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Amanda E. I. Proudfoot - One of the best experts on this subject based on the ideXlab platform.

  • the effect of the cc Chemokine Receptor Antagonist met rantes on experimental autoimmune uveitis and oral tolerance
    Journal of Neuroimmunology, 2005
    Co-Authors: Maria Diedrichsmohring, Amanda E. I. Proudfoot, Peter J Nelson, Stephan R Thurau, Gerhild Wildner
    Abstract:

    Lymphocyte trafficking is controlled in part by the actions of Chemokines. In rat experimental autoimmune uveitis (EAU) we observed differential therapeutic effects of Met-RANTES, a CCR1/CCR5 Receptor Antagonist, depending on the retinal antigen peptides inducing the disease and the time of application during the afferent or efferent immune response. CCR1 and/or CCR5 blockade may have inhibitory effects on different phases of the autoimmune response, depending on the antigen specificity of T cells in EAU. In contrast, Met-RANTES enhanced therapeutic oral tolerance independently of orally applied antigen.

  • antagonism of rantes Receptors reduces atherosclerotic plaque formation in mice
    Circulation Research, 2004
    Co-Authors: Niels R Veillard, Brenda R Kwak, Graziano Pelli, Flore Mulhaupt, Richard W James, Amanda E. I. Proudfoot, Francois Mach
    Abstract:

    Increasing evidence supports the involvement of inflammation in the early phases of atherogenesis. Recruitment of leukocytes within the vascular wall, controlled by Chemokines, is an essential process in the development of this common disease. In this study, we report that blocking a Chemokine pathway in vivo with the CC Chemokine Antagonist Met-RANTES reduces the progression of atherosclerosis in a hypercholesterolemic mouse model. The reduction of lesions was correlated with a diminution of expression of several major Chemokines and Chemokine Receptors, a decrease in leukocyte infiltration, and an increase of collagen-rich atheroma, features associated with stable atheroma. Treatment was well tolerated and serum lipid profiles were not affected. Whereas genetically engineered mice with deletion of either a CC Chemokine or its Receptor have demonstrated resistance to disease, to our knowledge, this is the first demonstration that treatment with a Chemokine Receptor Antagonist limits the progression of atherosclerosis in vivo. Thus, our findings indicate that blockade of Chemokine Receptor/ligand interactions might become a novel therapeutic strategy to reduce the evolution of this common disease.

  • antagonism of rantes Receptors reduces atherosclerotic plaque formation in mice
    Circulation Research, 2004
    Co-Authors: Niels R Veillard, Brenda R Kwak, Graziano Pelli, Flore Mulhaupt, Richard W James, Amanda E. I. Proudfoot, Francois Mach
    Abstract:

    Increasing evidence supports the involvement of inflammation in the early phases of atherogenesis. Recruitment of leukocytes within the vascular wall, controlled by Chemokines, is an essential process in the development of this common disease. In this study, we report that blocking a Chemokine pathway in vivo with the CC Chemokine Antagonist Met-RANTES reduces the progression of atherosclerosis in a hypercholesterolemic mouse model. The reduction of lesions was correlated with a diminution of expression of several major Chemokines and Chemokine Receptors, a decrease in leukocyte infiltration, and an increase of collagen-rich atheroma, features associated with stable atheroma. Treatment was well tolerated and serum lipid profiles were not affected. Whereas genetically engineered mice with deletion of either a CC Chemokine or its Receptor have demonstrated resistance to disease, to our knowledge, this is the first demonstration that treatment with a Chemokine Receptor Antagonist limits the progression of atherosclerosis in vivo. Thus, our findings indicate that blockade of Chemokine Receptor/ligand interactions might become a novel therapeutic strategy to reduce the evolution of this common disease.

