Investigators and Projects
Experimental autoimmune uveoretinitis (EAU) is an animal model of disease that correlates well with the spectrum of clinico-pathological features of human uveitides and, as a result, is a successful preclinical model for translation of immunotherapy. Furthermore, the model serves to dissect immuno-pathogenic mechanisms relating to immune-mediated tissue damage, studies that illuminate avenues for future treatment. Murine EAU arises following immunization with specific ocular antigens and the local activation of ocular-specific CD4+ T cells, within or around photoreceptor segments. Disease occurs subsequent to activated T cell infiltration into the target organ, with consequent recruitment and activation of macrophages, generating structural damage via mechanisms that include the IFNgamma induced secretion of nitric oxide (NO).
Macrophage responses are regulated by multiple secreted factors as well as by cell surface receptors including inhibitory signals resulting from ligation of myeloid CD200 receptors (CD200R) by CD200, a ligand that is widely distributed on both neuronal and endothelial cells in the retina. The ability to target inhibitory receptors is emerging as an effective mechanism to switch-off antigen non-specific effector cells during inflammatory disease. This is highlighted by the fact that in the absence of the CD200 negative signal, animals display increased susceptibility to autoimmunity and earlier onset aggressive autoimmune disease. One experimental approach that has proved successful in the treatment of disease is the use of DX109, an agonist monoclonal antibody (mAb), which is specific for the inhibitory CD200R. When DX109 binds to the receptor, it delivers a negative signal mimicking the normal effect of CD200. In vitro experiments demonstrate that classical, IFNgamma mediated NO and IL-6 production by macrophages can be suppressed upon CD200R engagement. In vivo studies have shown that systemic administration of DX109 suppresses EAU despite maintained T cell proliferation and IFNgamma production. Furthermore, delivery of DX109 directly into the eye also suppresses inflammation as well as promoting earlier resolution of disease. These experiments demonstrate that promoting CD200R-mediated signalling can successfully prevent full expression of IFNgamma mediated macrophage activation and protect against tissue damage during autoimmune responses. Work is now focussed on testing the efficacy of local administration as well as alternative delivery vehicles to facilitate long term mAb treatment strategies.g may also have a potential role in angiogenesis, and its role in retinal neovascularisation, as observed in late stage EAU or CNV models is of great interest. Exactly how CD200 signalling regulates neovascularisation, presumably through the involvement of macrophage/myeloid cells within eye, remains to be determined and is the current focus for investigation.
Copland, D.A., Calder, C.J., Raveney, B.J.E., Nicholson, L.B., Phillips, J., Cherwinski, H., Jenmalm, M., Sedgwick, J.D., and Dick, A.D. (2007) Monoclonal antibody-mediated CD200 receptor signalling suppresses macrophage activation and tissue damage in experimental autoimmune uveoretinitis. Am. J. Pathol. 171: 580-588.