Vaccine for atherosclerosis – a review on the role of immunity in
atherosclerosis
Jan Nilsson, Lund UniversityGöran K Hansson, Karolinska
Institutet, Sweden
Atherosclerosis – an inflammatory response to lipid retention
LDL entry
LDL retentionLDL retention& modification& modification
Adhesion moleculesChemokines
Proinflammatory lipidsactivate EC and Mø
LDL uptakeLDL uptakeand presentationand presentation
T cell activation
ProinflammatoryProinflammatory cytokinescytokines
InflammationDestruction & remodeling
Lesion growth & activation
Foam cell formation
G K Hansson & J NilssonIn: Crawford & DiMarco,
Cardiology
Innate immunity in plaque inflammation
InflammatorycytokinesProteases
ProcoagulantPro-apoptotic
TLR
LPS, HSP60, oxLDL(?)
TLR
Natural antibodies
G K Hansson
Atherosclerosis in the absence of adaptive immunity?
(G K Hansson & J Nilsson, in: Crawford & DiMarco, Cardiology)
Lack of adaptive immunity leads to dramatic reduction in atherosclerosis –
without affecting cholesterol levels
*
ApoE-SCID
ApoE-
T and B cells No Yes
Aortic lesion size
Zhou, Nicoletti,Elhage & HanssonCirc 102:29192000
Similar - but not as striking - effects in immunodeficientRAG1 x apoE KODansky, PNAS 97Daugherty, JCI 97
Atherosclerosis in the absence of adaptive immunity?
(G K Hansson & J Nilsson, in: Crawford & DiMarco, Cardiology)
Splenectomy leads to accelerated atherosclerosis in apoE -/- mice
020406080
100120140160
Sham Splenectomy
*Le
sion
siz
e x
103 µ
m
Sx at 6 weeks, analysis at 18 weeks ageCaligiuri et al, JCI 109:745, 2002
B cells of atherosclerotic mice carry atheroprotective immunity
0
50
100
150
200
250
Sham Sx Sx SxTransfer - - T B
*
*
‡
‡Lesi
on s
ize
Caligiuri et al, JCI 109:745, 2002
Do T cells recognize antigens in atherosclerosis?
0
1
2
3
4
5
oxLDL - - + + + +MC + - - + + + MAb - - - - anti-DR Ctrl ab
T cells of human plaques recognize oxLDL as antigen
Stemme et alPNAS 1995
G Cooper, The Cell
CD4+ T cells recognize oligopeptide epitopes
What aboutthe lipids?
NKT cells are specialised T cells that recognize glycolipid antigens
NKTNKT cells use TCR to recognize glycolipids
CD1 binds glycolipid antigens forpresentation to NKT cells
NKT APC
G K Hansson
A role for NKT cellsin atherosclerosis?
Experimental strategies:• Cross apoE0 with CD1d0
• Activate NKT cells in apoE0 with ”artificial” lipid antigen,
Galactosyl Ceramide
E Tupin et al, J Exp Med 2004; 199:417-422
E Tupin et al, J Exp Med 2004; 199:417-422
NKT cells increase atherosclerosis
GalCer activates NKTand increases atheroscl
No effect of GalCerin CD1d-/- apoE-/-
Reduced atherosclerosisin CD1d-/- apoE-/- mice
Lesions at 15 wk
TGF- inhibits T cell activation- role in atherosclerosis? -
TNFIL-4IL-10
IFN
Non-functionalreceptors
TGF
APC
T cell
No effect ofdampening signal!
Mouse carrying a dominant-negative TGFR in T cells(Gorelik & Flavell 2000)
Cross w/ apoE-/- mouse
Dramatically increased atherosclerosis in mice lacking TGF- regulation of T cells
Dominant-negative TGFR under CD4 promoter x apoE-/-
Robertson et al, J Clin Invest 2003; 112:1342-50
Adhesion
Chemotaxis
Recruitment of immune cells to forming atherosclerotic lesions
G K Hansson
APC
CD4+T
NKT
Antigens activate T cells in lesions
oxLDL, HSP60,
others?
Activation & Th1 differentiation
IL-12
IL-18, IL-15G K Hansson
Activation of macrophages, endothelial and smooth muscle cells
IFN-
IFN-
TNF-
CD40L/RTh1
MEC
SMC
AdhesionPermeability
Prothrombotic stateProteases
↓ proliferation↓ collagen
↓ actinIL-6
Inflammatorymediators
G K Hansson
Regulation of immune activity
IL-10
TGF-
TGF-
TregTh2
Th1
M
SMC
EC
Antigen-specificTreg activation
Atheroprotective immune mechanisms
• Regulatory T cells– Produce antiinflammatory/immunosuppressive cytokines– TGF-
• Robertson JCI 03; Mallat Blood 03; – IL-10
• Mallat Circ Res 99; Pinderski ATVB 99; Caligiuri Mol Med 02
• B cells– Spleen B cells; B1 cells – Stimulated by IL-5– Possibly due to production of ”natural” antibodies
• Caligiuri JCI 02; Binder Nat Med 02, JCI 04
Can we use protective immunity to protect against
atherosclerosis?
Protective immunization
Model: Mutant rabbits, mice
Antigen: OxLDL, MDA-LDL, HSP60, beta 2-glycoprotein
Administration: Th2 adjuvant sc or mucosal Significant protection after 3 months!
Palinski PNAS 95; Ameli ATVB 96;George Athero 99; Zhou ATVB 00Harats JACC 02; Maron Circ 02
Vaccination against atherosclerosis?
• Antigen-specific protective immunity• Mediated by B cells and regulatory T cells (?)• Protective immunization works in models
– MDA-LDL; Phosphorylcholine; HSP65/60
• Many remaining questions and challenges:– Precise epitopes, pure antigens– Administration routes, adjuvants
InflammationRepair
Innate immunity Adaptive Th1 immunity
IFN-IL-18
TNF-IL-1
Antiinflammatory immunityHumoral immunity
IL-10TGF-
Anti-oxLDL
M activationEndothelial activation
RadicalsProteinases
Prothrombotic state
AntiinflammationFibrosis
SMC proliferationPlaque stability
Antibody clearance
Immune regulation of plaque activity
G K Hansson
Nilsson, Hansson, Shah, ATVB, in press