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Title: Lympho-epithelial cross talk in the gut : implications for maintaining and restoring immune homeostasis
Author: Gicheva, Nadezhda
ISNI:       0000 0004 5993 9266
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2015
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Intestinal immunological environment is shaped by a continuous cross-talk involving three major components: intestinal epithelium, immune system and local microbiota. This work intended to investigate the role of lympho-epithelial interactions in response to food components and microorganisms. As part of this work the role of the immune-derived cytokine interleukin (IL)-12 in development of food allergy has been investigated. It was previously found that in peanut-sensitized mice there was decreased level of IL-12 in the intestine. We have observed that this is accompanied with increase in thymic stromal lymphopoietin (TSLP), a cytokine produced by the intestinal epithelium and indispensable for development of allergy. Oral delivery of recombinant Lactococcus lactis secreting bioactive IL-12 resulted in amelioration of the allergic symptoms and decrease in TSLP, thus suggesting a regulatory interaction between these two cytokines. Further investigation of the mechanism of this cross-regulation revealed that intestinal epithelial cells express incomplete but functional IL-12 receptor. However, mice deficient in IL-12 signalling displayed normal levels of TSLP implying involvement of other factors in the IL-12/TSLP axis. In addition, the availability of mice defective in IL-12 associated pathways prompted us to test the hypothesis that alteration of the cytokine network in the gut may contribute to shape the intestinal microbiota. Thus, by using 16S pyrosequencing we have studied the composition of the gut microbiota in mice deficient for IL-12p40, IL-12Rβ2, and IFN-γ in comparison to WT mice. In parallel, we have monitored the metabolome of the microbiota and the host intestinal tissue. Finally, we have described a novel pathogen-exclusion mechanism mediated by CX3CR1+ cells that migrate into the intestinal lumen upon Salmonella infection. This event is orchestrated by a lympho-epithelial crosstalk involving MyD88-dependant epithelial signal. CX3CR1-dependant migration is vital for pathogen protection in the early stages of infection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available