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Title: Restoring immune homeostasis in a mouse model of autoimmune arthritis
Author: Somenzi, Olivier
ISNI:       0000 0004 2707 5977
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Rheumatoid arthritis (RA) is a chronic inflammatory disorder with features of autoimmunity whose exact aetiology remains unknown although interactions between genetic factors, sex hormones and environmental factors are thought to play a role. Recent data support the view that RA is a disease characterised by aberrant adaptive immune responses, imposed in part via defective pathways of T cell activation. SKG mice carry a mutation in the protein tyrosine kinase ZAP-70, leading to attenuated TCR signalling and activation, and develop an autoimmune inflammatory arthritis resembling human RA, mediated by T cells. The hypothesis behind this project is that reconstitution of TCR signalling in mature, peripheral arthritogenic SKG T cells can restore immune homeostasis, which in turn suppresses the disease process. Firstly, it was demonstrated that naïve Balb/c and ZAP-70 mutant SKG CD4+ T cells expressing a TCR transgene differentiate into distinct subsets of effector Th cells following stimulation with specific antigen in the absence of a polarising cytokine environment. Significantly, SKG effector T cells are deficient in IL-2, IL-4 and IFN-γ production during differentiation and become IL-17 high-producers, when compared to wild type Balb/c T cells. The mechanism through which defective TCR signalling in SKG T cells favours the generation of arthritogenic IL-17 expressing T cells was then investigated, using two complimentary approaches. The first approach sought to establish virus-mediated gene transfer protocols to compare the effects of reconstituting SKG T cells with wild type or mutant ZAP-70 on the development of arthritis in a T cell-mediated adoptive transfer model. Despite trying both lentiviral and retroviral vector approaches, the efficiency of gene transduction into target murine primary T cells was insufficient for further in vitro functional analysis or for testing the arthritogenicity of transduced T cells in adoptive transfer experiments. Using a second approach, I tested the effects of reconstituting in vitro the defects in cytokine expression observed during differentiation of SKG T cells. Notably, supplementation of differentiating SKG T cells with exogenous recombinant IL-2 inhibited the differentiation to IL-17 producing T cells. This effect was associated with repression of induction of RORc, the master transcriptional regulator of IL-17 gene expression. The effects of IL-2 supplementation were also tested in vivo in the adoptive transfer model and found to have a suppressive effects on disease severity and incidence.
Supervisor: Cope, Andy ; Williams, Richard Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral