immunomodulatory pathways in atherosclerosis · 2017-07-12 · immunomodulatory pathways. in...
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Immunomodulatory Pathwaysin Atherosclerosis
Ziad Mallat, MD, PhD
Department of Medicine, University of Cambridge,Cambridge, UK
Inserm U970
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Moore KJ & Tabas I. Cell 2011
Targeting the Immuno-Inflammatory ResponseIn Atherosclerosis
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Weber C et al. Nat Med 2011
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Weber C et al. Nat Med 2011
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Wilensky RL et al., Nat Med 2008
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Serruys PW et al., Circulation 2008
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Weber C et al. Nat Med 2011
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Ridker PM et al. Circulation 2011
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JCI 2012
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Weber C et al.Nat Rev Immunol 2008
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Peptide-based Therapeutic Vaccination
Therapeutic ToleranceAuto-Immunity
Larché M & Wraith DC
Nat Med 2005
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Inducing tolerance to lipoproteins:
Atherosclerosis Vaccine?
ApoB peptideOVA ApoB mix
ApoB peptide-based vaccination reduces atherosclerosis by inducing a specific Treg cellresponse
OVA
P210 ApoB
ApoB
P210/P240/MDA-P210
ApoB Mix
Peptides infusion10μg/day
Follow-up
2 weeks 8 weeks
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Weber C et al.Nat Rev Immunol 2008
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Binder CJ et al., JCI 2004
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B cell pathways in atherosclerosis
Lahoute et al. Nat Rev Cardiol, 2011;8:348-58.
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Mackay FNat Rev Immunol 2009
They respond to T cell–dependent antigens and contribute to adaptive
immunity
They respond to T cell–indedependentantigens, selectivity for self antigens,
producers of natural IgM
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CD20 mAb-mediated B Cell Depletion in Atherosclerosis
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Decreased T cell infiltration after anti-CD20 therapy
CTR -CD20
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2010
Ait-Oufella et al.
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BAFF – B cell activating factor
BAFF
BAFFR
B Cell Physiology
B2 cell survivalClass switchingPlasma CellsAutoreactive B cells
Autoimmune Diseases
SLERheumatoid ArthritisSjogren’s SyndromeAnti-Phospholipid syndrome
T CellsMyeloid cells Atherosclerosis?
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BAFF Levels in Human Carotid Lesions and
Relation with Plaque Phenotype
P<0.001
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Lesion Size
Macrophages T lymphocytes
B cell-selective
BAFF-R deletion
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White HD & Chew DP, The Lancet 2008
Acute Myocardial Infarction
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Post-MI Inflammation
Blood
Ischemic
Myocardium
Pro-Inflammatory cytokines
High Proteolysis
Anti-inflammatory cytokines
Angiogenesis
ApoptosisCD11b+
Ly6G+
CCR2+Ly6Chi
7/4hi
CX3CR1lo
InflammatoryMonocytes
ResidentMonocytes
CX3CR1hi
CCR2-
Ly6Clo
7/4lo
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Role of B lymphocytes in immuno-inflammatory response and tissue remodelling after myocardial infarction
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Kinetics of inflammatory cell infiltration after Myocardial Infarction
Digestion
(Col I, XI, Hyaluronidase, DNase)
Gradient Density
Centrifugation
FACS
Analysis
LCAligation
7/4HI and 7/4LOW Monocytes
0
1000
2000
3000
4000
7/4LOW MI
7/4HI MI7/4HI MI sham
7/4LOW MI sham
Cel
ls/m
g tis
sue
**
***
***
***
**
Days post-MI
MIsham
Neutrophils
(CD11b+ Ly6G+ 7/4HI)
Cel
ls/m
g tis
sue
0
2000
4000
6000
8000***
***
Days post-MICD3+ T lymphocytes
0
50
100
150
200
250
300MIsham
***
***
Days post-MI
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Kinetics of B lymphocytes infiltration after Myocardial Infarction
Flow cytometry analysis
Sham D5 D5 after MI D14 after MI
B220 Immunostaining
B22
0Hi I
gM+
BC
ells
/mg
tissu
e
Heart
0
500
1000
1500
Days post-MI
MIsham
***
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Anti-CD20 antibody treatment reduces B lymphocyte levels
200g/mouse
1 hour after MI
B22
0Hi I
gM+
B
Cel
ls/m
l Blo
od [x
104 ] PBS
Anti-CD20
0
1
23
4
5
6
Days post-MI
Blood
Anti-CD20
IgM+
CD20 mAb
Mature B cells
*
**
* *
0
50
100
150
200
250
PBS Anti-CD20
B22
0Hi I
gM+
BC
ells
/mg
tissu
e
Heart D3
0
250
500
750
1000
1250
PBS Anti-CD20B
220H
i IgM
+B
Cel
ls/m
g tis
sue
*
Heart D5
0 102 103 104 105
0102
103
104
105
0 102 103 104 105
0102
103
104
105
PBS D3 CD20 D3
B220
IgM
B22
0Hi I
gM+
B
Cel
ls/s
plee
n [x
105 ]
25
0
5
10
15
20
Spleen D14
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B lymphocyte depletion limits adverse LV remodelling
0
10
20
30
40
50
PBS Anti-CD20
% In
farc
t siz
e
Infarct Size (Masson Trichrome staining)
PBS Anti-CD20D14
0
10
20
30
40
% S
F
*
Shortening Fraction
D14
0
0.1
0.2
0.3
0.4
PBS Anti-CD20
*
0
0.025
0.05
0.075
0.1
0.125
PBS Anti-CD20
*
LVID
s (m
m)
LVPW
s (m
m)
LV internal dimension in diastole LV Posterior Wall Thickness in systole
D14 D14
*
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0
0.5
1
1.5
**
0
0.5
1
1.5
PBS -CD20
*
0
0.5
1
1.5
2
PBS -CD20 0
0.5
1
1.5
PBS -CD20
*
mR
NA
leve
ls(A
.U.)
Heart D14
TNF- IL1- IFN- IL18
mR
NA
leve
ls(A
.U.)
PBS -CD200
0.5
1
1.5
*
TNF-
0
0.5
1
1.5
PBS -CD20
IL1-
0
0.5
1
1.5
*
PBS -CD20
IFN-
0
0.5
1
1.5
*
PBS -CD20
IL18
Spleen D14
B lymphocyte depletion reduces systemic and local post-MI inflammation
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B lymphocyte depletion alters monocyte distribution in post-MI setting
0
12
3
45
PBS -CD200
5
10
15
20
25
PBS-CD20
*
Mon
ocyt
es 7
/4H
I
Cel
ls/m
l x1
06
Mon
ocyt
es7/
4LOW
Cel
ls/m
l x1
05
Monocytes 7/4HI Monocytes 7/4Lo
Bone Marrow D3
0
2.5
5.0
7.5
10
PBS Anti-CD20 0
1
2
3
4
PBS Anti-CD20
Mon
ocyt
es 7
/4H
I
Cel
ls/m
l x1
04
Mon
ocyt
es 7
/4LO
W
Cel
ls/m
l x1
04
* *
Monocytes 7/4HI Monocytes 7/4Lo
Blood D3
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plasma
0
250
500
750
1000
D0 D1 D3 D5 D7
***
MCP-1/CCL2
MCP-1/CCL2Not Detected inB cell supernatants
B lymphocyte depletion selectively reduces MCP-3 levels in post-MI
MCP-3/CCL7plasma
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7/4 Hi Monocytes transmigration assay
Lower compartment :
- Medium RPMI 10% SVF
- B cells (2.106)
- -CD40 and IgM-treated B lymphocytes
Transwell insert (8 m)
7/4 Hi monocytes
Microporous col I coated membrane
B lymphocytes
4h
B lymphocytes trigger 7/4 Hi monocytes migration
Control B cells Activated B cells
MCP1 MCP3
020406080
100120140160180
Control B cells ActivatedB cells
ActivatedB cells
+MCP1
***
*** ***
ActivatedB cells
+MCP3
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D-7 D0 D14
Injection splenocytes WT,B cell-depleted splenocytes ±
WT or MCP-3-deficient B cells
MI
D3
FACS Echocardiography
Exogenous administration of B lymphocytes promotes adverse LV remodelling
Rag1-/-
B cells levelsSpleen D3
SplenoWT
SplenoCD20+WT
B cells
SplenoCD20
SplenoCD20
+MCP3-/-
B cells
0
5
10
15
20
25
***
###
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Exogenous administration of B lymphocytes enhances 7/4Hi monocytes mobilisationand infiltration into the ischemic heart
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Exogenous administration of B lymphocytes promotes adverse LV remodelling
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FAST-MI
• FAST-MI is a nationwide French registry carried out in 3059 consecutive pts
with AMI admitted in 223 CCUs
• 100 centers, which included 1036 patients, participated in the serum databank.
