Characterization of a primate model of asthma using anti-allergy/ anti-asthma agents

Turner, Claudia R.; Andresen, Catharine J.; Smith, William B.; Watson, J. W.

doi:10.1007/bf02259610

Cited by 29 publications

(37 citation statements)

References 26 publications

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“…Inhibition of airway eosinophilia and AHR in this non-human primate model was observed with several classes of compounds with disparate mechanisms of action. They include Rolipram, a specific inhibitor of phosphodiesterase IV (32), the corticosteroid dexamethasone (31,33), the leukotriene D 4 receptor antagonist, ICI 198,615 (34), and mAbs directed against intercellular adhesion molecule-1 (35) and interleukin-5 (TRFK-5) (36). Other therapeutic agents that have shown efficacy in AHR include the long acting ␤ 2 -agonist, Salmeterol (33), and the leukotriene B 4 antagonist, CP-105,696 (37).…”

Section: Discussionmentioning

confidence: 99%

“…They include Rolipram, a specific inhibitor of phosphodiesterase IV (32), the corticosteroid dexamethasone (31,33), the leukotriene D 4 receptor antagonist, ICI 198,615 (34), and mAbs directed against intercellular adhesion molecule-1 (35) and interleukin-5 (TRFK-5) (36). Other therapeutic agents that have shown efficacy in AHR include the long acting ␤ 2 -agonist, Salmeterol (33), and the leukotriene B 4 antagonist, CP-105,696 (37). Furthermore, agents that have shown efficacy in late phase bronchoconstriction include the platelet-activating factor receptor antagonist WEB 2170 (38), the 5-lipoxygenase inhibitor, BI-L-239 (39), and a monoclonal antibody directed against endothelial leukocyte adhesion molecule-1 (40), although it is unknown what effect these compounds have on eosinophil recruitment into the airways.…”

Section: Discussionmentioning

confidence: 99%

“…A prominent non-human primate model of asthma was established over a decade ago in the cynomolgus macaque (30,31), and its utility in the preclinical evaluation of therapeutic agents in humans has proven to be extremely valuable (31)(32)(33)(34)(35)(36)(37)(38)(39)(40). To gain a better understanding of the role of CCR3 and its ligands in this important animal model of asthma, we have cloned and functionally expressed the macaque CCR3 in the murine pre-B L1-2 cell line.…”

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confidence: 99%

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Functional Expression and Characterization of Macaque C-C Chemokine Receptor 3 (CCR3) and Generation of Potent Antagonistic Anti-macaque CCR3 Monoclonal Antibodies

Zhang

Soares

Guan

et al. 2002

Journal of Biological Chemistry

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Eosinophils are major effector cells implicated in a number of chronic inflammatory diseases in humans, particularly bronchial asthma and allergic rhinitis. The ␤-chemokine receptor C-C chemokine receptor 3 (CCR3) provides a mechanism for the selective recruitment of eosinophils into tissue and thus has recently become an attractive biological target for therapeutic intervention. In order to develop in vivo models of inflammatory diseases, it is essential to identify and characterize the homologues of human eotaxin (C-C chemokine ligand 11) and CCR3 from other species, such as non-human primates. Accordingly, we cloned the macaque eotaxin and CCR3 genes and revealed that they were 91 and 92% identical at the amino acid level to their human homologues, respectively. Macaque CCR3 expressed in the murine pre-B L1-2 cell line bound macaque eotaxin with high affinity (K d ‫؍‬ 0.1 nM) and exhibited a robust eotaxin-induced Ca 2؉ flux and chemotaxis. Characterization of ␤-chemokines on native macaque CCR3 on eosinophils was performed by means of eotaxin-induced shape change in whole blood using a novel signaling assay known as gated autofluorescence forward scatter. Additionally, mAbs were raised against macaque CCR3 using two different immunogens: a 30-amino acid synthetic peptide derived from the predicted NH 2 terminus of macaque CCR3 and intact macaque CCR3-transfected cells. These anti-macaque CCR3 monoclonal antibodies exhibited potent antagonist activity in receptor binding and functional assays. The characterization of the macaque eotaxin/CCR3 axis and development of antagonistic anti-macaque CCR3 monoclonal antibodies will facilitate the development of CCR3 small molecule antagonists with the hope of ameliorating chronic inflammatory diseases in humans.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Functional Expression and Characterization of Macaque C-C Chemokine Receptor 3 (CCR3) and Generation of Potent Antagonistic Anti-macaque CCR3 Monoclonal Antibodies

Zhang

Soares

Guan

et al. 2002

Journal of Biological Chemistry

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“…This model has been used effectively in the pharmaceutical industry to screen candidate asthma drugs, although this allergen is not normally associated with human asthma (Mauser et al, 1995;Turner et al, 1996). In the cynomolgus monkey asthma model, postchallenge BAL cell populations parallel those described in mice (Gonzalo et al, 1998), with an initial increase in macrophage/monocytes, probably as a consequence of elevated circulating CCL2 levels.…”