  • a Chemokine Receptor Antagonist inhibits experimental breast tumor growth
    Cancer Research, 2003
    Co-Authors: Stephen C Robinson, Amanda E. I. Proudfoot, Kate A Scott, Julia L Wilson, Richard G Thompson, Frances R Balkwill
    Abstract:

    The leukocyte infiltrate of human and murine epithelial cancers is regulated by Chemokine production in the tumor microenvironment. In this article, we tested the hypothesis that Chemokine Receptor Antagonists may have anticancer activity by inhibiting this infiltrate. We first characterized CC Chemokines, Chemokine Receptors, and the leukocyte infiltrate in the 410.4 murine model of breast cancer. We found that CCL5 (RANTES) was produced by the tumor cells, and its Receptors, CCR1 and CCR5, were expressed by the leukocyte infiltrate. As Met-CCL5 is an Antagonist of CCR1 and CCR5 with activity in models of inflammatory disease, we tested its activity against 410.4 tumors. After 5 weeks of daily treatment with Met-CCL5, the volume and weight of 410.4 tumors was significantly decreased compared with control-treated tumors. Met-CCL5 was also active against established tumors. The total cell number obtained after collagenase digestion was decreased in Met-CCL5-treated tumors as was the proportion of infiltrating macrophages. Furthermore, Chemokine Antagonist treatment increased stromal development and necrosis. Our results provide direct evidence that macrophages contribute to tumor development and are the first indication that Chemokine Receptor Antagonists may provide novel strategies in cancer prevention and treatment.

  • treatment of experimental autoimmune encephalomyelitis with the Chemokine Receptor Antagonist met rantes
    Journal of Neuroimmunology, 2002
    Co-Authors: Masaru Matsui, Amanda E. I. Proudfoot, Jennifer Weaver, Jerome R Wujek, Tao Wei, Edward Richer, Bruce D Trapp, Ashwin Rao, Richard M Ransohoff
    Abstract:

    Specific Chemokines and Chemokine Receptors have been implicated in inflammatory demyelinating diseases of the central nervous system (CNS), including multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Amino-terminal modifications of Chemokines can alter Receptor interactions, converting agonists to specific Antagonists. To examine the function in EAE of murine types 1 and 5 CC Chemokine Receptors (CCR1 and CCR5), we used Met-RANTES, a peptide that blocks both Receptors; controls received heat-inactivated peptide. There was no effect of active treatment on acute-monophasic EAE, regardless whether compound was given at onset or in a pre-treatment regimen. Administered at disease onset, Met-RANTES modestly but significantly ameliorated fixed neurological disability at the endpoint of chronic-relapsing EAE. Met-RANTES treatment did not reduce CNS cellular infiltrates or up-regulation of CCR1 and CCR5 in affected CNS tissues. Analysis of a subset of mice suggested a trend towards reduced axonal pathology in those receiving active treatment. These data indicate that Chemokine Receptor blockade with Met-RANTES does not affect leukocyte trafficking in chronic-relapsing EAE. Further analysis of the effects of Chemokine Receptor blockade may need to focus on leukocyte activation within the affected CNS as well as trafficking events.

Timothy N C Wells - One of the best experts on this subject based on the ideXlab platform.

  • met rantes reduces vascular and tubular damage during acute renal transplant rejection blocking monocyte arrest and recruitment
    The FASEB Journal, 1999
    Co-Authors: Hermann Josef Gröne, Amanda E. I. Proudfoot, Detlef Schlondorff, Christian Weber, Kim S C Weber, Elisabeth Grone, Ton J Rabelink, Christiane Klier, Timothy N C Wells, Peter J Nelson
    Abstract:

    Chemokines are thought to contribute to the cellular infiltrate characteristic of renal transplant rejection. We show that Met-RANTES, a Chemokine Receptor Antagonist, suppresses recruitment of inflammatory cells into renal allografts. In a renal transplant model (Fisher RT1lvl rat kidney into Lewis RT1l rat) where no additional immune suppressant was used, Met-RANTES-treated animals showed a significant reduction in vascular injury score (16.10 ± 5.20 vs. 62.67 ± 18.64) and tubular damage score (15.70 ± 5.22 vs. 33.00 ± 6.44) relative to untreated animals. In a more severe rejection model (Brown-Norway RT1n rat kidney into Lewis RT11 rat), Met-RANTES significantly augmented low-dose cyclosporin A treatment to reduce all aspects of renal injury including interstitial inflammation (score 71.00 ± 6.10 vs. 157.30 ± 21.30). The majority of infiltrating cells in these models (60–70%) consisted of monocytes. Potential mechanisms of action of Met-RANTES were tested using monocyte attachment assays on microvascul...

