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Title: Mechanisms of IL-10 transcriptional regulation
Author: Ng, Tien Haeng Sky
ISNI:       0000 0004 5994 9093
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2015
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Previous work has shown that subcutaneous (s.c) specific immunotherapy (SIT) using the myelin protein peptide MBP Acl-9 [4Y] induces protection against EAE in the TCR transgenic Tg4 mice. Repeated administration of MBP Ac1-9 [4Y] was found to induce IL-1O expressing TH1 like cells which were termed IL-l0 Tregs. To further the understanding of how IL-1O transcription is regulated, the expression of IFN-y, IL-4, IL-1O, c-Maf, NFIL3 protein and mRNA, Gata3 mRNA and epigenetic modifications at the Il10 promoter were characterised for each dose of s.c MBP Ac 1-9 [4 Y] administration. The analysis revealed that c-Maf and NFIL3 positively correlated with Il-IO expression, whilst levels of H3K27me3 at the Il10 promoter, an epigenetic mark associated with transcriptional repression, correlated inversely with IL-IO expression. To investigate the therapeutic potential of non-antigen specific immunoregulatory small molecules, GSK3 inhibitors were co-cultured with murine TH1, TH2 and human memory T cells. The analysis shows that GSK3 inhibitors also induce IL-10 expression via transcriptional mechanisms in both murine Th cells and human memory T cells. Similar to IL-l0 Tregs, murine TH1 GSK3 inhibitor treated cells expressed higher levels of NFIL3 and c-Maf whilst murine TH2 GSK3 inhibitor treated cells expressed higher levels of NFIL3 only. In contrast to IL-10 Tregs both THI and TH2 cells expressed higher levels of Gata3 in response to GSK3 inhibitor treatment. In addition, epigenetic changes also take place in the Il10 promoter of GSK3 inhibitor treated murine TH1 and human memory T cells. Collectively these results show that it is possible to alter epigenetic modifications and induce IL-1O expression in murine TH1 and TH1-like cells with in vivo and in vitro methods. Furthermore, we propose combining the antigen specific s.c SIT with GSK3 inhibitors to improve the efficacy and safety of both treatments.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available