06 rencontres biomédicale LIR A Tedgui

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06 rencontres biomédicale LIR A Tedgui

  1. 1. <ul><li>Targeting Inflammation in Atherosclerosis: </li></ul><ul><li>Novel Therapeutic Strategies </li></ul>Alain TEDGUI H E G P Inserm U970
  2. 2. Asymptomatic Stable Plaque S. Glagov M. Davies
  3. 3. Acute Heart Attack Unstable Plaque Plaque rupture  Thrombosis
  4. 4. Plaque development Inflammation Adaptive (Th1) Immunity Cholesterol-LDL Oxidized (phospho)lipids Lipid accumulation Progression Plaque antigen-specific Regulatory Immunity
  5. 5. Plaque development Inflammation Adaptive (Th1) Immunity Cholesterol-LDL Oxidized (phospho)lipids Lipid accumulation Progression Plaque antigen-specific Regulatory Immunity
  6. 6. Secondary Mediators <ul><ul><ul><li>Angiotensin II </li></ul></ul></ul><ul><ul><ul><li>Advanced Glycation End-Products (AGEs) </li></ul></ul></ul><ul><ul><ul><li>Oxygen radicals </li></ul></ul></ul><ul><ul><ul><li>Heat Shock Proteins (HSPs) </li></ul></ul></ul><ul><ul><ul><li>Immune complexes </li></ul></ul></ul><ul><ul><ul><li>Infectious agents </li></ul></ul></ul><ul><ul><ul><li>Apoptotic bodies </li></ul></ul></ul><ul><ul><ul><li>Mechanical factors </li></ul></ul></ul><ul><ul><ul><li>Platelets </li></ul></ul></ul>Primary Mediators Proximal Triggers for Vascular Inflammation <ul><ul><ul><li>Oxidized LDL </li></ul></ul></ul><ul><ul><ul><li>4-hydroxy-2-nonenal (4HNE) </li></ul></ul></ul><ul><ul><ul><li>Oxysterols </li></ul></ul></ul><ul><ul><ul><li>Oxidized phospholipids (oxPL) </li></ul></ul></ul><ul><ul><ul><li>lysophosphatidylcholine (lysoPC) </li></ul></ul></ul><ul><ul><ul><li>oxPAPC </li></ul></ul></ul>
  7. 7. Second category of therapeutic targets: intracellular pathways involved in inflammatory signaling (NF-  B, AP-1, JAK/STAT) operating as central transcriptional control points
  8. 8. Inflammatory genes Pro-atherogenic Antiapoptotic genes Anti-atherogenic IFN-  JAK1/2 JAK1/Tyk2 STAT3 JAK1 IL-10 IL-6 IL-12 IL-1/IL-18 PAMPs IFN-  TGF  TNF-  STAT1 Smad7 STAT3 AP1 TRAF2 MyD88 IRAK TRAF6 Caspase-1 Caspase-5 Inflammasome SOCS3 NF-  B Smad4/5 Smad2/3 SOCS3 SOCS1 gp130 CD40L TRAF3 Anti-inflammatory genes Tedgui&Mallat. Physiol Rev 2006
  9. 9. Thrombosis Apoptosis MMPs Plaque Rupture LesionDevelopment Chemokines Adhesion molecules Monocyte/Lymphocyte recruitment Inflammation Distal Effectors
  10. 10. Compound Target Study outcome TAK-779 CCR5 & CXCR3 Reduced atherosclerosis in mice Reduced Th1 immune responses NBI-74330 CXCR3 Reduced atherosclerosis in mice (Tularik;Amgen) Increased Treg cells CKEY2 CCL5 & CXCL4 Disruption of heterophilic interaction CCL5/CXCL4 Reduced atherosclerosis in mice MLN1202 CCR2 Humanized monoclonal antibody in Phase II clinical (Millennium) trial for atherosclerosis CCX140 CCR2 Reduced restenosis after stenting in pigs (ChemoCentryx) Currently in Phase II clinical trial for type 2 diabetes Targeting Chemokines to Treat Atherosclerosis
  11. 11. Targeting Atherosclerosis-Related Inflammation: Future Therapeutic Strategies
  12. 12. Tedgui&Mallat. PhysiolRev 2006. Atherosclerosis: A Th-1 driven inflammation controlled by regulatory T cells Th1 Treg Th2
  13. 13. CD4+CD25+ Treg Protect against Atherosclerosis Ait-Oufella et al. Nat Med 2006 Lesion size ( x10 5  m 2 ) ** Cont – w/o T cells T cells w/ Treg T cells w/o Treg
  14. 14. Oral Anti-CD3 AntibodyTreatment Induces Regulatory T cells and Inhibits Atherosclerosis in Mice Sasaki et al. Circulation . 2009. Control CD3-Ab Control CD3-Ab Atherosclerotic lesion size (x10 4 µm 2 ) 0 5 10 15 20 25
  15. 15. * Lesion size (x10 3 µm 2 ) PBS OVA P210 Peptide-based immunotherapy of atherosclerosis
  16. 16. Treatment with apoB Peptides Abrogate Lesion Progression Lesion size (x10 3 µm 2 ) T=0 OVA apoB peptides
  17. 17. Effector T cells Mature APC oxLDL T cell co-stimulation and Th profile B cells oxLDL-IgGab Ait-Oufella et al. J Exp Med 2010. Ctr α-CD20 ApoE –/– mice Anti-CD20 Treatment of Atherosclerosis 10 14 18 22 2 6 0 Ctr α-CD20 Lesion size (x10 4 μm 2 ) **
  18. 18. Summary <ul><li>Inflammation and immunity play major roles in the outcomes of coronary heart disease and stroke. </li></ul>
  19. 19. Summary <ul><li>Inflammation and immunity play major roles in the outcomes of coronary heart disease and stroke. </li></ul><ul><li>Measures thati nduce the development of regulatory T cells causing deviation of Th1 immune response show great promise in treating atherosclerosis. </li></ul>
  20. 20. Summary <ul><li>Inflammation and immunity play major roles in the outcomes of coronary heart disease and stroke. </li></ul><ul><li>Measures that induce the development of regulatory T cells causing deviation of Th1 immune response show great promise in treating atherosclerosis. </li></ul><ul><li>Taking into account the inter-individual diversity in the adaptive immune response would add to the benefit of current treatments of cardiovascular risk factors. </li></ul>
  21. 21. Moses and the burning bush Marc Chagall 1960-1966 Inflammation everywhere ?

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