  • the cc Chemokine Receptor Antagonist met rantes inhibits eosinophil effector functions
    International Archives of Allergy and Immunology, 1999
    Co-Authors: Jorn Elsner, Timothy N C Wells, Holger Petering, Daniela Kimmig, Amanda E J Proudfoot, Alexander Kapp
    Abstract:

    Eosinophils play an important role in allergic diseases such as allergic asthma, rhinoconjunctivitis and atopic dermatitis. Recruitement of eosinophils to the side of inflammation, the release of reac

  • the cc Chemokine Antagonist met rantes inhibits eosinophil effector functions through the Chemokine Receptors ccr1 and ccr3
    European Journal of Immunology, 1997
    Co-Authors: Jorn Elsner, Timothy N C Wells, Holger Petering, Daniela Kimmig, Alexander Kapp, Renate Hochstetter, Amanda E J Proudfoot
    Abstract:

    : Eosinophils are predominant effector cells not only in allergic diseases but also in connective tissue diseases. The recruitment of eosinophils to the site of inflammation and release of reactive oxygen species leading to tissue damage and propagation of the inflammatory response are mediated by Chemokines. Thus, agents that would be able to inhibit or antagonize Chemokine-induced eosinophil activation are interesting as therapeutical agents. We describe the effect of a Chemokine Receptor Antagonist, Met-RANTES, on human eosinophil effector functions in response to RANTES, monocyte chemoattractant protein (MCP)-3 and eotaxin. Met-RANTES was able to inhibit dose-dependently [Ca2+]i transients in eosinophils following stimulation with RANTES, MCP-3 and eotaxin. Whereas maximal and half-maximal inhibitory effect of Met-RANTES following stimulation with RANTES and MCP-3 were observed at 2 micrograms/ml and 1 microgram/ml, respectively, maximal and half-maximal inhibitory effects of Met-RANTES in response to eotaxin were detected at 10 micrograms/ml and 3 micrograms/ml. Moreover, eotaxin-induced [Ca2+]i transients were only half reduced at a Met-RANTES concentration at which RANTES and MCP-3 were completely blocked. Besides its effect on [Ca2+]i transients, Met-RANTES dose-dependently inhibited actin polymerization in eosinophils following Chemokine stimulation. Whereas Met-RANTES totally inhibited RANTES- and MCP-3-induced actin polymerization at 5 micrograms/ml, the eotaxin-induced response was only reduced by 50%. However, Met-RANTES inhibited dose-dependently the release of reactive oxygen species in response to RANTES, MCP-3 and eotaxin. Again, eotaxin-induced release of reactive oxygen species, however, was only half reduced at a Met-RANTES concentration (10 micrograms/ml) at which RANTES and MCP-3 were completely blocked. The results of this study show that (1) Met-RANTES is an effective and powerful Antagonist of effector functions of human eosinophils following stimulation with RANTES, MCP-3 and eotaxin; (2) Met-RANTES seems to be able to antagonize the response of eosinophils through Chemokine Receptor 1 (CCR1) preferentially to CCR3; (3) Met-RANTES antagonizes eosinophil but not neutrophil effector functions and might be therefore of interest for a new therapeutical approach to prevent the invasion and destructive power of eosinophils in diseases that are accompanied by eosinophil infiltration such as allergic asthma and connective tissue diseases.

