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Title: The effects of exogenous and endogenous ligands of the aryl hydrocarbon receptor on the activation of autoimmune diabetes
Author: Abu-Rizq, Hana'A.
ISNI:       0000 0004 2719 6250
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2012
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The aryl-hydrocarbon receptor (AhR) is an important receptor found in immune cells. It functions as a detector of environmental toxins, naturally occurring dietary products, and endogenous tryptophan derivatives for induction of gene transcription responses. Previous reports have implicated stimulation of AhR by various ligands in promoting T cell activation or regulatory function, with effects on autoimmune disease models. Also, effects of Ah toxins or natural products on increasing or suppressing inflammation and innate cytokine production, and dendritic cell function, have been reported. Different AhR-ligands could help in the development of either regulatory or pro-inflammatory T cells and consequently affect autoimmunity. In the present study, the effects of specific AhR-ligands on CD4 T cells, BMDC and CD8 T cells were investigated. Their effects were also tested for the first time on the induction of autoimmune diabetes using two different mouse models. Co-injection of the AhR-ligands curcumin, quercetin, or the ligand precursor tryptophan with sub-diabetogenic multiple low dose streptozotocin (MLD-STZ), increased the incidence of hyper-glycemia in C57Bl/6J mice. Furthermore, these ligands were able to significantly increase the development of Th17 and Th1 subsets and suppress Treg cells, in vivo and in vitro. In contrast, other ligands, including FICZ and I3C, decreased the incidence of diabetes in the MLD-STZ mouse model, in addition to their ability to increase the development of Th17, Th1 and Treg subsets, in vivo and in vitro. We found that injecting gp130fl/flCD4-Cre+ mice, which are characterized by enhanced production of Treg and reduced Th17 cell development, with MLD-STZ failed to cause hyper-glycemia, suggesting that the IL-6-receptor pathway controlling the Th17/Treg cell balance is important for diabetes induced by MLD-STZ. The effect of tryptophan, curcumin or quercetin was also tested for the first time using the RIP-LCMV-GP / P14 TCR transgenic diabetes model. We find that co-injection of these ligands together with immunisation with mature bone marrow-derived dendritic cells (BMDC) carrying self-antigen increased the incidence of diabetes in RIP-GP/P14 TCR transgenic mice. Also, these AhR-ligands were able to significantly increase Tc17 and Tc1 cell subsets, in vitro and in vivo. Furthermore, these ligands were able to increase the secretion of both pro-inflammatory, anti-inflammatory cytokines, and the expression of IDO by BMDC. FICZ and I3C, however, increased the expression of IDO and the anti-inflammatory cytokines TGF-β and IL-10. An immuno-suppressive function of FICZ and I3C was confirmed by co-injection of these AhR-ligands together with immunisation with mature BMDC carrying self-antigen, which resulted in a decrease in the incidence of diabetes in RIP-GP/P14 TCR transgenic mice. Suppression of diabetes was associated with increased development of IL-10+ CD8+ T cells, in vitro, while having no significant effect on either Tc1 or Tc17 subsets. It is concluded from this study that, the AhR-ligands FICZ and I3C could be attractive compounds to be used as therapeutics for diabetes and other autoimmune diseases, due to their ability to increase regulatory T cells (Treg and IL-10+ CD8+ ) subsets and enhance the secretion of anti-inflammatory cytokines and IDO expression by BMDC. However, activation of the AhR pathway by other AhR-ligands is associated with increased Th1/Tc1 and Th17/Tc17 responses, which could worsen autoimmunity.
Supervisor: Millar, Douglas; Else, Kathryn Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available