Thesis

Effect of phosphorylcholine-based small molecule analogues of the immunomodulatory nematode product ES-62 on mast cell function

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Awarding institution
  • University of Strathclyde
Date of award
  • 2010
Thesis identifier
  • T12792
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Abstract
  • ES-62, a phosphorylcholine (PC)-containg glycoprotein derived from the filarial nematode Acanthocheilonema viteae has a plethora of immunomodulatory properties. By virue of its PC moieties ES-62 has been shown to be anti-inflammatory in nature having the ability to reduce arthritis and asthma in animal models. With respect to this project, it was also shown that ES-62 prevented degranulation of human mast cells by forming a complex with TLR-4 and subsequently sequestering PKC-α away from the high affinity receptor for IgE, FcεRI. In this work, PKC-α was found to be critical for mast cell degranulation and its degradation provided a mechanism for the ES-62-mediated disruption of key PLD-SPHK-dependent pathways of calcium, PKC and NF-кB activation. These data raised the possibility that ES-62 could be employed as an anti-allergy drug however it is a large molecule and hence immunogenic molecule and PC attachment is nematode-specific. Therefore, 65 small molecule analogues were developed based on PC and tested for their ability to mimic some of the effects of ES-62. On testing these molecules on bone marrow derived mast cells, it was discovered that mast cells pre-incubated with SMA-63 and SMA-64 when sensitised and cross-linked with the antigen, showed inhibition of peak intracellular calcium mobilization dependent on SPHK. Furthermore, these molecules prevented degranulation in RBL-2H3 cells which is a rat mast cell line. In addition, these molecules reduced levels of IL-6 and TNF-α produced by BMMC activated by cross-linking bound IgE or ionomycin/PMA. Finally, immunofluorescent staining showed that SMAs 63 and 64 and in addition 39, induced the global degradation of PKC-α from both the cytoplasm and the plasma membrane. It can be assumed from these date, that these SMAs particularly 63 and 64 could be taken further to be developed for novel treatment of asthma and other allergic diseases.
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Note
  • This thesis was previously held under moratorium from 25th July 2011 until 25th July 2014.
DOI
Date Created
  • 2010
Former identifier
  • 823967

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