  • effect of a cc Chemokine Receptor Antagonist on collagen induced arthritis in dba 1 mice
    Immunology Letters, 1997
    Co-Authors: Platerzyberk Christine, Amanda E. I. Proudfoot, Arlene J Hoogewerf, Christine A Power, Timothy N C Wells
    Abstract:

    Chemokines are small proteins that selectively activate and recruit leukocytes to sites of inflammation. Several of them, including the CC Chemokines RANTES, MIP-1 alpha, MIP-1 beta, MCP-1, and the CXC Chemokines IL-8, GRO-alpha, ENA-78 have been identified in rheumatoid synovium, implicating a potential role for these molecules in rheumatoid arthritis. We have investigated the expression patterns of CC Chemokine Receptors in the joints of mice with collagen-induced arthritis, a model for human rheumatoid arthritis. In addition, we have investigated the incidence and severity of arthritis in mice receiving administration of MetRANTES, a modified Chemokine which is a nanomolar Antagonist of certain CC Chemokine Receptors. The mRNA expression pattern of the Chemokines and their Receptors in the joints of arthritic mice was investigated using reverse transcriptase-PCR and in situ hybridization. An upregulation of the CC Chemokine Receptors mCCR1, mCCR2; mCCR3 and mCCR5 was found in the joints from arthritic mice, compared to control animals. In addition, injections of MetRANTES reduced the incidence of disease in a dose dependent manner. Furthermore, in MetRANTES-treated mice that did develop arthritis a significantly lower severity of disease was observed compared with control animals. Our data clearly demonstrate a role for CC Chemokines and their Receptors in inflammatory joint destruction and support the use of Chemokine Receptor Antagonists as potential tools to control inflammatory diseases such as rheumatoid arthritis.

Alexander Kapp - One of the best experts on this subject based on the ideXlab platform.

  • the cc Chemokine Receptor Antagonist met rantes inhibits eosinophil effector functions
    International Archives of Allergy and Immunology, 1999
    Co-Authors: Jorn Elsner, Timothy N C Wells, Holger Petering, Daniela Kimmig, Amanda E J Proudfoot, Alexander Kapp
    Abstract:

    Eosinophils play an important role in allergic diseases such as allergic asthma, rhinoconjunctivitis and atopic dermatitis. Recruitement of eosinophils to the side of inflammation, the release of reac

  • the cc Chemokine Antagonist met rantes inhibits eosinophil effector functions through the Chemokine Receptors ccr1 and ccr3
    European Journal of Immunology, 1997
    Co-Authors: Jorn Elsner, Timothy N C Wells, Holger Petering, Daniela Kimmig, Alexander Kapp, Renate Hochstetter, Amanda E J Proudfoot
    Abstract:

    : Eosinophils are predominant effector cells not only in allergic diseases but also in connective tissue diseases. The recruitment of eosinophils to the site of inflammation and release of reactive oxygen species leading to tissue damage and propagation of the inflammatory response are mediated by Chemokines. Thus, agents that would be able to inhibit or antagonize Chemokine-induced eosinophil activation are interesting as therapeutical agents. We describe the effect of a Chemokine Receptor Antagonist, Met-RANTES, on human eosinophil effector functions in response to RANTES, monocyte chemoattractant protein (MCP)-3 and eotaxin. Met-RANTES was able to inhibit dose-dependently [Ca2+]i transients in eosinophils following stimulation with RANTES, MCP-3 and eotaxin. Whereas maximal and half-maximal inhibitory effect of Met-RANTES following stimulation with RANTES and MCP-3 were observed at 2 micrograms/ml and 1 microgram/ml, respectively, maximal and half-maximal inhibitory effects of Met-RANTES in response to eotaxin were detected at 10 micrograms/ml and 3 micrograms/ml. Moreover, eotaxin-induced [Ca2+]i transients were only half reduced at a Met-RANTES concentration at which RANTES and MCP-3 were completely blocked. Besides its effect on [Ca2+]i transients, Met-RANTES dose-dependently inhibited actin polymerization in eosinophils following Chemokine stimulation. Whereas Met-RANTES totally inhibited RANTES- and MCP-3-induced actin polymerization at 5 micrograms/ml, the eotaxin-induced response was only reduced by 50%. However, Met-RANTES inhibited dose-dependently the release of reactive oxygen species in response to RANTES, MCP-3 and eotaxin. Again, eotaxin-induced release of reactive oxygen species, however, was only half reduced at a Met-RANTES concentration (10 micrograms/ml) at which RANTES and MCP-3 were completely blocked. The results of this study show that (1) Met-RANTES is an effective and powerful Antagonist of effector functions of human eosinophils following stimulation with RANTES, MCP-3 and eotaxin; (2) Met-RANTES seems to be able to antagonize the response of eosinophils through Chemokine Receptor 1 (CCR1) preferentially to CCR3; (3) Met-RANTES antagonizes eosinophil but not neutrophil effector functions and might be therefore of interest for a new therapeutical approach to prevent the invasion and destructive power of eosinophils in diseases that are accompanied by eosinophil infiltration such as allergic asthma and connective tissue diseases.

