Functional roles of PD-L1 and PD-L2 in the pathogenesis of chronic lymphocytic leukaemia – an in vivo Analysis:
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| Format: | Thesis Book |
| Language: | English |
| Published: |
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2022
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| Online Access: | 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 |
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| 100 | 1 | |a Reinartz, Sebastian |e Verfasser |0 (DE-588)1277390967 |4 aut | |
| 245 | 1 | 0 | |a Functional roles of PD-L1 and PD-L2 in the pathogenesis of chronic lymphocytic leukaemia – an in vivo Analysis |c vorgelegt von Sebastian Reinartz |
| 264 | 1 | |a Köln |c 2022 | |
| 300 | |a IV, 172, xv Seiten |b Illustrationen |c 21 cm | ||
| 336 | |b txt |2 rdacontent | ||
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| 502 | |b Dissertation |c Universität zu Köln |d 2022 | ||
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| 653 | |a Text | ||
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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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| author | Reinartz, Sebastian |
| author_GND | (DE-588)1277390967 |
| author_facet | Reinartz, Sebastian |
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| id | DE-604.BV048662147 |
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| index_date | 2024-07-03T21:21:20Z |
| indexdate | 2024-07-10T09:45:14Z |
| institution | BVB |
| language | English |
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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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