Use this URL to cite or link to this record in EThOS:
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
Availability of Full Text:
Full text unavailable from EThOS.
Please contact the current institution’s library for further details.
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:  DOI: Not available