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Title: The immunoregulatory effects of interferon alpha 2b in ocular Behçet's disease
Author: Nouraeinejad, A.
Awarding Body: University College London
Current Institution: University College London (University of London)
Date of Award: 2012
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Behçet's disease (BD) is a multisystem inflammatory disorder, which can affect many organs in the body including the eye. In spite of treatment with immunosuppressive drugs, the visual prognosis of ocular BD is still poor. Immunosuppressive drugs also have potential side effects, especially in the eye, where they can raise intraocular pressure, leading to glaucoma and cataract formation. Recently, effects of interferon-alpha (IFN-α) have been investigated and in a number of open studies and case reports the efficacy of IFN-α for severe ocular BD has been demonstrated. In an ongoing, randomized, multi-centre clinical trial, patients with ocular BD, receiving treatment with steroids and/or second line immunosuppressive agents, were recruited at Moorfields Eye Hospital. For the IFN-α treatment group, once weekly pegylated IFN-α2b (Schering-Plough) was given for 6 months while the anti-inflammatory effects of IFN-α were investigated. T cell subsets, intracellular cytokine profiles in regulatory T cells, and antigen responsiveness using a panel of disease-related antigens were assessed ex vivo in two groups at different time points. The aim of this study was to investigate the immune mechanisms underlying IFN-α immunotherapy. An upregulation of Foxp3, IL-10, and TGF-β on ex vivo peripheral blood T cells in IFN-α treatment group was observed as well as a decline in CD4+ T cells and γδ T cells. Therefore, IFN-α may be involved in immunological tolerance through the induction of regulatory T cells to differentiate between self and non-self antigens in order to prevent autoimmunity. Also an inhibition in proliferative responses to most of the antigens except PDSAg was seen in patients under standard treatment while this suppressive effect was only significant for alpha-tropomyosin and HSP in patients under IFN-α therapy. This may indicate overall suppressive effects of immunosuppressants in patients under this treatment while showing specific suppressive effects of IFN-α in patients under IFN-α therapy. Furthermore, IFN-α therapy resulted in normalization of responses to the examined antigens. Studies also focused on the effects of IFN-α on T cell function in vitro, investigating proliferation, T cell survival, intracellular cytokine profiles, and cytokine production using flow cytometry. Results suggested preferential stimulatory effects of IFN-α on activated CD8+ T cells, inhibition in activated CD4+ T cells, and anti-apoptotic effects on T cell subsets which were dependent on the activation state of the T cells. IFN-α also upregulated IFN-γ and IL-10 production whereas it downregulated IL-5, IL-1β, TNF-α, and TNF-β production. By studying intracellular cytokine expression, the effects of IFN-α were mainly an upregulation of IFN-γ, CD69, and IL-10 and a downregulation of TNF-α. These data may explain how IFN-α downregulates activated CD4+ T cells in vivo and in vitro, suggesting immunoregulatory mechanisms of IFN-α on T cell functions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available