Experimental Monkey Model Sensitized with Mite Antigen

Yasue, Masaaki; Nakamura, Shin; Yokota, Toyokazu; Okudaira, Hirokazu; Okumura, Yasushi

doi:10.1159/000069461

Cited by 26 publications

(25 citation statements)

References 36 publications

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“…We first succeeded to induce asthmatic responses by the sensitization with DNP-As. Then, we tried to induce asthmatic responses by the sensitization with mites, because dust mites are commonly associated with human asthma (19) and has been shown to be effective in inducing symptoms of asthma in common laboratory animals, including mice (20,21), rats (22), rhesus monkeys (9,15), and rabbits (23). In addition, natural sensitivity to dust mites had been documented in monkeys (24), increasing the relevance of the allergen.…”

Section: Discussionmentioning

confidence: 99%

“…Thus far, although wildcaught cynomolgus monkeys (10 -13) and squirrel monkeys (14) sensitive to inhaled Ascaris suum allergen had been used, these wild-caught monkeys are not currently available. Recently, several studies showed that sensitization of monkeys with allergens could elicit allergen-specific IgE production (9) and allergic asthma symptoms upon allergen provocation (15,16). However, a long period of time is required for the development of these models (15,16).…”

Section: Introductionmentioning

confidence: 99%

“…Although the majority of asthmatic patients is sensitized with mites, very few investigators used mites or mite extracts as immunizing agents (9,15,16). Therefore, we sensitized cynomolgus monkeys by house dust mite extracts (HDM) under the similar protocol.…”

Section: Introductionmentioning

confidence: 99%

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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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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…A small number of primate studies have used clinically meaningful aeroallergens, such as ragweed [11] or house dust mite (HDM) delivered in aerosol form [6,12,13]. PLOPPER and HYDE [3] addressed the validity of these models at the anatomical and cellular levels, and ZOU et al [14] documented changes in gene expression by microarray profiling following acute challenge with allergen.…”

mentioning

confidence: 99%

Modelling asthma in macaques: longitudinal changes in cellular and molecular markers

Ayanoglu¹,

Desai²,

Fick³

et al. 2010

European Respiratory Journal

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The aim of the present study was to determine whether systemic sensitisation and chronic aeroallergen challenge in macaques replicate the classical and emerging immunology and molecular pathology of human asthma.Macaques were immunised and periodically challenged over 2 yrs with house dust mite allergen. At key time-points, serum, bronchoalveolar lavage (BAL) and bronchial biopsies were assayed for genes, proteins and lymphocyte subpopulations relevant to clinical asthma.Immunisation and periodic airway challenge induced changes in immunoglobulin E, airway physiology and eosinophilia consistent with chronic, dual-phase asthma. Sensitisation increased interleukin (IL)-1b and -6 concentrations in serum, and IL-13 expression in BAL cells. Airway challenge increased: early expression of IL-5, -6, -13 and -19, and eotaxin; and variable late-phase expression of IL-4, -5 and -13, and thymus-and activation-regulated chemokine in BAL cells. CD4+ lymphocytes comprised 30% of the CD3+ cells in BAL, increasing to 50% in the late phase. Natural killer T-cells represented ,3% of the CD3+ cells. Corticosteroid treatment reduced serum histamine levels, percentage of CD4+ cells and monocyte-derived chemokine expression, while increasing CD3+ and CD8+ cells in BAL.Sensitisation and periodic aeroallergen challenge of cynomolgus macaques results in physiological, cellular, molecular and protein phenotypes, and therapeutic responses observed in human asthma, providing a model system useful in target and biomarker discovery, and translational asthma research.KEYWORDS: Asthma, corticosteroid treatment, natural killer T-cell, primate model A sthma continues to present a significant unmet medical need [1] and the search for effective asthma drugs with novel mechanisms of action continues. Nonhuman primate models most closely replicate the genetics, physiology, immunology and pathology of the human disease [2][3][4]. The availability of these models uniquely allows examination of both induction of chronic allergy-driven airway inflammation and bronchoconstriction in a controlled setting, as well as identification of key mediators for the maintenance of chronic asthma. Additionally, these models provide a platform to assess pre-clinical safety, and proof of activity and efficacy for novel asthma therapeutics, under conditions that are observed in human patients.Models of asthma have been developed in a variety of common laboratory animals, including guinea pigs, rabbits, rats, mice, sheep, cats, dogs and macaques (see review by BICE et al.[5]).However, there are significant differences in airway architecture and immune responses to chronic allergen between species. Few species develop spontaneous allergic sensitivity to allergens, chronic or prolonged immune and inflammatory responses following pulmonary allergen exposure, progressive worsening of airway responses with repeated antigen challenge, and significant accumulation of lymphoid cells outside the bronchial-associated lymphoid tissue. Murine models have been instrumental ...

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“…Large animal models of asthma have been developed in sheep [63], dogs [64] and nonhuman primates (macaques) [65][66][67][68][69]. The rhesus monkey model of asthma is used because of the genetic and physiological similarity to humans that allows pulmonary function measurements commonly used in humans [66].…”

Section: Uniqueness Of the Rhesus Monkey Model Of Asthmamentioning

confidence: 99%

Asthma: a comparison of animal models using stereological methods

Hyde

Miller

Schelegle

et al. 2006

European Respiratory Review

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Asthma is a worldwide health problem that affects 300 million people, as estimated by the World Health Organization. A key question in light of this statistic is: ''what is the most appropriate laboratory animal model for human asthma?''The present authors used stereological methods to assess airways in adults and during postnatal development, and their response to inhaled allergens to compare rodents and nonhuman primates to responses in humans.An epithelial-mesenchymal trophic unit was defined in which all of the compartments interact with each other. Asthma manifests itself by altering not only the epithelial compartment but also other compartments (e.g. interstitial, vascular, immunological and nervous). All of these compartments show significant alteration in an airway generation-specific manner in rhesus monkeys but are limited to the proximal airways in mice. The rhesus monkey model shares many of the key features of human allergic asthma including the following: 1) allergen-specific immunoglobulin (Ig)E and skin-test positivity; 2) eosinophils and IgE+ cells in airways; 3) a Thelper type 2 cytokine profile in airways; 4) mucus cell hyperplasia; 5) subepithelial fibrosis; 6) basement membrane thickening; and 7) persistent baseline hyperreactivity to histamine or methacholine.In conclusion, the unique responses to inhaled allergens shown in rhesus monkeys make it the most appropriate animal model of human asthma.

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Experimental Monkey Model Sensitized with Mite Antigen

Cited by 26 publications

References 36 publications

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

Modelling asthma in macaques: longitudinal changes in cellular and molecular markers

Asthma: a comparison of animal models using stereological methods

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