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Jelena M. Kezic, Michael P. Davey, Tibor T. Glant, James T. Rosenbaum, Holly L. Rosenzweig; The Exacerbation Of Uveitis In The Context Of IFN Deficiency in Proteoglycan-induced Arthritis is Prevented Through the Blockade of IL-17 and IL-23. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3396.
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Ankylosing spondylitis (AS) is the most common systemic disease associated with uveitis in North America and Europe. Prior data demonstrated exacerbated ocular inflammation with corresponding reduced axial and peripheral joint disease in the context of IFNγ deficiency in the murine model of AS, proteoglycan-induced arthritis (PGIA). Here we sought to determine the mediator of uveitis in the absence of IFNγ.
Female BALB/c IFNγ knockout (KO) mice also transgenic for the T cell receptor specific for a dominant epitope of aggrecan (GKO/TCR-Tg mice) were immunized with proteoglycan (PG) in dimethy-dioctadecyl ammonium bromide and pertussis toxin, in the presence or absence of IL-17, IL-23p19 (unique chain for IL-23) or IL23p40 (common chair for IL-12/23) neutralizing antibodies. Ocular inflammation was assessed at 3 weeks post-immunization by intravital microscopy and histology, with corresponding joint inflammation examined using an established clinical scoring system and histology. Splenocytes from GKO/TCR-Tg mice were stimulated with 20 µg/ml purified recombinant form of the G1 domain of aggrecan, and cytokines measured by multiplex ELISA 48h later.
Cytokine analysis of supernatants from cultured splenocytes revealed an increased production of IL-17 in the absence of IFNγ. Intravital microscopy and histological analysis of eyes from PG-immunized GKO/TCR-Tg mice that had also been treated with anti-IL-17 blocking antibody showed a marked reduction in rolling and adhering cells of the iris vasculature, and infiltrating cells of the iris tissue. Histological analysis confirmed intravital microscopy observations, but also revealed retinal phototoxicity to the anti-IL17 antibody treatment, in that the photoreceptors were frequently obliterated. Clinical arthritis scores and peripheral joint inflammation were reduced in mice treated with anti-IL17 antibody. A similar reduction in both ocular and peripheral joint inflammation was observed following the treatment with anti-IL23p19 and anti-IL23p40 antibodies. Some retinal phototoxicity was also observed with the use of anti-IL23 blocking antibody.
Our data reveal a critical role for Th17 responses in uveitis and arthritis in the absence of IFNγ. However, the retinal phototoxicity observed shows the need to proceed with caution prior to the use of anti-IL-17 in the treatment of certain ocular inflammatory diseases.
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