Type 1 diabetes (T1D) is an autoimmune disease, resulting from the specific destruction of the insulin‐producing beta‐cells in the islets of the pancreas. Islet‐specific autoreactive T cells are instrumental in this process and although these cells are present in individuals with and without T1D, their exhibition of a memory phenotype in diabetic individuals indicates they may have been previously activated in these patients. This suggests a breakdown in peripheral tolerance, implying regulatory T cells (Tregs) may be involved. Indeed, CD4+ CD25hi FOXP3+ Tregs do not differ in frequency in T1D, but their function is impeded. This defect is present in both recentonset type‐1 diabetics (ROT1D) and long‐standing type 1 diabetics (LST1D) suggesting it is a stable phenotype, possibly under genetic control. Also, it is known that the production and signalling of interleukin‐2 (IL‐2); a cytokine essential for the maintenance of Tregs, is defective in T1D. The aim of this thesis was to ascertain whether defective Treg function in T1D is genetically determined or a consequence of the disease. The first section of this thesis examined the effect of a T1D‐associated IL2RA single nucleotide polymorphism (SNP) on Treg function, by means of a genotype‐immunophenotype study. Non‐diabetic donors homozygous for the susceptible allele at this SNP exhibited diminished Treg fitness and suppressive action, suggesting that defective Treg function is a contributing factor in T1D. The latter section utilised T1D‐discordant monozygotic twins and healthy controls to examine Treg function and the IL‐2‐dependent generation of regulatory type 1 (Tr1) cells. Due to the low number of twins obtained nothing conclusive can be drawn from the study on Treg function. However, the results from the Tr1 generation assay suggest the possible existence of an IL‐2 signalling defect in non‐diabetic twins.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:634148 |
| Date | January 2013 |
| Creators | Tyler, Jennie |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/defective-regulatory-t-cell-function-in-type-1-diabetes(e3b3ac01-273b-4014-8a17-af5b6d0e21c6).html |
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