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confidence: 99%

Chemokine Receptor 2 Blockade Prevents Asthma in a Cynomolgus Monkey Model

Mellado

Ana²,

Gómez³

et al. 2007

J Pharmacol Exp Ther

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The pathophysiology of asthma is characterized by accumulation and activation of several cell types in the lung, which correlates with coordinated production of specific cytokines and chemokines. To study the effect of selective CCR2 chemokine receptor blockade on leukocyte recruitment to the lung and on bronchial function, we used a nonhuman primate model of allergic airway disease that closely resembles human asthma. Allergic cynomolgus monkeys were treated with the antagonist anti-CCR2 (CCR2-05) monoclonal antibody and then challenged with Ascaris suum antigen; the effect of antibody treatment on macrophage and eosinophil infiltration was determined. Pulmonary function was calculated by measurement of lung resistance and dynamic compliance. Local inflammatory responses were analyzed after intradermal challenge with A. suum antigen. CCL2 up-regulation in bronchoalveolar lavage (BAL) was analyzed by enzyme-linked immunosorbent assay, and in vitro CCR2-05 antagonistic activity was tested in monkey peripheral blood mononuclear cells using chemotaxis and calcium mobilization assays. The results show that neutralization of CCR2 reduces antigen-induced bronchial hyperresponsiveness and attenuates macrophage and eosinophil accumulation in the BAL of asthmatic monkeys. The results confirm that selective blockade of a single chemokine receptor involved in early stages of asthma can condition later disease stages and suggest the utility of anti-CCR2-neutralizing monoclonal antibodies in the treatment of asthma in man.

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“…9 The allergens, however, are not common environmental antigens. In addition, various allergic asthma models have been experimentally developed in nonhuman primates (principally rhesus and cynomolgus macaques) by sensitization and subsequent airway challenge with A suum, 14 house dust mite allergen (Dermatophagoides farinae), 8,12,15 and birch pollen allergens. 3 Many investigators have experimentally demonstrated a prominent infiltration of eosinophils in the airway of nonhuman primates following a repeated inhalation of such allergens, 6,8,9,12,14 and this finding is consistent with the present case.…”

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confidence: 99%

Eosinophilic Airway Inflammation in a Cynomolgus Monkey

Shirai

Geoly

2009

Vet Pathol

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The present article describes an occurrence of eosinophilic airway inflammation of a 4-year-old female cynomolgus monkey in a vehicle control group of a routine toxicology study. Histologically, the airway lesion was characterized by prominent eosinophilic infiltrates, accompanied by mast cells, lymphocytes, and plasmacytes. The eosinophilic infiltrates were distributed throughout the airway: from trachea through respiratory bronchioles in the lung. The morphological feature of the lesion was indicative of an allergic airway disorder that can occur in humans with asthma. The present case is remarkable in that there is a paucity of reports on naturally occurring allergic airway disorders in nonhuman primates. Keywords airway, cynomolgus, eosinophilic, inflammationHuman allergic disorders, such as anaphylaxis, hay fever, eczema, and asthma, have been increasing in the developed world, with roughly 25% of the population currently being affected. 4 For many asthma patients, the disease has its roots in infancy, and factors both genetic and environmental contribute to its inception and evolution.2 Allergic asthma can be referred to as abnormal adaptive immune responses in the airway. Briefly, this begins with presentation of an allergen to naive CD4þ helper T cells by dendritic cells. Then, T-helper-2 (T H 2) cells are generated and cytokines (IL-4, IL-5, IL-13) are released from T H 2 cells. These cytokines induce activation of eosinophils (IL-5) and immunoglobulin E-producing (IgE-producing) B cells (IL-4 and IL-13) and mast cells (IL-4); subsequently, IgE binds to mast cells. After that, exposure of IgE-coated mast cells to the allergen leads to the release of proinflammatory mediators (including those stored in the cytoplasmic granules), lipid-derived mediators, and newly synthesized cytokines, chemokines, and growth factors, as well as other mediators. These induce the recruitment and activation of T H 2 cells, eosinophils, and other leucocytes and the persistent mediator production by resident cells (such as mast cells). Prolonged or repetitive exposure to specific allergens ultimately results in airway remodeling, characterized by goblet cell hyperplasia and increases in submucosal tissue, the adventitia, and smooth muscle. 4,13The animal was a captive-bred 4-year-old female cynomolgus monkey (Macaca fascicularis), which was originally from Mauritius, obtained via commercial supplier and kept at our facilities for 18 months, then assigned to a vehicle (0.5% methylcellulose) control group consisting of 3 females for a 1-month oral toxicity study. The monkeys were housed in same-sex pairs in stainless-steel cages in a single room with a temperature of 70 + 5 F (21 + 3 C), a relative humidity of 50 + 10%, a minimum of 12 air changes per hour with air filtered through 90 to 95% efficiency filters, then through highefficiency particulate air (HEPA) filters, and an approximately 12-hour light/dark cycle. A standard diet of pelleted food (Certified Primate Diet 5K91, PMI Feeds, Inc, Gray Summit, MO) supplemen...

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Characterization of a primate model of asthma using anti-allergy/ anti-asthma agents

Cited by 29 publications

References 26 publications

Functional Expression and Characterization of Macaque C-C Chemokine Receptor 3 (CCR3) and Generation of Potent Antagonistic Anti-macaque CCR3 Monoclonal Antibodies

Functional Expression and Characterization of Macaque C-C Chemokine Receptor 3 (CCR3) and Generation of Potent Antagonistic Anti-macaque CCR3 Monoclonal Antibodies

Chemokine Receptor 2 Blockade Prevents Asthma in a Cynomolgus Monkey Model

Eosinophilic Airway Inflammation in a Cynomolgus Monkey

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