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Title: Spontaneous model of experimental autoimmune uveoretinitis : IRBP-HEL transgenic mice
Author: Makinen, Kimmo
ISNI:       0000 0001 3617 203X
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2006
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To generate a spontaneous EAU model, transgenic mice expressing membrane-bound hen egg lysozyme (HEL) under control of the IRBP promoter were generated. The mice expressed HEL in the photoreceptors, and in the thymus as measured by immunofluorescent confocal microscopy and real-time RT-PCR, respectively. When crossed with the 3A9 TCR-transgenic mice whose CD4+ T cells are HEL-specific, double-transgenic mice developed spontaneous EAU with 100% incidence and an onset age of 22 days post-partum. The ocular inflammation was multifocal and affected the posterior segment of the eye, and led to complete retinal destruction over 5-8 weeks. The lesions comprised multiple retinal granulomas, vasculitis, perivasculitis, mild vitritis and infiltration at the limbus (junction between cornea and sclera). The retina contained numerous CD4+T cells, which made contact with perivascular MHC II+CD11c+ dendritic cells, whilst F4/80 + macrophages were found within the photoreceptor cell layer, implicating them in structural damage. Therefore, the features of spontaneous EAU resembled those of IRBP-induced EAU. One difference, however, was that there were many CD3+CD4-gammadelta-like T cell cells in the inflamed retina, which were also the earliest T cells to enter the eye at EAU onset. CD4SP thymocytes were severely deleted in the double-tg mice, leading to peripheral CD4+ T cell deficiency at EAU onset, which bestowed a CD44hi pseudomemory phenotype on clonotype low CD4+T cells, and may have enabled breakdown of tolerance. The early activation marker CD69 was not upregulated on CD4+ T cells in any of the secondary lymphoid tissues studied, suggesting that HEL presentation may have been exclusive to the eye. The IRBP-HEL mice also constitute a new EAU model system in which self-tolerance and the efficacy of therapeutics can be studied.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available