• Outcome events were defined as all-cause death, recurrent AMI and
incident stroke
• The 24-month follow-up of mortality was complete for 95% of patients
170 events occurred during follow-up
Impact of circulating levels of BAFF/CCL7 on 24 months-survival, recurrent myocardial infarction and incident stroke in patients with acute MI
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B Lymphocytes Trigger CCL7-Dependent Monocyte Mobilisation and Promote
Adverse Ventricular Remodelling afterAcute Myocardial Infarction
B cell depleting and CCL7-targeting therapies may be cardioprotective
Zouggari Y et al., Nature Medicine, In Press
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B2 cell depleting agents
Anti-IL1beta
PLA2 inhibitors
Peptide-based vaccination
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University of CambridgeBritish Heart Foundation
Andy SAGEXuan LIDeirdre MURPHYLauren BAKERJames HARRISONLeanne MASTERS
Inserm U970Alain TEDGUIHafid AIT-OUFELLAOlivier HERBINPatrick BRUNEVAL
Jean-Sébastien SILVESTREYasmine ZOUGGARI
CeMM, Medical Universityof Vienna, AustriaChristoph J. BINDER
AP-HP, Pierre et Marie Curie UniversityTabassome SIMON
Duke University, USAThomas F. TEDDER
University of Utrecht,The NetherlandsGerard PASTERKAMPUCSF, USA
Israel F. CHARO
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Rader DJ & Daugherty A. Nature 2008
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O
O
C R1
O
O
C R2
CH2
CH
CH2O
O
P O
O-
R Fatty Acids
Phosphate Group
Glycerol Head
PLA2
PLA2 enzymes hydrolyze phospholipids at the
sn-2 position to generate lysophospholipids and
fatty acids
sn-1
sn-2
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Kolodgie et al., Arterioscler Thromb Vasc Biol 2006
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sPLA2 inhibitor acts synergistically with statinto decrease atherosclerosis
apoE-/- mice treated with varespladib (A-002) +/- pravastatin
Shaposhnik et al. J Lipid Res, 2009, 50: 623–629.
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Effects of 1-H-indole-3-glyoxamide (A-002, (Varespladib, Anthera Pharmaceuticals) on concentration of sPLA2 (PLASMA study): a phase II double-blind, randomised,
placebo-controlled trial
Rosenson et al. Lancet, Vol 373 February 21, 2009
393 patients randomly assigned received placebo (n=79) or the sPLA2 inhibitor, A-002: 50 mg (n=79), 100 mg (n=80), 250 mg (n=78), or 500 mg (n=77) twice daily, for 8 weeks.
Primary endpoint:change in sPLA2 IIA concentration or activity from baseline to week 8
Results: Dose dependent reduction in sPLA2-IIA concentration in the A-002 groups (from 69±2% in the 50 mg group to 95 ± 8% in the 500 mg group), significantly different from placebo (p<0.0001)
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B lymphocyte depletion limits adverse LV remodelling
Apoptotic cells number (Tunel)
0
5
10
15
20
PBS Anti-CD20
Tune
l cel
ls/fi
eld
*
PBS Anti-CD20D14
Capillary Density (BS1 lectin, WGA)
0
0.5
1
1.5
2
capi
llarie
s/m
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te *PBS Anti-CD20 D14
Arteriolar Density (-actin)
0
5
10
15
20
PBS Anti-CD20
Arte
riole
s/m
m2
PBS Anti-CD20 D14
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0
123456
WT MCP3KO
**
Monocytes 7/4HI
Blood D0
0
2
4
6
8
10
*
WT MCP3KO
Blood D14 BM D14
Cel
l/fem
urx1
05
WT MCP3KO0
2468
10121416 *
MCP-3 deficiency preserves LV function after acute MI
Shortening Fraction
0
10
20
30
40
% S
F
*D14