Infection with the helminth parasite Schistosoma mansoni leads to chronic inflammation and Th2 mediated fibrosis, which result in severe pathology characterised by hepatosplenomegaly. Dendritic cells (DCs) are adept initiators of CD4+ T cell responses, but their fundamental importance in this regard in Th2 settings remains to be demonstrated. Indeed, the role of DCs at different stages of infection with S. mansoni is also yet to be determined. In addition, the importance of the interaction of DCs with tissue factors in the tissue microenvironment on the development of Th2 response to S. mansoni antigens is an area of active research and debate. This thesis is comprises of four studies. The first study tackles the involvement and importance of DCs in the induction and development of Th2 responses against S. mansoni using CD11c–diphtheria toxin receptor mice to deplete CD11c+ cells during the priming stage of the CD4+ Th2 response against S. mansoni. Diphtheria toxin treatment significantly depleted CD11c+ DCs from all tissues tested, with 70-80% efficacy. Even this incomplete depletion resulted in dramatically impaired CD4+ T cell production of Th2 cytokines, altering the balance of the immune response and causing a shift towards IFN-γ production. In contrast, basophil depletion using Mar-1 antibody had no measurable effect on Th2 induction in this system. These data underline the vital role that CD11c+ antigen presenting cells can play in orchestrating Th2 development against helminth infection in vivo, a response that is ordinarily balanced so as to prevent the potentially damaging production of inflammatory cytokines. The second study addresses whether the exposure of DCs to the cercarial stage of the parasite is critical for either parasite survival or the subsequent development of the Th2 immune response against later stages of infection. It was found that CD11c depletion prior to infection resulted in increased parasite survival, but did not impair the development of CD4+ T cell Th2 response later in infection. The third study asked whether DCs continue to be necessary for the maintenance of the chronic immune response during infection with S. mansoni. In contrast, depletion of CD11c+ cells during the initiation (4 to 6 weeks) or maintenance (6 to 8 weeks or 12 to 14 weeks) of Th2 response to eggs, resulted in severely impaired Th2 cytokine production. Interestingly, depletion during the later stages of infection led to dramatic weight loss and mortality, coincident with impaired CD4+ T cell responses. These data suggest that CD11c+ antigen presenting cells, in addition to being important in the early priming phase, also play a vital role in the maintenance and homeostasis of chronic CD4+ T cell responses in a Th2 infection setting, the disruption of which can have lethal consequences. The final study in this thesis aimed to establish whether the tissue factor thymic stromal lymphopoietin (TSLP) is able to enhance or modulate the Th2 responses initiated by DCs stimulated with SEA. Contrary to previous studies, it was found that BMDCs do not become phenotypically activated by TSLP, in particular, they do not up-regulate the costimulatory molecule OX40L, nor does TSLP suppress the production of IL-12p40 or IL-12p70 in response to LPS or CpG. Further, exposure to TSLP had no impact on DC cytokine production or survival. Irrespective of this unaltered profile in vitro, TSLP exposed DCs transferred in vivo induced the production of significantly more Th1 and Th2 cytokines from polyclonally restimulated splenocytes than DCs exposed to medium alone. In addition to this, TSLP altered the kinetic of the immune response induced by DCs stimulated with the soluble egg antigen (SEA) of S. mansoni. This was characterised by the antigen specific production of T cell cytokines starting more rapidly than with non-TSLP treated control DCs. The alteration in the kinetics of the immune response was not restricted to Th2 antigens and was also seen to some extent in Propionibacterium acnes stimulated DCs. This suggests a possible role for TSLP in either inducing faster DC migration or greater production of T cell chemoattractants and thus, enhancing the rate of DC interaction with T cells.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:563414 |
| Date | January 2011 |
| Creators | Phythian-Adams, Alexander Thomas Luke |
| Contributors | Adams, Alexander Thomas Luke Phythian. ; MacDonald, Andrew S. ; Maizels, Rick |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/5288 |
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