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D. Copland, C. J. Calder, B. J. E. Raveney, J. Phillips, H. Cherwinski, M. Jenmalm, J. D. Sedgwick, L. B. Nicholson, A. D. Dick; CD200R Signalling Controls Macrophage Activation During Experimental Autoimmune Uveoretinitis. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5203.
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© ARVO (1962-2015); The Authors (2016-present)
To determine whether stimulating CD200 receptor (CD200R) signalling using an agonist mAb, DX109 can modulate macrophage activation and thus ameliorate the severity of Experimental Autoimmune Uveoretinitis (EAU).Background:Macrophage responses are regulated by stimulatory and inhibitory signalling delivered by secreted factors or cell surface receptors. It has been previously demonstrated that ligation of CD200R by the widely distributed CD200 molecule mediates inhibition of macrophage activation. The murine model of human inflammatory eye disease, EAU, is characterized by structural retinal damage mediated by infiltrating macrophages. CD200-/- mice display increased susceptibility to autoimmunity and earlier onset aggressive disease, suggesting a role for CD200R signalling in preventing autoimmunity.
EAU was induced in B10.RIII mice by immunization with hRBP-3161-180. At certain time-points, eyes were enucleated and spleens dissected for histological disease and functional assessment, respectively. As a therapeutic intervention, DX109 was systemically administered on day 10, 14 and 18 post-immunization. Efficacy of local treatment with DX109 was also assessed by intra-vitreal injection at day 10 and 14. To determine the mechanism of DX109 action, in vitro experiments were performed where bone marrow derived macrophages were treated with DX109 prior to activation.
Systemic administration of DX109 agonist CD200R mAb suppressed EAU, despite normal T cell proliferative responses. Local administration of DX109 during efferent phase of disease effectively suppressed disease. Pre-incubation of macrophages with DX109 resulted in suppression of in vitro activation as measured by nitric oxide and IL-6 production.
These experiments demonstrate that promoting CD200R signalling can successfully prevent full expression of IFNγ-mediated macrophage activation and protect against tissue damage during autoimmune responses in the retina.
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