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      Inhibition of B7-1 (CD80) by RhuDex ® reduces lipopolysaccharide-mediated inflammation in human atherosclerotic lesions

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          Abstract

          Background

          Atherosclerosis is based on a chronic inflammatory process including the innate and adaptive immune response. Costimulatory molecules and their receptors provide decisive signals for antigen-specific cell activation. The contribution of B7-related pathways to atherosclerosis has hardly been explored.

          Methods

          In the present study, we investigated the contribution of B7-1 to inflammation and tissue injury in the human plaque microenvironment in order to identify possible target structures of future therapeutic agents ex vivo and in vitro.

          Results

          Carotid artery plaque stimulation with lipopolysaccharides (LPS) could be significantly inhibited by RhuDex ®, a specific inhibitor of the costimulatory molecule B7-1 ex vivo ( P<0.001). Coculture of antigen-presenting cells with T-cells demonstrated that the inhibitory effects of RhuDex ® derived from reduced T-cell activation. In addition, incubation of monocytes/macrophages with LPS and RhuDex ® resulted in an inhibitory negative feedback on antigen-presenting cells. Signaling pathways affected by RhuDex ® seem to be nuclear transcription factor kappa B, activator protein-1, and extracellular signal-regulated kinase 1/2.

          Conclusion

          The present data support B7-1 alone as an important costimulatory molecule in the context of LPS-mediated inflammation in atherosclerotic lesions. Due to its marked inhibitory effects, RhuDex ® may be a useful therapy to modulate the inflammatory milieu in atherosclerosis.

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          Most cited references 38

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          Lessons From Sudden Coronary Death

          Arteriosclerosis, Thrombosis, and Vascular Biology, 20(5), 1262-1275
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            Interleukin-10: new perspectives on an old cytokine.

            Interleukin-10 (IL-10) has long been recognized to have potent and broad-spectrum anti-inflammatory activity, which has been unequivocally established in various models of infection, inflammation, and even in cancer. However, because of the marginal successes of the initial clinical trials using recombinant IL-10, some of the interest in this cytokine as an anti-inflammatory therapeutic has diminished. New work showing IL-10 production from regulatory T cells and even T-helper 1 T cells has reinvigorated the field and revealed the power of this cytokine to influence immune responses. Furthermore, new preclinical studies suggest that combination therapies, using antibodies to IL-10 along with chemotherapy, can be effective in treating bacterial, viral, or neoplastic diseases. Studies to understand IL-10 gene expression in the various cell types may lead to new therapeutics to enhance or inhibit IL-10 production. In this review, we summarize what is known about the regulation of IL-10 gene expression by various immune cells. We speculate on the promise that this cytokine holds to influence immune responses and mitigate immune pathologies.
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              Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation.

              Naturally occurring CD4(+)CD25(+) regulatory T cells (Treg) suppress in vitro the proliferation of other T cells in a cell-contact-dependent manner. Dendritic cells (DCs) appear to be a target of Treg-mediated immune suppression. We show here that, in coculture of dye-labeled Treg cells and CD4(+)CD25(-) naïve T cells in the presence of T cell receptor stimulation, Treg cells, which are more mobile than naïve T cells in vitro, out-compete the latter in aggregating around DCs. Deficiency or blockade of leukocyte function-associated antigen-1 (LFA-1) (CD11a/CD18) abrogates Treg aggregation, whereas that of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) (CD152) does not. After forming aggregates, Treg cells specifically down-regulate the expression of CD80/86, but not CD40 or class II MHC, on DCs in both a CTLA-4- and LFA-1-dependent manner. Notably, Treg exerts this CD80/86-down-modulating effect even in the presence of strong DC-maturating stimuli, such as GM-CSF, TNF-alpha, IFN-gamma, type I IFN, and lipopolysaccharide. Taken together, as a possible mechanism of in vitro Treg-mediated cell contact-dependent suppression, we propose that antigen-activated Treg cells exert suppression by two distinct steps: initial LFA-1-dependent formation of Treg aggregates on immature DCs and subsequent LFA-1- and CTLA-4-dependent active down-modulation of CD80/86 expression on DCs. Both steps prevent antigen-reactive naïve T cells from being activated by antigen-presenting DCs, resulting in specific immune suppression and tolerance.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2014
                12 May 2014
                : 8
                : 447-457
                Affiliations
                [1 ]Department of Cardiology, University of Heidelberg, Germany
                [2 ]Department of Vascular Surgery, University of Heidelberg, Germany
                [3 ]Department of Cardiology, SLK Hospital Heilbronn, Bad Friedrichshall, Germany
                Author notes
                Correspondence: Christian Erbel, Department of Cardiology, Angiology and Pneumology Medical Clinic III, Heidelberg University Hospital, INF 410, Heidelberg 69120, Germany, Tel +49 6221 563 8879, Fax +49 6221 565 515, Email christian.erbel@ 123456med.uni-heidelberg.de
                [*]

                These authors contributed equally to this article

                Article
                dddt-8-447
                10.2147/DDDT.S59594
                4026407
                © 2014 Doesch et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                b7, cd86, costimulation, atherosclerosis

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