Immunomodulation of experimental autoimmune uveoretinitis (EAU) : a model of tolerance induction with retinal antigens
Idiopathic endogenous posterior uveitis encompasses a spectrum of chronic intraocular inflammatory disorders which are thought to be autoimmune in nature. The animal model experimental autoimmune uveoretinitis (EAU) is mediated by CD4+ T-lymphocytes, and has proved invaluable in the study of the underlying immunopathogenesis of uveitis and alternative immunosuppressive therapies, for example, oral tolerance induction. This thesis describes, in a model of retinal-extract induced EAU, the effects of intranasal administration of retinal antigens prior to induction of EAU with retinal extract. The thesis has demonstrated that immunisation with emulsified retinal extract and CFA (without pertussis) induces a dose-dependent intraocular inflammation, which at high doses leads ultimately to total loss of rod photoreceptor outer segments and retinal necrosis. A course of intranasal inoculations with retinal extract (tolerance induction), prior to immunisation with antigen suppresses the histological and clinical response of EAU. Animals which were tolerised with microgram quantities of antigen showed evidence of mild inflammation of the ciliary body and inner retinal vessels (vasculitis) but no evidence of direct photoreceptor damage when compared to controls. Intranasal inoculation with retinal extract suppressed S-Ag-induced EAU but not vice versa, despite the ability of S-Ag intranasal inoculations to suppress S-Ag induced disease. Tolerised animals demonstrated normal antibody responses to S-Ag, IRBP and retinal extract, and exhibited a significantly suppressed delayed hypersensitivity response to retinal extract but normal response to a non-specific antigen, PPD. Adoptive transfer of splenocytes from tolerised animals suppressed the induction of EAU in some naive recipients. These findings suggest that active suppressor mechanisms are involved in the induction of tolerance, which concurs with other findings of CD8+ T-lymphocyte mediated suppression in oral tolerance models. In order to study the future application of 'tolerance therapy', we attempted to suppress sensitised animals by intranasal tolerance which resulted in an incomplete suppression of EAU.