Background-Oxidation of low-density lipoprotein (LDL) and the subsequent processing of oxidized LDL (oxLDL) by macrophages results in activation of specific T cells, which contributes to the development of atherosclerosis. Oral tolerance induction and the subsequent activation of regulatory T cells may be an adequate therapy for the treatment of atherosclerosis. Methods and Results-Tolerance to oxLDL and malondialdehyde-treated LDL (MDA-LDL) was induced in LDL receptor Ϫ/Ϫ mice fed a Western-type diet by oral administration of oxLDL or MDA-LDL before the induction of atherogenesis. Oral tolerance to oxLDL resulted in a significant attenuation of the initiation (30% to 71%; PϽ0.05) and progression (45%; PϽ0.05) of atherogenesis. Tolerance to oxLDL induced a significant increase in CD4 ϩ CD25 ϩ Foxp3

Background-Interleukin-12 (IL-12) has been identified as a key inducer of a type 1 T-helper cell cytokine pattern, which is thought to contribute to the development of atherosclerosis. We sought to study the role of IL-12 in atherosclerosis by inhibition of IL-12 using a newly developed vaccination technique that fully blocks the action of IL-12. Methods and Results-LDL receptor-deficient (LDLr Ϫ/Ϫ ) mice were vaccinated against IL-12 by 5 intramuscular injections of IL-12-PADRE complex in combination with adjuvant oil-in-water emulsion (low dose)/MPL/QS21 every 2 weeks. Two weeks thereafter, atherogenesis was initiated in the carotid artery by perivascular placement of silicone elastomer collars. IL-12 vaccination resulted in the induction of anti-IL-12 antibodies that functionally blocked the action of IL-12 as determined in an IL-12 bioassay. Blockade of IL-12 by vaccination of LDLr Ϫ/Ϫ mice resulted in significantly reduced (68.5%; PϽ0.01) atherogenesis compared with control mice without a change in serum cholesterol levels. IL-12 vaccination also resulted in a significant decrease in intima/media ratios (66.7%; PϽ0.01) and in the degree of stenosis (57.8%; PϽ0.01). On IL-12 vaccination, smooth muscle cell and collagen content in the neointima increased 2.8-fold (PϽ0.01) and 4.2-fold (PϽ0.01), respectively. Conclusions-Functional blockade of endogenous IL-12 by vaccination resulted in a significant 68.5% reduction in atherogenesis in LDLr Ϫ/Ϫ mice. Vaccination against IL-12 also improved plaque stability, from which we conclude that the blockade of IL-12 by vaccination may be considered a promising new strategy in the treatment of atherosclerosis.

Objective-Scavenger receptor BI (SR-BI) is a cell surface receptor that promotes the selective uptake of cholesteryl esters from high-density lipoprotein (HDL) by the liver. In mice, SR-BI deficiency results in increased plasma HDL cholesterol levels and enhanced susceptibility to atherosclerosis. The aim of this study was to investigate the role of SR-BI deficiency on platelet function. Methods and Results-SR-BI-deficient mice were thrombocytopenic, and their platelets were abnormally large, probably because of an increased cholesterol content. The FeCl 3 acute injury model to study arterial thrombosis susceptibility showed that SR-BI wild-type mice developed total arterial occlusion after 24Ϯ2 minutes. In SR-BI-deficient mice, however, the time to occlusion was reduced to 13Ϯ1 minutes (Pϭ0.02). Correspondingly, in SR-BI-deficient mice, platelets circulated in an activated state and showed increased adherence to immobilized fibrinogen. In contrast, platelet-specific disruption of SR-BI by bone marrow transplantation in wild-type mice did not alter plasma cholesterol levels or affect platelet count, size, cholesterol content, or reactivity, suggesting that changes in plasma cholesterol levels were responsible for the altered responsiveness of platelets in SR-BI-deficient mice. A cute coronary events are not the result of progressive growth of the lesion but rather of lesion disruption and superimposed thrombus formation. Damage to the endothelial cell layer of the vessel wall results in the exposure of the extracellular matrix to the flowing blood, which triggers platelet activation, platelet plug formation, coagulant activity, and the formation of fibrin-containing thrombi that occlude the site of exposed subendothelium. 1 Several lines of evidence suggest that platelet function is modulated by lipoproteins. High levels of proatherogenic lipoproteins, including native and oxidized low-density lipoprotein, are associated with an increased susceptibility to thrombosis by enhancement of platelet responsiveness to aggregation-inducing agents. 2,3 In contrast, several studies, using human platelets, have shown that high-density lipoproteins (HDLs) inhibit platelet responses, such as aggregation and secretion. 4 -8 In agreement, platelets of patients with low HDL levels are hyperresponsive to low doses of aggregating agents, 9 and high HDL-cholesterol levels in hyperlipidemic and normolipidemic patients are associated with reduced plateletdependent thrombus formation ex vivo. 10 Scavenger receptor BI (SR-BI) is the first identified cell surface receptor mediating HDL metabolism. 11 It is a multifunctional receptor, capable of binding a wide array of native and modified lipoproteins, 12,13 and is abundantly expressed in liver, steroidogenic tissues, and cells within the arterial wall, including endothelial cells, smooth muscle cells, and macrophages. [13][14][15][16][17][18][19] It mediates the selective uptake of cholesteryl esters from HDL by the liver and facilitates the efflux of cholesterol from cells in periph...