Amanda E J Proudfoot - One of the best experts on this subject based on the ideXlab platform.

  • the cc Chemokine Receptor Antagonist met rantes inhibits eosinophil effector functions
    International Archives of Allergy and Immunology, 1999
    Co-Authors: Jorn Elsner, Timothy N C Wells, Holger Petering, Daniela Kimmig, Amanda E J Proudfoot, Alexander Kapp
    Abstract:

    Eosinophils play an important role in allergic diseases such as allergic asthma, rhinoconjunctivitis and atopic dermatitis. Recruitement of eosinophils to the side of inflammation, the release of reac

  • the cc Chemokine Antagonist met rantes inhibits eosinophil effector functions through the Chemokine Receptors ccr1 and ccr3
    European Journal of Immunology, 1997
    Co-Authors: Jorn Elsner, Timothy N C Wells, Holger Petering, Daniela Kimmig, Alexander Kapp, Renate Hochstetter, Amanda E J Proudfoot
    Abstract:

    : Eosinophils are predominant effector cells not only in allergic diseases but also in connective tissue diseases. The recruitment of eosinophils to the site of inflammation and release of reactive oxygen species leading to tissue damage and propagation of the inflammatory response are mediated by Chemokines. Thus, agents that would be able to inhibit or antagonize Chemokine-induced eosinophil activation are interesting as therapeutical agents. We describe the effect of a Chemokine Receptor Antagonist, Met-RANTES, on human eosinophil effector functions in response to RANTES, monocyte chemoattractant protein (MCP)-3 and eotaxin. Met-RANTES was able to inhibit dose-dependently [Ca2+]i transients in eosinophils following stimulation with RANTES, MCP-3 and eotaxin. Whereas maximal and half-maximal inhibitory effect of Met-RANTES following stimulation with RANTES and MCP-3 were observed at 2 micrograms/ml and 1 microgram/ml, respectively, maximal and half-maximal inhibitory effects of Met-RANTES in response to eotaxin were detected at 10 micrograms/ml and 3 micrograms/ml. Moreover, eotaxin-induced [Ca2+]i transients were only half reduced at a Met-RANTES concentration at which RANTES and MCP-3 were completely blocked. Besides its effect on [Ca2+]i transients, Met-RANTES dose-dependently inhibited actin polymerization in eosinophils following Chemokine stimulation. Whereas Met-RANTES totally inhibited RANTES- and MCP-3-induced actin polymerization at 5 micrograms/ml, the eotaxin-induced response was only reduced by 50%. However, Met-RANTES inhibited dose-dependently the release of reactive oxygen species in response to RANTES, MCP-3 and eotaxin. Again, eotaxin-induced release of reactive oxygen species, however, was only half reduced at a Met-RANTES concentration (10 micrograms/ml) at which RANTES and MCP-3 were completely blocked. The results of this study show that (1) Met-RANTES is an effective and powerful Antagonist of effector functions of human eosinophils following stimulation with RANTES, MCP-3 and eotaxin; (2) Met-RANTES seems to be able to antagonize the response of eosinophils through Chemokine Receptor 1 (CCR1) preferentially to CCR3; (3) Met-RANTES antagonizes eosinophil but not neutrophil effector functions and might be therefore of interest for a new therapeutical approach to prevent the invasion and destructive power of eosinophils in diseases that are accompanied by eosinophil infiltration such as allergic asthma and connective tissue diseases.

