1. Towards Immune Modulation
against Vulnerable Plaque
Göran K Hansson
Center for Molecular Medicine
Karolinska Institutet
Stockholm, Sweden
Vulnerable Plaque Symposium
Chicago, IL, November 2002
3. Potential targets for
immunomodulation of
atherosclerosis
• Specific antigens
– oxLDL, HSP65, β2GpI,
microbial
• C pneum, CMV, others
• Co-stimulatory
molecules
– CD40/CD40L, CD28/B7
• Cytokines
– IFNγ, TNFα (aggravating)
– IL-10, TGFβ (protective)
• Vaccines
• Recombinant proteins
• Antibodies
• Cells
• Small molecule drugs
4. Atherosclerosis in the absence of
adaptive immunity?
(G K Hansson & J Nilsson, in: Crawford & DiMarco, Cardiology)
5. CD4+
T cells aggravate atherosclerosis
in immunodeficient apoExSCID mice
*
ApoE-
SCID
ApoE-
T and B cells No CD4+
T Yes
transfer
Aortic lesion
size
Zhou, Nicoletti,
Elhage & Hansson
Circ 102:2919
2000
ApoE-
SCID
6. Immunosuppression to reduce
CD4+ T cell activity?
• General immunosuppression is likely to
reduce atherosclerosis
– Some support from animal studies
• But substantial side effects
– Infections
– Direct vascular effects of drugs
• Therefore, general immunosuppression is
unlikely to be used to treat atherosclerosis or
even vulnerable plaque
11. Antiatherosclerotic cytokines
- useful for therapy?
• Powerful, direct approach
• Recombinant cytokines available
• But these cytokines are usually
immunosuppressive / antiinflammatory,
therefore
– Increased sensitivity to infections
– Cytokine-specific side effects
• E.g. TGFβ – fibrosis
• Therefore, these cytokines might be useful in
acute coronary syndromes,
• although not in chronic atherosclerosis
13. B cells of atherosclerotic mice
carry atheroprotective immunity
0
50
100
150
200
250
Sham Sx Sx Sx
Transfer - - T B
*
*
‡
‡
Lesionsize
Caligiuri et al, JCI 109:745, 2002
ApoE mice
Sx, trf 6 wk age
Analysis 18 wk
14. Atheroprotective immunity
• Carried by spleen B cells
• Reduces lesion size and stage
• Reduces CD4+ T cell infiltration in
lesions
• Correlates with anti-oxLDL antibodies
• Protective effect of antibodies?
– Clearance of oxLDL?