RANTES, a monocyte and T lymphocyte chemotactic cytokine releases histamine from human basophils.
ABSTRACT Chemotaxis of different populations of cells and release of proinflammatory mediators in response to antigenic stimulation are important processes in allergic diseases. These lead to the late phase response, a hallmark of chronic allergic diseases. Recombinant RANTES, a member of the "intercrine/chemokine" family of cytokines, has been previously shown to be chemotactic for monocytes and T cells of memory/helper phenotype. In this manuscript, we show that it is capable of inducing histamine release from human basophils at concentrations as low as 10(-10) M and compare its activity with that of monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 (MCAF/MCP-1), another intercrine/chemokine. RANTES (10(-7) M) caused histamine release from the leukocytes of 26 of 33 donors tested (mean 21.8 +/- 3.1%). In the same group of donors, MCAF/MCP-1, goat anti-human IgE (anti-IgE; 1 microgram/ml), and FMLP (10(-5) M) released 41.1 +/- 2.9%, 40.5 +/- 4.6%, and 44 +/- 3.1% histamine, respectively. The percent histamine release by RANTES in atopic vs nonatopics was 30.3 +/- 6.7 and 16.5 +/- 2.4, respectively (p less than 0.05), and histamine release by RANTES correlated significantly with histamine release by MCAF (r = 0.69; p less than 0.001) but not with histamine release by anti-IgE (r = 0.29; p greater than 0.05). Histamine release by RANTES and MCAF/MCP-1 was extremely rapid, reaching a maximum within 1 min. RANTES was also shown to activate highly purified basophils (80% pure), and its activity was inhibited by a polyclonal anti-RANTES antibody. At a suboptimal concentration (6 x 10(-9) M), RANTES did not prime basophils to enhance histamine release by secretagogues such as anti-IgE, C5a, or FMLP. On the other hand, preincubation of basophils with RANTES or MCAF/MCP-1 desensitized basophils to either factor but not to anti-IgE, C5a, or FMLP. Preincubation of basophils with pertussis toxin markedly diminished the basophil response to either RANTES or MCAF/MCP-1. These results suggest that RANTES and MCAF/MCP-1: 1) are potent activators of basophils; 2) may function via the same, or a closely related, receptor system in basophils; and 3) may represent a link between activation of monocytes, lymphocytes, and basophils in inflammatory disorders such as the late phase allergic reaction.
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ABSTRACT: The intranasal lethal mousepox model employing the A/Ncr mouse strain is used to evaluate anti-orthopoxvirus therapies. These infections mimic large droplet transmission and result in 100% mortality within 7-10 days with as little as 1 PFU of ectromelia virus. Unlike the A/Ncr model, humans are less susceptible to lethal respiratory infections with variola virus and monkeypox virus as demonstrated by their lower mortality rates. In this study we show that a low dose intranasal infection of C57BL/6 mice results in 60-80% mortality and better models smallpox. Comparing CMX001 (HDP-cidofovir) efficacy in the A/Ncr strain and the C57BL/6 strain revealed that delayed treatment with CMX001 is more efficacious at preventing severe disease in the C57BL/6 strain. The increased efficacy of CMX001 in C57BL/6 over A/Ncr following an intranasal infection with ectromelia appears to be mediated by a stronger Th1 cell mediated response. Following footpad infection we show that the C57BL/6 strain has earlier and more robust transcriptional activity, Th1 cytokine secretions, antigen presenting activity and IFNγ splenic CD8+ T cell responses as compared to the A/Ncr strain. As a result of the enhanced immune response in the C57BL/6 strain, non-lethal intradermal ectromelia infections can therapeutically protect up to 3 days following a homologous, lethal intranasal infection – much like how smallpox vaccination can protect humans for up to 4 days following intranasal variola infection.Virology 03/2009; 385(1-385):11-21. DOI:10.1016/j.virol.2008.11.015 · 3.28 Impact Factor
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ABSTRACT: Murine gammaherpesvirus 68 replicates in the alveolar epithelium and induces an inflammatory infiltrate in the lung, following intranasal challenge, and is cleared 10 and 13 days after infection by a T-cell-dependent mechanism. In order to understand the development of the immune response to this virus and how leukocyte trafficking to the lung is regulated, chemokine expression during MHV-68 infection was examined in lung tissue using an RNase protection assay. Expression of RANTES, eotaxin, MIP-1 alpha, MIP-1 beta, IP-10, and MCP-1 was upregulated by day 7 after infection. Chemokine concentrations in lung lavage fluid were also determined by ELISA. MCP-1, RANTES, MIP-1 alpha, eotaxin, and KC were upregulated during MHV-68 infection. Most of these chemokines have been reported to be chemoattractants for either activated T cells or monocytes, which are the major cellular components of the inflammatory infiltrate induced by the virus. Upregulated expression of the corresponding receptors for the chemokines, including CCR1, CCR2, CCR3, CCR5, and CXCR3, coincided with the development of the inflammatory infiltrate. The chemokine levels peaked at around day 7 after infection, coinciding with peak viral titers and slightly preceding maximal T cell infiltration. In vitro chemotaxis assays confirmed that lung lavage fluid from MHV-68-infected mice had chemotactic activity, which was partially blocked by antibodies to IP-10 and RANTES. These observations suggest that the chemokines detected play an important role in regulating leukocyte trafficking to the lungs during MHV-68 infection.Virology 03/2002; 293(1):54-62. DOI:10.1006/viro.2001.1221 · 3.28 Impact Factor
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ABSTRACT: The effect of hrRANTES was studied after the injection in the sole of the rat paw, an area particularly rich in mast cells. Subcutaneous injections of RANTES 50 ng/10 microl produced an erythematous reaction which was inhibited by anti-RANTES antibody 50 microg/rat injected in the tail vein 30 min before hrRANTES 50 ng/10 microl was injected. In another set of experiments the animals were injected subcutaneously in the sole of the paw with PBS 10 microl (control), LPS (100 ng/10 microl) hrRANTES 50 ng/10 microl or anti-RANTES 50 microl/rat injected in the tail vein 30 min before hrRANTES 50 ng/10 microl was injected. The biopsies were analysed after 4 h and counted in an optic field. hrRANTES produced a strong recruitment of mast cells selectively coloured with 0.1% toluidine blue and inhibited by anti-RANTES antibody. In addition to the optical and electron microscope study, in some of the excised tissue Northern blot analysis for histidine decarboxylase (HDC) mRNA was performed to estimate the amount of histamine generation in the tissue of the injection sites. We found that subcutaneous injections of hrRANTES 50 ng/10 microl in the sole of the rat paw produced an accumulation of a great number of mast cells compared to PBS 10 microl (negative control) or LPS 100 ng/10 microl (positive control) after 4 h. The hrRANTES effect was inhibited by anti-RANTES antibody injected in the tail vein 30 min before hrRANTES exposure. Moreover, hrRANTES increased HDC mRNA and histamine generation.British Journal of Haematology 01/1999; 103(3):798-803. DOI:10.1046/j.1365-2141.1998.01060.x · 4.96 Impact Factor