Jorn Elsner - One of the best experts on this subject based on the ideXlab platform.

  • the cc Chemokine Receptor Antagonist met rantes inhibits eosinophil effector functions
    International Archives of Allergy and Immunology, 1999
    Co-Authors: Jorn Elsner, Timothy N C Wells, Holger Petering, Daniela Kimmig, Amanda E J Proudfoot, Alexander Kapp
    Abstract:

    Eosinophils play an important role in allergic diseases such as allergic asthma, rhinoconjunctivitis and atopic dermatitis. Recruitement of eosinophils to the side of inflammation, the release of reac

  • the cc Chemokine Antagonist met rantes inhibits eosinophil effector functions through the Chemokine Receptors ccr1 and ccr3
    European Journal of Immunology, 1997
    Co-Authors: Jorn Elsner, Timothy N C Wells, Holger Petering, Daniela Kimmig, Alexander Kapp, Renate Hochstetter, Amanda E J Proudfoot
    Abstract:

    : Eosinophils are predominant effector cells not only in allergic diseases but also in connective tissue diseases. The recruitment of eosinophils to the site of inflammation and release of reactive oxygen species leading to tissue damage and propagation of the inflammatory response are mediated by Chemokines. Thus, agents that would be able to inhibit or antagonize Chemokine-induced eosinophil activation are interesting as therapeutical agents. We describe the effect of a Chemokine Receptor Antagonist, Met-RANTES, on human eosinophil effector functions in response to RANTES, monocyte chemoattractant protein (MCP)-3 and eotaxin. Met-RANTES was able to inhibit dose-dependently [Ca2+]i transients in eosinophils following stimulation with RANTES, MCP-3 and eotaxin. Whereas maximal and half-maximal inhibitory effect of Met-RANTES following stimulation with RANTES and MCP-3 were observed at 2 micrograms/ml and 1 microgram/ml, respectively, maximal and half-maximal inhibitory effects of Met-RANTES in response to eotaxin were detected at 10 micrograms/ml and 3 micrograms/ml. Moreover, eotaxin-induced [Ca2+]i transients were only half reduced at a Met-RANTES concentration at which RANTES and MCP-3 were completely blocked. Besides its effect on [Ca2+]i transients, Met-RANTES dose-dependently inhibited actin polymerization in eosinophils following Chemokine stimulation. Whereas Met-RANTES totally inhibited RANTES- and MCP-3-induced actin polymerization at 5 micrograms/ml, the eotaxin-induced response was only reduced by 50%. However, Met-RANTES inhibited dose-dependently the release of reactive oxygen species in response to RANTES, MCP-3 and eotaxin. Again, eotaxin-induced release of reactive oxygen species, however, was only half reduced at a Met-RANTES concentration (10 micrograms/ml) at which RANTES and MCP-3 were completely blocked. The results of this study show that (1) Met-RANTES is an effective and powerful Antagonist of effector functions of human eosinophils following stimulation with RANTES, MCP-3 and eotaxin; (2) Met-RANTES seems to be able to antagonize the response of eosinophils through Chemokine Receptor 1 (CCR1) preferentially to CCR3; (3) Met-RANTES antagonizes eosinophil but not neutrophil effector functions and might be therefore of interest for a new therapeutical approach to prevent the invasion and destructive power of eosinophils in diseases that are accompanied by eosinophil infiltration such as allergic asthma and connective tissue diseases.