Identification of Differentially Expressed Genes in a Monkey Model of Allergic Asthma by Microarray Technology

Abstract. The development of non-human primate models of asthma requires a period of time (e.g., 0.5 -1 year). To develop the models in a short period, male cynomolgus monkeys were sensitized with dinitrophenyl-Ascaris suum (DNP-As) allergen by intraperitoneal and intramuscular injection and by intratracheal inhalation. All sensitized animals developed positive intradermal skin reaction to DNP-As. Sensitization elevated allergen-specific IgE levels in serum, the number of CCR4-positive T helper lymphocytes in peripheral blood, and IL-4 and IL-5 releases from phorbol 12-myristate 13-acetate-and ionomycin-stimulated peripheral blood. In addition, allergen challenge induced increases in lung resistance, airway inflammation, and hyperresponsiveness to inhaled methacholine. Next, animals were sensitized with house dust mite extracts (HDM) under the similar procedure. In these animals sensitized with DNP-As or HDM, inhaled fluticasone propionate and oral prednisolone inhibited the allergen-induced airway hyperresponsiveness. Taken together, monkey asthma models were successfully developed by sensitization with DNP-As or HDM under a short-term protocol (within 7 weeks). These models should be useful for the evaluation of anti-inflammatory drugs for asthma treatment.

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“…Cynomolgus monkeys exhibit 95% homology with humans (18), making this a candidate species suitable for genomic studies. Pre- Fig.…”

Section: Discussionmentioning

confidence: 99%

Shortening of the Induction Period of Allergic Asthma in Cynomolgus Monkeys by Ascaris suum and House Dust Mite

et al. 2008

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“…2 Increases in CCL18 have also been reported in the lungs of patients with other pulmonary diseases characterized by T-cell involvement and collagen deposition, such as hypersensitivity pneumonitis and idiopathic pulmonary fibrosis, 3,4 pulmonary sarcoidosis, 5 and allergic asthma. 6,7 CCL18, which is also known as pulmonary and activation-regulated chemokine (PARC), macrophage inflammatory protein 4 (MIP-4), alternative macrophage activation-associated CC chemokine 1 (AMAC-1), dendritic cell-derived chemokine 1 (DC-CK1), and small secreted cytokine A 18 (SCYA-18), is constitutively expressed at high levels in the lungs 3,8 -10 and is selectively chemotactic for T cells. 11 We recently reported [12][13][14] and others have recently confirmed 4 that CCL18 in high concentrations (300 to 1000 ng/ml) acts directly on cultured primary pulmonary fibroblasts, activates intracellular signaling, and stimulates collagen production in a time-and dose-dependent manner.…”

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confidence: 99%

Complex Regulation of Pulmonary Inflammation and Fibrosis by CCL18

Pochetuhen

Luzina

Lockatell

et al. 2007

The American Journal of Pathology

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Elevated pulmonary levels of CCL18 have been associated with influx of T lymphocytes, collagen accumulation, and a decline in lung function in pulmonary fibrosis patients. We previously reported that overexpression of CCL18 in mouse lungs triggers selective infiltration of T lymphocytes and moderate lymphocyte-dependent collagen accumulation. We hypothesized that in combination with bleomycin injury, overexpression of CCL18 will worsen the severity of lung inflammation and fibrosis. Mice were infected with a replication-deficient adenovirus encoding CCL18 and then instilled with bleomycin; control mice were challenged with either CCL18 overexpression or bleomycin. Additive effects of CCL18 overexpression and bleomycin injury were observed on pulmonary inflammation, particularly on T-cell infiltration, and increased levels of tumor necrosis factor-␣, interferon-␥, matrix metalloproteinase (MMP)-2, and MMP-9. Despite the additive effect on inflammation, CCL18 overexpression unexpectedly attenuated the bleomycin-induced collagen accumulation. Pulmonary levels of active transforming growth factor-␤1 mirrored the changes in collagen levels. Depletion of T cells with antilymphocyte serum or pharmacological inhibition of MMPs with GM6001 abrogated accumulation of collagen and increases in the levels of tumor necrosis factor-␣, interferon-␥, and active transforming growth factor-␤1. Thus, CCL18-stimulated T-lymphocytic infiltration is by itself mildly profibrotic to a healthy lung, whereas it partially protects against lung fibrosis in an inflammatory profibrotic pulmonary milieu. (Am J Pathol

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“…10,11 Because of its low frequency in the Tunisian population, the CCR5D32 allele could not be assessed in our study. Although the polymorphism of the CCL2 receptor (CCR2-64I) was not associated with childhood asthma in either the casecontrol or the family study, numerous animal models indicate that the CCL2/CCR2 axis may play a major role in asthma [26][27][28][29] and that it is a potential target for therapeutic intervention. 32,33 These discordances highlight once again the importance of the homogeneity of the study population, its genetic background and its exposure to environmental factors.…”

Section: Discussionmentioning

confidence: 99%

“…The studied SNPs were selected because of their functional relevance in leukocyte migration as shown in numerous reports 12,25 and because animal models have assigned a role for these proteins in asthma development. [26][27][28][29] In addition, based on HapMapreleased public data, all SNPs used in our study (except CCR2-V64I) are tagged SNPs in European and African populations. Genotype frequencies showed no deviation from Hardy-Weinberg equilibrium in either groups (data not shown).…”

Section: Case-control Studymentioning

confidence: 99%

A polymorphism in the CCL2 chemokine gene is associated with asthma risk: a case–control and a family study in Tunisia

et al. 2008

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Asthma is a complex genetic disorder characterized by chronic airway inflammation. We hypothesized that genetic polymorphisms in chemokines and their receptors alter leukocyte mobilization and may thus influence the risk and severity of childhood asthma. Distributions of the chemokine CCL2-2578G, CCL2-927C, CCR2-V64I, CX3CR1-V249I and CX3CR1-T280M receptor polymorphisms were examined in a case-control study of 121 children with asthma and 226 age-matched healthy controls and then replicated in a family study of 99 simplex families (297 individuals). The case-control study revealed that the CCL2-2578G allele was less frequent in children with than in those without asthma (P ¼ 0.0012). No association with asthma was found for the CCL2-927, CCR2 or CX3CR1 polymorphisms. The finding in the family study that the CCL2-2578G allele was transmitted less often by heterozygous parents to their children with asthma (P ¼ 0.0016) confirms the association of CCL2-2578G with asthma risk. Biochemical studies indicated that plasma CCL2 concentrations were higher in both patients (P ¼ 0.0214) and controls (P ¼ 0.001) carrying the G allele than in subjects with other polymorphisms. Both case-control and family-based studies suggest a protective effect of allele CCL2-2578G in Tunisian asthmatic children.

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Identification of Differentially Expressed Genes in a Monkey Model of Allergic Asthma by Microarray Technology

Cited by 47 publications

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Shortening of the Induction Period of Allergic Asthma in Cynomolgus Monkeys by Ascaris suum and House Dust Mite

Shortening of the Induction Period of Allergic Asthma in Cynomolgus Monkeys by Ascaris suum and House Dust Mite

Complex Regulation of Pulmonary Inflammation and Fibrosis by CCL18

A polymorphism in the CCL2 chemokine gene is associated with asthma risk: a case–control and a family study in Tunisia

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