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Title: Intranasal tolerance induction in experimental autoimmune uveoretinitis (EAU) : effector mechanisms and therapeutic implications
Author: Laliotou, Barbara
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1999
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Experimental Autoimmune Uveoretinitis (EAU) is an organ-specific CD4+ T cell mediated autoimmune disease which is used as an investigatory model of immunotherapy as the model parallels well the immunopathological features of uveitis in humans. Soluble antigen (S-Ag) and interphotoreceptor retinoid binding protein (IRBP) are two major autoantigens within soluble retinal extract (RE). It was demonstrated that S-Ag and IRBP are the main contributors to the tolerogenicity within RE, despite the known uveitogenicity of other retinal antigens within RE. Furthermore, suppression induced by single antigen administration is antigen specific although concomitant bystander suppression may also play a role. Intranasal administration of retinal antigens induces tolerance and suppresses target oran destruction in EAU although leukocytes still infiltrate the retina. Leukocytic infiltrate is not only reduced in number but also shows distinct phenotypic differences compared to controls, implying a reduced activation status of infiltrating monocytes, accompanied by an increase in IL-10mRNA expression in eyes of tolerised animals. The present data further shows that splenocytes or fractionated splenic T cells and not regional drainage lymph node cells transfer tolerance to naive animals. Analysis of apparent mechanistic differences show that during intranasal antigen administration, the proportion of CD4+ T cells within drainage lymph nodes increases, concurrent with a burst of IFN-. Following subsequent antigen challenge, T cells downregulate TCR expression and undergo apoptosis in regional drainage lymph nodes. Therefore, spleen derived regulatory cells which suppress Th1 responses and deletion/apoptosis are mechanisms which co-exist in low dose tolerance in rats. Th2 activity after immunisation is not antigen-specific and appears consequential to tolerance induced Th1 suppression. Proposals of interdependent mechanisms are discussed. Finally, the effect of nasal antigen administration in sensitised CsA-treated animals is investigated, in which it is shown that suppression of target damage occurs, despite an intraocular inflammatory infiltrate. Results and mechanisms are discussed with respect to possible therapeutic applications.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available