Thesis

Immunomodulatory effect of small molecule analogues of the Acanthocheilonema viteae anti-inflammatory product ES-62 in a house dust mite model of asthma

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Awarding institution
  • University of Strathclyde
Date of award
  • 2015
Thesis identifier
  • T14068
Person Identifier (Local)
  • 201385537
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Qualification Name
Department, School or Faculty
Abstract
  • The hygiene hypothesis states that, amongst other factors, the lack of pathogen-induced immune responses in childhood leads to development of medical conditions such as hypersensitivities later in life. Parasitic worms are able to modulate inflammatory responses in order to survive within the host which simultaneously helps the host to be protected from allergic disorders.ES-62, a protein derived from the filarial nematode Acantocheilonema viteae, which is anti-inflammatory by virtue of phosphorylcholine (PC)-containing N-glycans, was previously shown to inhibit ovalbumin-induced allergic airway hyperresponsiveness in a mouse model. As a potentially immunogenic molecule, ES-62 is unsuitable for development as a therapeutic. However Small Molecule Analogues (SMAs) based on its active PC moiety have been produced and two of them SMAs 11a and 12b were assessed for their ability to reduce airway inflammation in a house dust mite (HDM) model of asthma.Although SMA 11a did not improve the clinical signs of experimental asthma, 12b was shown to greatly reduce the influx of cells into the lungs of mice sensitised and challenged with HDM extracts when 1 μg SMA injections were co-administered. In particular, there was a significant decrease in eosinophil infiltration and a significant decrease in IL-17A mRNA levels. Histological analysis by haematoxylin and eosin (H&E) and periodic acid staining (PAS) further confirmed the protective effects of 12b.12b administered prophylactically (at sensitisation only) or therapeutically (at challenge points only) also reduced eosinophil flux but the latter was associated with a significant increase in IL-17A mRNA levels. The latter data may reflect the cytokine's dual role of being required for the establishment of asthma, but also for attenuating responses in established asthma.Overall, in this work SMA 12b was shown to be effective in reducing symptoms of asthma in a mouse model and is therefore a candidate for development of an anti-asthma drug.
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Note
  • This thesis was previously held under moratorium from 21st July 2015 until 21st July 2016.
DOI
Date Created
  • 2015
Former identifier
  • 9912316303402996

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