN MAJOR SPLENIC IMMUNE CELL TYPES OF 8 MONTHS OLD 145 VII .1. 2.1 PD-11 DEFICIENT SPLENIC HEALTHY B CELLS 145 III VII .1 .2.2 PD-11 DEFICIENT SPLENIC CLL CELLS . 146 VII .1. 2.3 SPLENIC CD4 + AND CD8 + T CELLS IN EP-TCLI^PD-IT^ MICE . 148 VII .2 AIM 2: EXAMINING THE ROLE OF PD-11 AND PD-I2 EXPRESSION IN THE TUMOUR MICROENVIRONMENT (TME) OF CLL . 151 VII . 2.1 CLL DEVELOPMENT AND PROGRESSION IN MURINE ADOPTIVE TRANSFER MODELS EITHER LACKING PD-11 OR PD-I2 IN THE TUMOUR MICROENVIRONMENT (TME) . 151 VII .2.2 IMPACT OF PD-1 LIGAND EXPRESSION ON THE FEEDER CAPACITY OF MBMDMS IN A 154 VII .3 AIM 3: INVESTIGATING THE IMPACT OF B CELL RECEPTOR (BCR) SIGNALLING ON THE REGULATION OF PD-L1 AND PD-L2 EXPRESSION. 155 VII .3.1 IMPACT OF SMALL MOLECULE BCR-INHIBITORS ON THE SURFACE EXPRESSION OF PD 1 155 VIII . OUTLOOK . 157 VIII .1 FUNCTIONAL CHARACTERISATION OF CYTOTOXIC T CELLS IN EFJ-TCLI^PD-H^ MICE 157 VIII . 2 INVESTIGATING THE FUNCTIONAL ROLE OF TIM3 UPREGULATION ON CD8 + T CELLS IN EU-TCL1TG/*PD-11" MICE AND ITS SUITABILITY AS A POTENTIAL TARGET TO RESTORE CYTOLYTIC T CELL FUNCTION 158 VIII . 3 ADOPTIVE TRANSFER OF EU-TCL1TG/W ' PD-11 CLL CELLS INTO WT RECIPIENT MICE . 159 VIII .4 GENERATION AND CHARACTERISATION OF B CELL-SPECIFIC PD-11 KNOCK-OUT IN EU TCL1 T9/WT MICE . 159 IX . REFERENCES . 160 APPENDICES . I SUPPLEMENTAL FIGURES . I ABBREVIATION . III LIST OF FIGURES . IX LIST OF TABLES . XI ACKNOWLEDGEMENTS . XIII ERKLARUNG ZUR DISSERTATION . XIV DECLARATION FOR THE DOCTORAL THESIS . XV IV
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spelling	Reinartz, Sebastian Verfasser (DE-588)1277390967 aut Functional roles of PD-L1 and PD-L2 in the pathogenesis of chronic lymphocytic leukaemia – an in vivo Analysis vorgelegt von Sebastian Reinartz Köln 2022 IV, 172, xv Seiten Illustrationen 21 cm txt rdacontent n rdamedia nc rdacarrier Dissertation Universität zu Köln 2022 ddc:570 ddc:610 doc-type:other Text (DE-588)4113937-9 Hochschulschrift gnd-content https://kups.ub.uni-koeln.de/56127/2/Abstract_PhD%20Thesis_Druckversion_Sebastian%20Reinartz_englisch.pdf=x This 856 field was generated using the WorldCat Digital Collection Gateway B:DE-101 application/pdf https://d-nb.info/1267596716/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=034036808&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis 1\p emakn 0,59452 20230109 DE-101 https://d-nb.info/provenance/plan#emakn 2\p dnb 20230109 DE-101 https://d-nb.info/provenance/plan#dnb
spellingShingle	Reinartz, Sebastian Functional roles of PD-L1 and PD-L2 in the pathogenesis of chronic lymphocytic leukaemia – an in vivo Analysis
subject_GND	(DE-588)4113937-9
title	Functional roles of PD-L1 and PD-L2 in the pathogenesis of chronic lymphocytic leukaemia – an in vivo Analysis
title_auth	Functional roles of PD-L1 and PD-L2 in the pathogenesis of chronic lymphocytic leukaemia – an in vivo Analysis
title_exact_search	Functional roles of PD-L1 and PD-L2 in the pathogenesis of chronic lymphocytic leukaemia – an in vivo Analysis
title_exact_search_txtP	Functional roles of PD-L1 and PD-L2 in the pathogenesis of chronic lymphocytic leukaemia – an in vivo Analysis
title_full	Functional roles of PD-L1 and PD-L2 in the pathogenesis of chronic lymphocytic leukaemia – an in vivo Analysis vorgelegt von Sebastian Reinartz
title_fullStr	Functional roles of PD-L1 and PD-L2 in the pathogenesis of chronic lymphocytic leukaemia – an in vivo Analysis vorgelegt von Sebastian Reinartz
title_full_unstemmed	Functional roles of PD-L1 and PD-L2 in the pathogenesis of chronic lymphocytic leukaemia – an in vivo Analysis vorgelegt von Sebastian Reinartz
title_short	Functional roles of PD-L1 and PD-L2 in the pathogenesis of chronic lymphocytic leukaemia – an in vivo Analysis
title_sort	functional roles of pd l1 and pd l2 in the pathogenesis of chronic lymphocytic leukaemia an in vivo analysis
topic_facet	Hochschulschrift
url	https://kups.ub.uni-koeln.de/56127/2/Abstract_PhD%20Thesis_Druckversion_Sebastian%20Reinartz_englisch.pdf=x This 856 field was generated using the WorldCat Digital Collection Gateway https://d-nb.info/1267596716/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=034036808&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
work_keys_str_mv	AT reinartzsebastian functionalrolesofpdl1andpdl2inthepathogenesisofchroniclymphocyticleukaemiaaninvivoanalysis

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