Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.665121
Title: Investigation and characterisation of T-Lymphocytes in chronic pancreatitis
Author: Jupp, James Aubrey
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2012
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Abstract:
It has been suggested that T-lymphocytes play a role in the pathogenesis of chronic pancreatitis (CP), but little is known about the composition of T-cell subsets in this disease. I therefore aimed to characterise T-lymphocytes and in particular T-helper (Th), T-regulatory (Treg) and mucosal-associated invariant T- (MAIT) lymphocytes in CP tissue and peripheral blood. I first developed a reproducible method to extract infiltrating mononuclear cells to allow their further examination. Mononuclear cells isolated from the pancreatic tissue and blood of patients with CP and controls were then examined using flow cytometry. Pancreatic tissue lymphocytes were also assessed using immunohistochemistry. The following results were obtained: Pancreatic tissue from patients with CP contained a significant infiltrate of CD3+ T-cells comprised of equal proportions of CD4+ and CD8+ cells. There was a proportional reduction in CD4+ T-cells in pancreatic tissue when it was compared to blood in CP patients, but no difference in CD8 or double negative (DN) T-cells was detected. The peripheral blood of CP patients trended towards a lower proportion of CD4+ and higher a proportion of CD8+ T-cells compared to controls, with an associated trend of a lower CD4:CD8 ratio. A trend towards a lower proportion of CD8+ Integrin α4β7+ cells was also noted suggesting their accumulation in inflamed pancreatic tissue. This work is the first to demonstrate a significant increase in the number of Th1, Th2, Th17 and Treg cells in the peripheral blood of CP patients compared to controls. Furthermore patients who consume excess alcohol have significantly more Th1 cells than non-drinkers. Pancreas infiltrating CD4+ T-helper cells are predominantly Th1 and Th17 cells, with few or no Th2 or Treg cells identified. MAIT cells were detected in CP but not normal pancreatic tissue and DN MAIT cells were found to be enriched in CP tissue compared to blood. Interestingly there is no polarisation of the peripheral blood T-helper cell response in CP towards either a Th1 or Th2 phenotype. It appears therefore that the blood of CP patients is primed to respond non-specifically to inflammatory stimuli. Intriguingly patients who consume excess alcohol have more peripheral blood Th1 cells. This may be explained by the fact that alcohol increases gut permeability causing high circulating levels of lipopolysaccharide which is known to generate Th1 cell responses. The identification of MAIT cells in CP tissue is novel and the enrichment of DN MAIT cells in the tissue of CP patients compared to blood suggests a specific role in local immune responses. These combined features support the notion that the pancreatic inflammatory T-cell infiltrate contributes to the pathogenesis of CP.
Supervisor: Gadola, Stephan D. Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.665121  DOI: Not available
Keywords: RC Internal medicine
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