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A.D. Dick, D.A. Copland, J. Phillips, H. Cherwinski, M. Jenmalm, J.D. Sedgwick, L.B. Nicholson, C.J. Calder; Control of Macrophage Activation via Myeloid CD200R Signaling During Experimental Autoimmune Uveoretinitis . Invest. Ophthalmol. Vis. Sci. 2005;46(13):971.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Control of myeloid activation occurs via inhibitory signals through CD200receptor expressed on myeloid cells. We wished to determine whether in absence of or by induced CD200R signalling by DX109 agonist mAb, modulation of macrophage activation and/or severity of Experimental Autoimmune Uveoretinitis (EAU) was observed. Methods: EAU was induced in CD200–/– and WT (C57BL/6) mice following immunisation with IRBP1–20. For therapeutic interventional studies, B10.RIII mice were immunised with IRBP161–180, and at time points indicated received i.v. injections of DX109 mAb. At different time–points eyes were enucleated and spleens dissected for histological disease score and functional assessment, respectively. For macrophage activation studies, bone–marrow derived–macrophages (BM–MΦ) were generated in Teflon bags containing M–CSF media and stimulated in vitro with TGFß , TNFα and/or IFNγ . Results: As previously reported we again showed in CD200–/– mice, earlier disease onset, with histologically increased structural damage concomitant with increased numbers of macrophages infiltrating the retina. Whilst microglial–derived nitrite production was constitutively greater in CD200–/– mice, TGFß–mediated suppression of nitrite was not seen in CD200–/– tissue–derived macrophages (spleen and retina). CD200R signalling was induced via an agonist binding mAb, DX109. Incubation of macrophages with DX109 abolished IFNγ stimulated TNFα and IL–6 production, but not nitrite secretion. In vivo, the efficacy of systemic treatment of EAU in B10.RIII mice with DX109 was unpredictable but suppression of histological disease was observed compared with mice treated with an isotype control. Conclusions: DX109, an agonist antibody targeted at the CD200R prevented full expression of classical IFNγ –induced macrophage activation. The inconclusive suppression of EAU may suggest that local tissue penetration of mAb is required to generate a significant therapeutic effect.
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