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Towards immune modulation vp 16 11 gkh

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Towards immune modulation vp 16 11 gkh

  1. 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
  2. 2. Hansson, Libby, Schönbeck & Yan, Circ Res 2002
  3. 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. 4. Atherosclerosis in the absence of adaptive immunity? (G K Hansson & J Nilsson, in: Crawford & DiMarco, Cardiology)
  5. 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. 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. 7. Complexity of immune regulatory networks • Counterbalancing cell subsets • Idiotypic antibody networks • Regulatory cytokines
  8. 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 APC Th IL-4 Th2Th2 B IL-3, 5 IL-4 IL-10 IL-13 - IL-4, 10, 13 Antibodies Allergy
  9. 9. Hypothesis: Th1/Th2 balance controls atherosclerosis – 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. 10. Increased atherosclerosis in IL-10 deficient 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. 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
  12. 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. 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. 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?
  15. 15. Protective immunity against atherosclerosis • Can we induce it by immunization? • A vaccination strategy against atherosclerosis?
  16. 16. Protective immunization 1. Oxidized LDL 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. 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. 18. Protective immunization 2. Heat shock 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. 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. 20. Small molecule drugs that 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. 21. Statins inhibit Th1 immunity • 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. 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

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