Subacute house-dust mite induced asthma modell in marmoset monkeys

Human asthma affects 300 million people worldwide with a tendency to increase, thus development of novel therapeutics is needed. In old world monkeys, allergic asthma models have been established, as they display airways with the highest homology and physiology to humans. Due to the high homology of immunologically relevant genes (Kohu et al., 2008) and proteins (Ebeling et al., 2011), non-human primates are of interest for development of biopharmaceuticals targeting the immune system, when cross-reactivity to respective targets in other species is absent.

Asthma is characterized by a primarily eosinophil cell influx into the lungs, accompanied by an upregulation of inflammatory cytokines including IL-13. In rhesus (Macaca mulatta) and cynomolgus macaques (M. fascicularis), allergic asthma can be induced by house dust mite allergen (Yasue et al., 1998; Schelegle et al., 2001; Van Scott et al., 2004). Treatment with glucocorticoids or biologicals improves allergic airway disease manifestations in non-human primate (NHP) asthma models.

In an in vivo trial, acute asthma was induced in marmoset monkeys (Callithrix jacchus) in a sensitization and a challenge phase followed by an intratracheal therapeutic intervention. Sensitization success was determined in skin prick tests, peripheral blood mononuclear cell stimulation (PBMC) assays, and serum immunoglobulin G enzyme linked immunosorbent assays. After intratracheal HDM challenge, bronchoalveolar lavage fluid (BALF) revealed an increase of eosinophils and mast cells in sensitized animals, in contrast to control animals. These changes were complemented by increased levels of IL-13. To investigate a therapeutic effect, animals were treated with either an intratracheally applied control or the glucocorticoid budesonide for three consecutive days. The earlier observed increase of eosinophils and mast cells in BALF were significantly reduced by treatment with the glucocorticoid. After euthanasia, lungs of the sensitized and non-sensitized animals were analyzed for airway hyper responsiveness in applying the technique of precision-cut lung slices, which revealed a specific response in sensitized, control treated animals. HDM-induced features of asthma were sensitive to therapeutic intervention, offering new possibilities to test novel therapeutics in marmoset monkeys.

Species

Marmoset monkeys (Callithrix jacchus)

Field of application

  • Preclinical efficacy testing

Endpoints/Outcome parameter

  • Allergic Airway Inflammation & Airway Hyperresponsiveness

Readout parameter

  • Bronchoalveolar lavage: cell count + differential cell count (incl. inflammatory cells), cytokine profiles
  • Lung function measurements e.g. airway hyperresponsiveness (AHR)
  • Blood analysis: cell count + differential cell count (incl. inflammatory cells), serology, house dust mite-specific immunoglobulin G (ELISA)
  • Cytokine profiles (ELISA) of stimulated peripheral blood mononuclear cells
  • Histology: conventional staining and tissue pathohistology/ conventional microscopy (e.g. tissue cell infiltration), immunohistochemistry/fluorescence microscopy
  • Lung tissue analysis (RNA isolation, cytokine profiles)
  • Precision-cut lung slices

Quality management and validation

  • Internal quality management
  • Historical data available
  • Reference compounds e.g. dexamethasone, budesonide
  • Accurate observance of EU directive 2010/63/EU on the protection of animals used for scientific purposes and of the German animal protection law

References

  • Curths C, Dahlmann F, Wichmann J, Becker T, Knauf Y, Kaup F-J, Braun A, and Knauf S (2015). House-Dust-Mite Induced Features Of Asthma In Marmoset Monkeys. American Thoracic Society Conference, Denver, CO. Am J Respir Crit Care Med 191;2015: A4228.

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