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.
"Regulated upon activation, normal T-cell expressed and secreted (RANTES) is a C-C chemokine that has been shown to be a potent chemoattractant for T cells, eosinophils, basophils, monocyte/macrophages, and mast cells 22. It has been shown that RANTES induces recruitment of eosinophils and their up regulation into the airways of asthmatic patients causing tissue damage 23-25. Both atopic asthma and nonatopic asthma are associated with increased levels of RANTES in bronchoalveolar lavage fluid 26 and bronchial mucosal expression of RANTES (together with eosinophil-active cytokines such as interleukin-5, granulocyte macrophage colony-stimulating factor, and interleukin-3), which contributes to the bronchial mucosal accumulation of activated eosinophils 27. "
[Show abstract][Hide abstract] ABSTRACT: Regulated upon activation, normal T-cell expressed and secreted (RANTES) is one of the most extensively studied C-C chemokines in allergic inflammation. A growing body of evidence suggests that many cell types present in asthmatic airways have the capacity to generate RANTES, which directly supported the potential role of RANTES in asthma. A number of studies have evaluated the functional polymorphism -28C/G in the RANTES promoter region, which had been found to affect the transcription of the RANTES gene, in relation to asthma susceptibility. However, the results remain conflicting rather than conclusive. This meta-analysis on 1894 asthma cases and 1766 controls for -28C/G from 9 published case-control studies showed that the variant allele -28G was associated with significantly increased risk of asthma (GG+CG vs CC: OR=1.24, 95%CI=1.08-1.41) without any between-study heterogeneity.
In the stratified analysis by asthma type, age and ethnicity, we found that the increased asthma risk associated with -28G/C polymorphism was more evident in children (OR=1.24, 95%CI=1.06-1.45), Asian group (OR=1.27, 95%CI=1.04-1.56) and African group (OR=1.72, 95%CI=1.07-2.78). These results suggest that RANTES -28G/C polymorphism may contribute to asthma development, especially in children and in Asian population. Additional well-designed large studies were required for the validation of this association.
International journal of medical sciences 02/2010; 7(1):55-61. DOI:10.7150/ijms.7.55 · 2.00 Impact Factor
"MCP-1, a monocyte chemoattractant, was elevated in the lung of aged mice (Fig. 6C), which followed a similar pattern as TNF-α and IL-1α. There was a biphasic expression pattern of RANTES (monocyte and lymphocyte chemoattractant [25,26]) in the adult mice with a peak in concentration at day 5 and then again at day 15 post-infection (Fig. 6D). In aged mice, there was an increase in RANTES between days 3-5 that was 2-4 fold lower than observed in adult mice, which then plateau at ~1500 pg/ml for the remainder of the experiment. "
[Show abstract][Hide abstract] ABSTRACT: Each year, influenza virus infection causes severe morbidity and mortality, particularly in the most susceptible groups including children, the elderly (>65 years-old) and people with chronic respiratory diseases. Among the several factors that contribute to the increased susceptibility in elderly populations are the higher prevalence of chronic diseases (e.g. diabetes) and the senescence of the immune system.
In this study, aged and adult mice were infected with sublethal doses of influenza virus (A/Puerto Rico/8/1934). Differences in weight loss, morbidity, virus titer and the kinetics of lung infiltration with cells of the innate and adaptive immune responses were analyzed. Additionally, the main cytokines and chemokines produced by these cells were also assayed.
Compared to adult mice, aged mice had higher morbidity, lost weight more rapidly, and recovered more slowly from infection. There was a delay in the accumulation of granulocytic cells and conventional dendritic cells (cDCs), but not macrophages in the lungs of aged mice compared to adult animals. The delayed infiltration kinetics of APCs in aged animals correlated with alteration in their activation (CD40 expression), which also correlated with a delayed detection of cytokines and chemokines in lung homogenates. This was associated with retarded lung infiltration by natural killer (NK), CD4+ and CD8+ T-cells. Furthermore, the percentage of activated (CD69+) influenza-specific and IL-2 producer CD8+ T-cells was higher in adult mice compared to aged ones. Additionally, activation (CD69+) of adult B-cells was earlier and correlated with a quicker development of neutralizing antibodies in adult animals.
Overall, alterations in APC priming and activation lead to delayed production of cytokines and chemokines in the lungs that ultimately affected the infiltration of immune cells following influenza infection. This resulted in delayed activation of the adaptive immune response and subsequent delay in clearance of virus and prolonged illness in aged animals. Since the elderly are the fastest growing segment of the population in developed countries, a better understanding of the changes that occur in the immune system during the aging process is a priority for the development of new vaccines and adjuvants to improve the immune responses in this population.
Respiratory research 11/2009; 10(1):112. DOI:10.1186/1465-9921-10-112 · 3.09 Impact Factor
"After 6 hours p.i. the level of Rantes continued to increase to significantly higher levels, and more rapidly than those of the A/Ncr strain at 12, 24 and 48 hours p.i. (Fig. 5B). This chemotactic chemokine is responsible for recruitment of T cells, eosinophils, basophils and NK cells (Kuna et al., 1992; Maghazachi et al., 1994; Schall et al., 1990). Interestingly, Parker et al have previously observed that NK cells are crucial for recovery from mousepox and the trafficking of IFNγ secreting NK cells to the PLN peaks at 56 hours p.i. following an ECTV footpad infection in C57BL/ 6 mice (Parker et al., 2007a). "
[Show abstract][Hide abstract] 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.
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