Cyclin dependent kinases as Cyclin dependent kinases as therapeutic agents in Rheumatoid therapeutic agents in Rheumatoid Arthritis Arthritis Professor Janet M Lord Professor Janet M Lord Rheumatology Research Group Rheumatology Research Group MRC Centre for Immune Regulation MRC Centre for Immune Regulation University of Birmingham University of Birmingham
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Cyclin dependent kinases as therapeutic agents in Rheumatoid Arthritis Professor Janet M Lord Rheumatology Research Group MRC Centre for Immune Regulation.
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Cyclin dependent kinases as therapeutic Cyclin dependent kinases as therapeutic agents in Rheumatoid Arthritis agents in Rheumatoid Arthritis
Professor Janet M LordProfessor Janet M LordRheumatology Research GroupRheumatology Research Group
MRC Centre for Immune RegulationMRC Centre for Immune RegulationUniversity of BirminghamUniversity of Birmingham
Lecture content
• What is Rheumatoid Arthritis?
• Neutrophils and their role in RA
• Identifying novel drugs to regulate neutrophil function and survival
• CDKs as regulators of neutrophil function and apoptosis
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Inflammatory Response and Rheumatoid arthritis
Meet the Neutrophil
Rolling, adhesion and
diapedesis.
Phagocytosis. Degranulation, and activation of NADPH oxidase
Microbe
Destructionof microbe
Phagocytosis byTissue macrophages
Apoptosis
Neutrophils and Rheumatoid Arthritis high numbers can be found in Synovial Fluid (SF) secretion of pro- inflammatory cytokines loss of viscosity of SF and cartilage destruction caused
by ROI and granule enzymes result in joint damage
ResolutionEarly synovitis
Rheumatoid Arthritis
The Big Question in RA is…….
Chronic inflammation in Rheumatoid Chronic inflammation in Rheumatoid ArthritisArthritis
IFN-
DeathDeath
DivisionDivision
EmigrationEmigrationRecruitmentRecruitment
X
SDF-1TNF-
Neutrophil apoptosis in synovial fluid
from patients with arthritis
RA0
5
10
15
20
CrystalArthritis
% A
po
pto
tic
Neu
tro
ph
ils
Prevention versus Treatment
Very earlysynovitis
EstablishedRA
Normal
synovium
synovial fluid?
Understanding the switch to persistence in RA
0 3 18months from symptom onset
RA
Non-RApersistent
Resolving
The early arthritis clinic
Ultrasound guided joint aspiration
Tibia Talus
Very early RA has a distinct cytokine profile
Early RA
Other early arthritis
0 1 2 3
IL-13
IL-2
IL-15
bFGF
IL-4
EGF
Eotaxin
IL-1β
MIP1β
GM-CSF
IL-12
MIP1α
MCP-1
IL-17
IL-10
IFNG-CSF
VEGF
TNFα
RANTES
IL-8
IL-6
IL-5
Decrease inclassification accuracy
-0.6 -0.4 -0.2 0.0 0.2
0.3
0.2
0.1
0.0
-0.1
-0.2
Synovial fluid leukocyte apoptosis is inhibited in very early RA
0
1
2
3
RA non-RApersistent
resolving%
lym
ph
ocy
te a
po
pto
sis
0
10
20
30
% n
eutr
op
hil
apo
pto
sis
RA non-RApersistent
resolving
**
Very early RA
•Cytokine profile that is distinct & transient•This response may generate the microenvironment required for persistent disease:•IL13 + bFGF promote synoviocyte proliferation and survival•IL4 promotes DC maturation for T cell priming and B cell differentiation and secondary lymphoid tissue formation•Several factors promote neutrophil survival and priming
EstablishedNormal
synovium
synovial fluid
IL-2, IL-4, IL-13, IL-15GM-CSF, bFGF, EGF
Synovial cytokines prevent Neutrophil and T cell apoptosis
Control NAC Desf.0
25
50
75
% a
po
pto
tic
neu
tro
ph
ils
Control 10ng/ml 50 ng/ml
GM-CSF
T cells
What Next?
Very earlysynovitis
EstablishedRA
Normal
synovium
synovial fluid
Therapy in very early RA
Does this phase represent a window in which treatment can modify the subsequent course of disease?
What are the appropriate therapeutic targets?
Therapy in very early RA• Treat patients at very high risk of the subsequent development of
RA
• Small scale pilot studies to test the therapeutic value of specific agents:
Anti-TNF – etanercept B cells – rituximab
T cells – CTLA4 Ig Fibroblasts and neutrophils ?
Neutrophils and inflammation Neutrophils are the most abundant
leukocytes but are short lived (24h)
First line of defense against bacterial and fungal infection
Removal of apoptotic neutrophils is important for inflammation resolution
Dysregulation of neutrophil apoptosis has been implicated in many inflammatory diseases
Neutrophils help maintain inflammation, cause tissue damage and promote survival of autoimmune B cells