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075 immune modulation
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 againstVulnerable Plaque Göran K Hansson Center for Molecular Medicine Karolinska Institutet Stockholm, Sweden Vulnerable Plaque Symposium Chicago, IL, November 2002
- 2. Hansson, Libby, Schönbeck& Yan, Circ Res 2002
- 3. Potential targets for immunomodulationof 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 theabsence of adaptive immunity? (G K Hansson & J Nilsson, in: Crawford & DiMarco, Cardiology)
- 5. CD4+ T cells aggravateatherosclerosis 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
- 7. Complexity of immune regulatorynetworks • Counterbalancing cell subsets • Idiotypic antibody networks • Regulatory cytokines
- 8. The Th1/Th2 Paradigm Th IL-12 MHC Peptide TCRTCR IFN-γ IL-18 Th1 IFN-γ MΦ IFN-γ B Ab DTH InflammationAPC APCTh IL-4 Th2Th2 B IL-3, 5 IL-4 IL-10 IL-13 - IL-4, 10, 13 Antibodies Allergy
- 9. Hypothesis: Th1/Th2 balance controlsatherosclerosis – Th1 cells dominate in lesions and are proatherogenic • CD4+ Th1 cells (Hansson 89; Uyemura 96; Frostegård 99) • Interferon-γ, TNF-α; IL-12, IL-18 (Zhou 00; Mallat 01; Daugherty 01) –Th2 cytokines that inhibit Th1 may be antiatherogenic? – IL-10-/- B6 mice develop larger fatty streaks – IL-10 administration reduces disease » Mallat et al; Pinderski et al. 99
- 10. Increased atherosclerosis in IL-10deficient apoE-/- mice IL10-/- E-/- IL10+/+ E-/- Caligiuri, Hansson, Rudling, Michel, Nicoletti 2002 * 100 50 Lesion size (x 103 µm2) in 16 wks old mice
- 11. Antiatherosclerotic cytokines - usefulfor 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
- 12. Inflammation Repair Innate immunity /TLRs Adaptive Th1 immunity IFN-γ TNF-α, IL-1 Inhibitory cytokines Cells? IL-10 TGF-β Ab? Accelerated athero Plaque activation Reduced athero Stable plaque Silent disease Immune regulation of plaque activity
- 13. B cells ofatherosclerotic 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 • Carriedby 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?
- 15. Protective immunity against atherosclerosis •Can we induce it by immunization? • A vaccination strategy against atherosclerosis?
- 16. Protective immunization 1. OxidizedLDL Parenteral immunization (sc) Model: Mutant rabbits, mice Antigen: OxLDL, MDA-LDL Freund´s adjuvant Repeated inj 3 wk intervals Significant protection after 3 months! Palinski PNAS 95; Ameli ATVB 96; George Athero 99; Zhou ATVB 00
- 17. MDA-LDL ”vaccination” reduces atherosclerosis Immunogen(PBS) Plaque MDA-LDL extract ApoE-/- mice Immun wk 6 / FCA Boost wk 8,10,12,14 Analysis wk 18 Zhou et al, ATVB 2000
- 18. Protective immunization 2. Heatshock protein 65/60 • HSP60 released upon cell injury and in atherosclerosis – Wick, Xu et al. 1992 • HSP65/60 X-reacts man-microbe • Mucosal administration of HSP65 – Nasal, oral • Reduced lesions in LDLR mice – Maron, Libby, Weiner, Circ 2002 – Harats, Shoenfeld, George, JACC 2002
- 19. Inflammation Repair Innate immunity /TLRs Adaptive Th1 immunity IFN-γ TNF-α, IL-1 Inhibitory cytokines Protective B cells IL-10 TGF-β Ab? MΦ activation Endothelial activation Radicals Proteinases Prothrombotic state Antiinflammation Fibrosis SMC proliferation Antibody clearance Immune regulation of plaque activity Vaccine
- 20. Small molecule drugsthat modulate athero-immunity • Pentoxifyllin – Inhibits Th1 immune responses – Inhibits atherosclerosis in mice • Laurat et al Circ 2001 • Statins – Inhibit Th1 responses! • Kwak Nat Med 2000; Youssef Nature 2002 – Inhibit atherosclerosis in mice and men
- 21. Statins inhibit Th1immunity • Downregulate interferon-γ induced HLA-II transcription in macrophages – Kwak, Mach et al, Nature Med 2000 • Inhibit Th1 signalling • Increase Th2 cytokines • Inhibit autoimmune encephalomyelitis – Youssef, Steinman et al, Nature 2002
- 22. Inflammation Repair Innate immunity /TLRs Adaptive Th1 immunity IFN-γ TNF-α, IL-1 Inhibitory cytokines Protective B cells IL-10 TGF-β Ab MΦ activation Endothelial activation Radicals Proteinases Prothrombotic state Antiinflammation Fibrosis SMC proliferation Antibody clearance Immune modulation of vulnerable plaque Vaccines Drugs