Initiation and regulation of experimental autoimmune uveoretinitis

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Non-infectious uveitis is an autoimmune disease characterised by infiltrating leukocytes such as T cells due to loss of immune tolerance to retinal proteins. Experimental autoimmune uveitis (EAU) is an animal model of non-infectious uveitis that shares many features with human disease and can be induced in mice by the transfer of autoantigen specific lymphocytes. The purpose of this thesis was to look at leukocyte trafficking specifically CD4+ T cells during initiation of clinical disease and throughout active clinical disease.
The data presented uses an adoptive transfer to induce clinical disease. This was developed to study antigen specific and non-antigen specific recruitment during EAU. This robust technique also allows investigation into the role of specific chemokine and cytokine receptors during EAU by using knockout mice.
The results demonstrate that antigen specific CD4+ T cells that initiate disease or their progeny persist within the tissue during active clinical disease and after active clinical disease has subsided. At day 2 after transfer, increased recruitment of endogenous CD4+ T cells and retention of transferred CD4+ T cells was observed, this was further investigated using non antigen specific cell transfers using ovalbumin specific CD4+ T cells which showed that the pathogenic stimulus needed to be present locally to initiate clinical disease in recipients. Further to this ovalbumin specific cells are recruited to the eye if the antigen is introduced to the ocular tissue or if a pathogenic stimulus is present. Using the adoptive transfer technique further analysis using chemokine knockout mice showed that during active clinical disease CX3CR1 is expressed on CD4+ T cells which are selectively retained within the eye. Using cytokine receptor knockout mice IL-27Rα-/- cells were found to be more potent in nature to drive a more persistent and severe disease phenotype.
Date of Award28 Sep 2021
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorLindsay B Nicholson (Supervisor) & Andrew David Dick (Supervisor)

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