Ward, E.M.; (2010) Novel fusion protein-expressing lentiviral vectors ameliorate collagen induced arthritis. Doctoral thesis , UCL (University College London).

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Abstract

Collagen induced arthritis (CIA) is a mouse model of autoimmunity that closely resembles human rheumatoid arthritis (RA), a debilitating disease with no cure. This study has been undertaken to generate antigen-specific tolerance to an autoantigen implicated in RA and immunodominant in animal models. Gene therapy protocols for RA that have gone to clinical trial have been designed to drive expression of therapeutic molecules at the site of inflammation, but not to modulate the immune response to key autoantigens. This study has shown that lentiviral vectors (lvv) expressing fusion proteins (FP-lvv) confer antigen-specific tolerance in CIA. Fusion proteins comprised of an endosomal-targeting domain coupled to the immunodominant CII259-273 peptide and an eGFP tag, were expressed in APCs. Confocal microscopy revealed substantial colocalisation with endosomes and lysosomes. Expression of the fusion proteins in APCs resulted in MHCII-presentation of the immunodominant CII259-273 peptide to CII259-273-reactive CD4+ T cell hybridomas. Furthermore, co-transduction with a lvv expressing the enzyme lysyl-hydroxylase 3 enhanced glycosylation of the expressed CII construct. Administering mice iv with FP-lvv one month prior to disease induction reduces by half the arthritic score during the first two weeks of clinical symptoms in CIA, providing partial but significant protection. The use of suitable controls showed that this effect is antigen-specific and measurements of α-CII IgG show a significantly lower titre in treated animals. This study provides evidence that lvv-mediated MHCII-presentation can be tolerogenic and hence, this approach could form an important part of future treatments for autoimmune diseases.

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