This document discusses potential immune-based therapies for modulating atherosclerosis and vulnerable plaque. It summarizes that:
1. Specific antigens, co-stimulatory molecules, cytokines, vaccines, recombinant proteins, antibodies, and cells could be potential targets for immunomodulation of atherosclerosis.
2. While general immunosuppression may reduce atherosclerosis in animal studies, it has substantial side effects for infections and direct vascular effects that make it unsuitable for chronic treatment in humans.
3. Modulating the Th1/Th2 balance, inducing protective antibodies through vaccination against oxidized LDL or heat shock proteins, and using small molecule drugs that inhibit Th1 responses like statins and pentoxifyllin are promising
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075 immune modulation
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?