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Title: Immunomodulation by Schistosoma mansoni antigens in non obese diabetic mice
Author: Burton, O.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
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The non obese diabetic (NOD) mouse is an animal model of type 1 diabetes. Certain infectious pathogens, including the parasitic worm Schistosoma mansoni can modify the immune system such that it no longer causes diabetes. This dissertation explores the phenotypic changes to the immune system that occur following treatment of NOD mice with preparations derived from S. mansoni eggs (SEA) or worms (SWA). SEA and SWA treatments drove T helper (Th) 2 responses and alternatives activation of macrophages in NOD mice. Protection from diabetes onset by SEA was associated with expansion of Foxp3-expressing regulatory T cells (Tregs) in the pancreas and depletion of CD25+ cells suggested that these Tregs were required to regulate diabetogenic T cells in an adoptive transfer. In vitro investigations into the mechanism of Foxp3+ T cell induction suggested that although SEA induces a tolerogenic phenotype in dendritic cells, which often initiate immune responses, actions of SEA on T cells were at least as important. SEA directly activated and enhanced T cell secretion of transforming growth factor-beta (TGFβ), and this cytokine was required for induction of Foxp3 expression in vitro. Furthermore, in the absence of Toll-like receptor (TLR) 2 on T cells, SEA was unable to induce Foxp3+ T cells. The ability of a single protein from S. mansoni eggs, namely Omega-1, to modulate immune responses in NOD mice is explored. As with SEA, Omega-1 proved capable of driving both Th2 and Foxp3+ T cell responses in vitro and in vivo. Foxp3 induction by Omega-1 and SEA in vitro required TGFβ and retinoic acid (RA). Stimulation of dendritic cells with either SEA or Omega-1 in combination with lipopolysaccharide enhanced secretion of TGFβ and the expression of an enzyme that synthesizes RA.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available