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The study of experimental autoimmune uveoretinitis (EAU) induction in mice

Hankey, Deborah Jayne Rachel; (1999) The study of experimental autoimmune uveoretinitis (EAU) induction in mice. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

This study has demonstrated that a highly reproducible model of experimental autoimmune uveoretinitis (EAU) can be achieved in the BIO.RIII mice using a human interphotoreceptor retinoid binding protein peptide corresponding to amino acid residues 161-180. Using a histological grading system which graded both cellular and structural scores individually, the time course of disease in this model was examined and found to be predictable and consistent. Disease was acute in nature characterised by rapid onset of a massive inflammatory response which resulted in extensive damage to the rod outer segments and neuronal layers of the retina. Treatment with potent immunosuppressive agents, CD4 monoclonal resulted in the inhibition of disease and a reduction in disease incidence. In addition, treatment with p55-tumor necrosis factor receptor-Ig (p55-TNFR-Ig) fusion protein reduced structural damage to the retina despite a high level of cellular infiltration in the eye. This suggests that target organ damage in an acute model of EAU can be modulated. However, the value of the B10.RIII human IRBP161-180 induced model maybe of limited value in the study of immunosuppressive agents. The albino Biozzi ABHdql mice are susceptible to experimental allergic encephalomyelitis (EAE), however their susceptibility to EAU induction was unknown. Initial, studies demonstrated that ABH mice were susceptible to EAU induction with native bovine interphotoreceptor retinoid binding protein (IRBP), but not S-Antigen (S-Ag). The uveitogenic domain of interphotoreceptor retinoid binding protein was then identified for this mouse strain using recombinant domains of human IRBP expressed from an Escherichia coli expression system. Following sensitisation with the individual domains of IRBP, ABH mice were found to be susceptible to disease induction with IRBP domain 2. The mice developed disease with high incidence and moderate disease scores. Examination of the disease course over a six week period indicated that disease was of a chronic progressive nature. However, in this model although an inflammatory insult had occurred in the eye the resulting level of retinal destruction less severe than that seen in the B10.RIII IRBP161-180 induced model of EAU and an intact retina still remained at six weeks post-immunisation. Using synthetic overlapping peptides corresponding IRBP domain 2, a uveitogenic and immunogenic epitope was identified. The uveitogenic epitope corresponded to human IRBP511-530 and incidence disease with high incidence and mild disease scores. Further immunogenic epitopes residing in IRBP domain 2 were identified which may be involved in the amplification of disease in the ABH mice. IRBP511-530 also contains some characteristics which have been identified to be involved in the H-2Ag7 binding motif. However, further analysis of the amino acid residues is required to determine the important residues. This study also examined EAU in (ABH X BIO.RIII) FI mice and showed that these mice are susceptible to disease induction with retinal antigens which are positive in both B10.RIII and ABH mice. Furthermore, (ABH X BiO.RIII) FI mice are susceptible to a novel antigen, corresponding to IRBP domain 3, which is not uveitogenic in either the ABH or B10.RIII mice. The (ABH X B10.RIII) FI mice may provide a useful system for studying the effects of B10. background genes and bystander suppression studies.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The study of experimental autoimmune uveoretinitis (EAU) induction in mice
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Uveoretinitis
URI: https://discovery.ucl.ac.uk/id/eprint/10120567
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