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Publications (5)28.24 Total impact

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    ABSTRACT: Patients suffering from cardiovascular disease have well-established atherosclerotic lesions, rendering lesion regression of therapeutic interest. The OX40 (TNFRSF4)-OX40 ligand (OX40L; TNFSF4) pathway is important for the proliferation and survival of T cells, stimulates B cells, and is associated with cardiovascular disease. We hypothesized that interference with the OX40-OX40L pathway, in combination with decreases in cholesterol, may induce regression of atherosclerosis. LDLr(-/-) mice were fed a Western-type diet for 10 wk, after which they received chow diet and were treated with anti-OX40L or PBS for 10 wk. A significant regression of lesions was observed in the aorta and aortic arch of anti-OX40L-treated mice compared with control mice. Interference of the OX40-OX40L pathway reduced Th2 responses, as shown by decreases in GATA-3 and IL-4 levels. Also, IgE levels were decreased, as demonstrated by reduced mast cell presence and activation. Notably, IL-5 production by T and B1 cells was increased, thus enhancing atheroprotective oxidized low-density lipoprotein-specific IgM production. The increase in IL-5 production and IgM was mediated by IL-33 production by APCs upon OX40L blockade. We conclude that interruption of the OX40-OX40L signaling pathway, combined with decreases in dietary cholesterol, induces the regression of atherosclerosis through induction of IL-5-producing T cells and oxidized low-density lipoprotein-specific IgM and reductions in Th2 and mast cells.
    The Journal of Immunology 09/2013; · 5.52 Impact Factor
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    ABSTRACT: Atherosclerosis is a chronic autoimmune-like disease in which lipids and fibrous elements accumulate in the arterial blood vessels. T cells are present within atherosclerotic plaques, and their activation is partially dependent on costimulatory signals, which can either provide positive or negative signals that promote T-cell activation or limit T-cell responses, respectively. T-cell immunoglobulin and mucin domain 3 (Tim-3) is a coinhibitory type 1 transmembrane protein that affects the function of several immune cells involved in atherosclerosis, such as monocytes, macrophages, effector T cells, and regulatory T cells. In the present study, we determined the role of Tim-3 in the development of atherosclerosis. Western-type diet-fed LDLr(-/-) mice were treated with an anti-Tim-3 antibody for 3 and 8 weeks. Anti-Tim-3 administration increased fatty streak formation with 66% and increased atherosclerotic plaque formation after 8 weeks with 35% in the aortic root and with 50% in the aortic arch. Furthermore, blockade of Tim-3 signaling increased percentages of circulating monocytes with 33% and lesional macrophages with 20%. In addition, anti-Tim-3 administration increased CD4(+) T cells with 17%, enhanced their activation status, and reduced percentages of regulatory T cells with 18% and regulatory B cells with 37%. It is known that Tim-3 acts as a negative regulator of both innate and adaptive immune responses, and in the present study, we show that anti-Tim-3 treatment augments lesion development, accompanied by an increase in the number of monocytes/macrophages and CD4(+) T cells and by decreased regulatory T cells and regulatory B cells.
    Arteriosclerosis Thrombosis and Vascular Biology 08/2013; · 6.34 Impact Factor
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    ABSTRACT: OBJECTIVE: Costimulatory molecules tightly control immune responses by providing positive signals that promote T-cell activation or by transducing inhibitory signals that limit T-cell responses. CD30 and CD30L are members of the tumor necrosis factor receptor superfamily and are involved in the activation and proliferation of T and B cells, which have been implicated in the initiation and progression of atherosclerosis. In the present study, we thus aimed to determine the role of the CD30-CD30L pathway in the development of atherosclerosis. METHODS AND RESULTS: Western-type diet-fed low-density lipoprotein receptor-deficient mice were treated with an anti-CD30L antibody for 8 weeks, which resulted in a reduction of atherosclerotic lesion formation in the aortic root by 35%. Reduced numbers of adventitial CD3(+) T cells were found in anti-CD30L-treated mice, whereas no differences were observed in collagen and macrophage content of the atherosclerotic lesions. B-cell and mast cell responses were also not affected on anti-CD30L treatment. Interestingly, splenocyte proliferation was reduced by 53%, whereas T-cell numbers were concomitantly reduced in anti-CD30L-treated mice compared with control mice. These data thus indicate that the CD30-CD30L pathway solely exerts its function via inhibition of T-cell responses. CONCLUSIONS: In the present study, we are the first to show that interruption of the CD30-CD30L pathway reduced initial atherosclerosis development by modulating T-cell function.
    Arteriosclerosis Thrombosis and Vascular Biology 10/2012; · 6.34 Impact Factor
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    ABSTRACT: The A(2B) adenosine receptor (A(2B)R) is highly expressed in macrophages and vascular smooth muscle cells and has been established as an important regulator of inflammation and vascular adhesion. Recently, it has been demonstrated that A(2B)R deficiency enhances neointimal lesion formation after vascular injury. Therefore, we hypothesize that A(2B)R agonism protects against injury-induced intimal hyperplasia. Apolipoprotein E-deficient mice were fed a Western-type diet for 1 week, after which the left common carotid artery was denuded. Mice were treated with the A(2B) receptor agonist BAY60-6583 or vehicle control for 18 days. Interestingly, lumen stenosis as defined by the neointima/lumen ratio was inhibited by treatment with the A(2B) receptor agonist, caused by reduced smooth muscle cell proliferation. Collagen content was significantly increased in the BAY60-6583-treated mice, whereas macrophage content remained unchanged. In vitro, vascular smooth muscle cell proliferation decreased dose dependently whereas collagen content of cultured smooth muscle cells was increased by BAY60-6583. Our data show that activation of the adenosine A(2B) receptor protects against vascular injury, while it also enhances plaque stability as indicated by increased collagen content. These outcomes thus point to A(2B) receptor agonism as a new therapeutic approach in the prevention of restenosis.
    Arteriosclerosis Thrombosis and Vascular Biology 06/2012; 32(9):2197-205. · 6.34 Impact Factor
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    ABSTRACT: Regulatory T cells (Tregs) play an important role in the regulation of T cell-mediated immune responses through suppression of T cell proliferation and cytokine production. In atherosclerosis, a chronic autoimmune-like disease, an imbalance between pro-inflammatory cells (Th1/Th2) and anti-inflammatory cells (Tregs) exists. Therefore, increased Treg numbers may be beneficial for patients suffering from atherosclerosis. In the present study, we determined the effect of a vast expansion of Tregs on the initiation and regression of well-established lesions. For in vivo Treg expansion, LDL receptor deficient (LDLr(-/-)) mice received repeated intraperitoneal injections of a complex of IL-2 and anti-IL-2 mAb. This resulted in a 10-fold increase in CD4(+)CD25(hi)Foxp3(+) T cells, which potently suppressed effector T cells ex vivo. During initial atherosclerosis, IL-2 complex treatment of LDLr(-/-) mice fed a Western-type diet reduced atherosclerotic lesion formation by 39%. The effect on pre-existing lesions was assessed by combining IL-2 complex treatment with a vigorous lowering of blood lipid levels in LDLr(-/-) mice. This did not induce regression of atherosclerosis, but significantly enhanced lesion stability. Our data show differential roles for Tregs during atherosclerosis: Tregs suppress inflammatory responses and attenuate initial atherosclerosis development, while during regression Tregs can improve stabilization of the atherosclerotic lesions.
    Atherosclerosis 05/2011; 218(1):53-60. · 3.71 Impact Factor