7. Second category of therapeutic targets: intracellular pathways involved in inflammatory signaling (NF- B, AP-1, JAK/STAT) operating as central transcriptional control points
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
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. 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. * Lesion size (x10 3 µm 2 ) PBS OVA P210 Peptide-based immunotherapy of atherosclerosis
16. Treatment with apoB Peptides Abrogate Lesion Progression Lesion size (x10 3 µm 2 ) T=0 OVA apoB peptides
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 ) **
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21. Moses and the burning bush Marc Chagall 1960-1966 Inflammation everywhere ?
Editor's Notes
Proinflammatory cytokines IL-6 and IL-12 bind to the gp130, which mainly activate JAK1 and STAT3. IFN-g utilizes JAK1 and JAK2 and mainly activates STAT1. Interestingly, anti-inflammatory cytokine IL-10 also activates STAT3 (O’Farrell et al. 1998). STAT4 and STAT6 are essential for Th1 and Th2 development since these are activated by IL-12 and IL-4, respectively (Kaplan et al. 1996; Shimoda et al. 1996; Takeda et al. 1996). SOCS1 binds to the JAKs and inhibits catalytic activity, SOCS3 binds to JAK-proximal sites on cytokine receptors and inhibits JAK activity,
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