Objective-HIV combination therapy using protease inhibitors is associated with elevated plasma levels of atherogenic lipoproteins and increased risk for atherosclerosis. We investigated whether the HIV entry inhibitor TAK-779 affects lipoprotein levels and atherogenesis in low-density lipoprotein receptor-deficient mice. TAK-779 is an antagonist for the chemokine receptors CCR5 and CXCR3, which are expressed on leukocytes, especially T-helper 1 cells, and these receptors may be involved in recruitment of these cells to atherosclerotic plaques. Methods and Results-TAK-779 treatment of low-density lipoprotein receptor -deficient mice did not elevate the levels of atherogenic lipoproteins, whereas it dramatically reduced atherosclerosis in the aortic root and in the carotid arteries. The number of T cells in the plaque was reduced by 95%, concurrently with a 98% reduction in the relative IFN-␥ area. TAK-779-treated animals showed a decreased percentage of CD4 ϩ and CD8 ϩ T cells in peripheral blood and in mediastinal lymph nodes compared with control-treated animals. L eukocyte recruitment into the vessel wall is a key step in atherosclerotic lesion formation, and chemokines are known to regulate this process. Chemokines can be divided into 2 families: the CC receptors, which bind CC chemokines, and the CXC receptors, which bind CXC chemokines. 1 CCR5 and CXCR3 are 2 chemokine receptors that are implicated in the migration of activated T-helper (Th)1 cells to the site of inflammation, and both receptors have been suggested as potential targets for the treatment of autoimmune-like diseases. 2,3 Conclusions See page 2448A 32-bp deletion in the CCR5 gene (CCR5⌬32) results in a nonfunctional receptor, and individuals that are homozygous for this deletion are resistant to infection with HIV. 4,5 Interestingly, it is also shown that this natural deficiency in CCR5 protects individuals from early myocardial infarction and severe coronary artery disease. The ligands for CCR5, RANTES and MIP-1␣, have been detected in atherosclerotic plaques of both humans and mice. 6 -9 Furthermore, inhibition of CCR5/CCR1 using the receptor antagonist met-RANTES attenuates atherosclerosis in low-density lipoprotein receptor (LDLr Ϫ/Ϫ )-deficient mice. 10 Antibody-mediated blockade of CXCR3 results in a decreased recruitment of Th1 cells to the site of inflammation. 3 TAK-779 {N,N-dimethyl-N-[4-({[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl}amino)benzyl]-tetrahydro-2H-pyran4-aminium chloride} is a nonpeptide CCR5/CXCR3 antagonist that was developed for the treatment of HIV infection by inhibiting HIV cell entry via CCR5. 11-13 TAK-779, however, has also some antiimmunogenic effects. It has been shown to block the influx of CCR5-and CXCR3-positive T cells into inflamed joints in an experimental model for arthritis. 14 Both CCR5 and CXCR3 are predominantly expressed on Th1 cells. 15 Because atherosclerosis is considered to be a Th1-mediated disease, 16,17 treatment with TAK-779 could possibly attenuate atherogenesis by b...