Treatment with the C5a receptor/CD88 antagonist PMX205 reduces inflammation in a murine model of allergic asthma

Elizabeth B. Staab, Sam D. Sanderson, Sandra M. Wells, Jill A Poole

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Allergic asthma is a chronic inflammatory airway disease arising from an aberrant immune response following exposure to environmental stimuli in genetically susceptible persons. The complement component 5 (C5)/C5a Receptor (C5aR/CD88) signaling pathway has been implicated in both experimental allergic asthma and human asthmatic disease. Targeting the C5a/C5aR signaling pathway in rodent models has been shown to either enhance or reduce allergic asthma consequences. Treatment with a recombinant humanized monoclonal antibody directed against C5 has shown unclear results in patients with asthma. The objective of this proof-of-concept animal study was to determine whether the low molecular weight C5aR peptidomimetic antagonist, PMX205, would reduce experimental allergic asthma consequences in mice. PMX205 or vehicle control was administered subcutaneously to BALB/c mice prior to and during standard ovalbumin (OVA) allergen sensitization and aerosolized challenge phases. PMX205 substantially reduced OVA-induced total cell (60%), neutrophil (66%) and eosinophil (65%) influxes in lavage fluid sampling. There were also significant reductions in OVA-induced lavage fluid IL-13 protein and lung Th2 cytokine gene expression with PMX205 administration. PMX205 treatment also diminished OVA-induced lung parenchyma cellular infiltration. PMX205 administration did not reduce OVA-induced serum IgE levels or epithelial mucous/goblet cell generation. There was no evidence of toxicity observed with PMX205 treatment in saline or OVA-challenged animals. These data provide evidence that pharmacologic blockade of C5aR by a low molecular weight antagonist (PMX205) reduces airway inflammatory cell and cytokine responses in experimental allergic asthma, and suggests that PMX205 might represent a novel therapeutic agent for reducing asthmatic outcomes.

Original languageEnglish (US)
Pages (from-to)293-300
Number of pages8
JournalInternational Immunopharmacology
Volume21
Issue number2
DOIs
StatePublished - Jan 1 2014

Fingerprint

Anaphylatoxin C5a Receptor
Asthma
Ovalbumin
Inflammation
Therapeutics
Therapeutic Irrigation
Molecular Weight
Complement C5
Cytokines
Peptidomimetics
Antibodies, Monoclonal, Humanized
hydrocinnamate-cyclo(ornithyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl)
Lung
Goblet Cells
Interleukin-13
Reducing Agents
Environmental Exposure
Eosinophils
Allergens
Immunoglobulin E

Keywords

  • Allergy
  • Asthma
  • C5a receptor
  • Complement
  • Inflammation
  • Therapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

Cite this

Treatment with the C5a receptor/CD88 antagonist PMX205 reduces inflammation in a murine model of allergic asthma. / Staab, Elizabeth B.; Sanderson, Sam D.; Wells, Sandra M.; Poole, Jill A.

In: International Immunopharmacology, Vol. 21, No. 2, 01.01.2014, p. 293-300.

Research output: Contribution to journalArticle

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abstract = "Allergic asthma is a chronic inflammatory airway disease arising from an aberrant immune response following exposure to environmental stimuli in genetically susceptible persons. The complement component 5 (C5)/C5a Receptor (C5aR/CD88) signaling pathway has been implicated in both experimental allergic asthma and human asthmatic disease. Targeting the C5a/C5aR signaling pathway in rodent models has been shown to either enhance or reduce allergic asthma consequences. Treatment with a recombinant humanized monoclonal antibody directed against C5 has shown unclear results in patients with asthma. The objective of this proof-of-concept animal study was to determine whether the low molecular weight C5aR peptidomimetic antagonist, PMX205, would reduce experimental allergic asthma consequences in mice. PMX205 or vehicle control was administered subcutaneously to BALB/c mice prior to and during standard ovalbumin (OVA) allergen sensitization and aerosolized challenge phases. PMX205 substantially reduced OVA-induced total cell (60{\%}), neutrophil (66{\%}) and eosinophil (65{\%}) influxes in lavage fluid sampling. There were also significant reductions in OVA-induced lavage fluid IL-13 protein and lung Th2 cytokine gene expression with PMX205 administration. PMX205 treatment also diminished OVA-induced lung parenchyma cellular infiltration. PMX205 administration did not reduce OVA-induced serum IgE levels or epithelial mucous/goblet cell generation. There was no evidence of toxicity observed with PMX205 treatment in saline or OVA-challenged animals. These data provide evidence that pharmacologic blockade of C5aR by a low molecular weight antagonist (PMX205) reduces airway inflammatory cell and cytokine responses in experimental allergic asthma, and suggests that PMX205 might represent a novel therapeutic agent for reducing asthmatic outcomes.",
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