Akhtar, N.; (2007) Cytokine profiles and immunomodulation of T cells in immune-mediated ocular diseases. Doctoral thesis , University of London.

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Abstract

Thyroid associated ophthalmopathy (TAO) and chronic allergic eye disease (CAED) both can be classified as immune deviated eye diseases. Both diseases affect the eye, are associated with a localised CD4+ T cell infiltration, chronic inflammation and a high risk of visual impairment. Localised T cell lines had previously been characterised as Thl-Uke in TAO and Th2-like in VKC using ELISA and RT-PCR However, using these techniques peripheral blood-derived T cell lines did not show any bias. This study has sought to establish whether using intracellular cytokine staining, a more sensitive method of single cell cytokine analysis, of TAO and CAED peripheral blood T cell lines revealed any skewing of cytokine profiles. At the same time this technique allows the analysis of cytokine expression from both CD4+ and CD8+ T cells to be investigated. Using peripheral blood T cell lines, stained intracellularly for Thl and Th2 cytokines, a skewing of cytokine profiles towards Thl in TAO and Th2 in CAED was observed, suggesting that the blood-derived T cells might reflect the localised immune cell processes occurring during disease. Because of the cytokine profiles observed in vivo cytokine immunotherapy for patients suffering from ocular inflammatory conditions (TAO, CAED) might be of benefit. Hence the latter part of these Ph.D. studies has focussed on strategies to modulate cytokine expression in vitro. Current therapy for chronic inflammatory disease relies predominantly on corticosteroids and cyclosporin A (CsA). The effect of dexamethasone on cytokine profiles has been investigated in this study as well as CsA, both having suppressive actions on T cells. Other approaches that may have potential in inflammatory conditions have also been investigated. Firstly the effects of the application of exogenous cytokines along with blocking cytokines have been studied. An alternative approach that may be adopted to alter cytokine profiles in inflammatory conditions could be by targeting molecules involved in the signalling pathways for pro inflammatory cytokines. NFkB is known to be involved in the signalling pathway for the generation of several pro-inflammatory cytokines. In this study the consequences of blockading NFkB in T cells has been investigated. Work towards this thesis has involved the study of T cell cytokine profiles in CD4+ T cell mediated inflammatory diseases affecting the eye in vitro. Hopefully, this data will be helpful in understanding the basic mechanisms involved and contribute to the future design of immunotherapeutic interventions.

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