The role of antigen presentation in the induction of immune tolerance

Experimental Autoimmune Dveoretinitis (EAD), a CD4+ T cell-mediated retinaspecific disease, is a model for the sight-threatening human posterior uveitis. Dendritic cells (DC) are key regulators of immune responses. Mature DC are traditionally considered to be immunogenic due to their ability to directly activate naIve T cells, though there is accumulating evidence that mature DC can also be tolerogenic and induce antigen-specific regulatory T cells (Treg). Although many studies have demonstrated that systemic administration of DC can suppress the induction ofautoimmune disease, the mechanism ofthis disease suppression in vivo is largely undefined. Here in this thesis, we have examined the mechanism of disease suppression by the subcutaneous (s.c.) transfer oftolerogenic DCs. Tolerogenic DC were prepared by altemative activation of bone marrow derived DC using LPS. In Chapter 3 we have characterised the phenotype and function of differential LPS-activated mature DCs that secrete either the immunoregulatory cytokine 11-10 (ILIO-DC) or the pro-inflammatory cytokine IL-12 (1112-DC). In addition, we have identified their differential expression of TLR4/CDI4 and phosphorylation of the MAPkinase ERKI. The'in vivo tolerogenicity of IRBPpeptide- pulsed ILIO-DC (ILIO-DC+IRBP ) was examined in Chapter 4, where it was evident that the s.c. administration of 1110-DC+IRBP at the nape can significantly suppress the induction of IRBP-peptide-induced EAD at the inguinal, and this effect correlates strongly with an increase in the absolute number of CD4+CD25+Poxp3+ regulatory T cells as well as the cellularity ofthe DC-dLNs.EThOS - Electronic Theses Online ServiceGBUnited Kingdo