Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.657449
Title: The role of dendritic cells in response to cytokine gene adjuvants
Author: Matthews, K.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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Abstract:
The aim of the work carried out in this thesis was to investigate the effects of GM-CSF and IL-3 after gene-gun vaccination. Initial studies focused on the histological effects of GM-CSF and IL-3 in ovine skin. GM-CSF induced a linear increase in IL-1β transcripts from 1-24 hours concomitant with pronounced neutrophilic infiltration and micro-abscess formation by 24 hours. Maximal GM-CSF and IL-3 mRNA expression was evident at approx. 4 hours, whereas IL-1β and TNF-α transcripts remained highly elevated up to 96 hours. Infiltration of DC, co-ordinately with a rise in MHC class II DRα expression in perivascular regions, was observed 72-96 hours after administration of IL-3, whereas infiltates of B cells and DC were observed at 24 and 72 hours, respectively. Subsequent work characterised DC draining skin before and after GM-CSF administration by means of cannulation of the pseudoafferent lymphatics. Two sub-populations of afferent lymph DC (ALDC) were isolated based on differential expression of SIRPα as described in both cattle and rats, Ovine SIRPα+ ALDC constitutively express high levels of IL-1β, IL-18 and IL-10 mRNA. Conversely, SIRPα- ALDC does not express IL-10 but express high levels of IL-12p40. SIRPα+ ALDC may contain Langerhans’ cells since both ATPase and langerin were detected. Both subpopulations express Toll-like receptor 3 (TLR3) and TLR9, whereas SIRPα+ ALDC uniquely express TLR4 (+/- CD14). Vaccination with pGM-CSF resulted in increased cytokine production by ALDC subpopulations and upregulation of MHC class IIα, CD1b, CD40, CD86 and CD11c. These studies have extended the knowledge of GM-CSF and IL-3 as adjuvants and highlight the use of the cannulation model to further decipher the immune mechanisms of adjuvants. This work has demonstrated that GM-CSF not only recruits DC into skin but also activates DC, possibly as a result of increased expression of “danger signals” including IL-1β and TNF-α.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.657449  DOI: Not available
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