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D. A. Copland, S. M. Nicholls, A. Vitova, L. Kuffova, J. V. Forrester, A. D. Dick; Modulation of CD200-CD200R Signalling Does Not Alter Corneal Graft Survival. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1551.
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To further interrogate the role of macrophages in allograft rejection by investigating whether perturbation of the inhibitory interaction between CD200 and its receptor (CD200R) on macrophages by i) local agonist treatment or ii) CD200 depletion, respectively suppresses or accelerates corneal graft rejection. Depletion of macrophages prolongs corneal grafts survival in rats. Therefore selective treatments to down-regulate macrophage function may have clinical benefit.
The phenotype of cells expressing CD200 and CD200R in the anterior segments of normal PVG and LEW strain rat eyes and rejected LEW to PVG grafts was determined by immuno-peroxidase and immuno-fluorescence histology. Further graft recipients were treated with the CD200R agonist, CD200-Fc: groups of rats (n=6 per group) were each injected with 20µg CD200-Fc in 10µl PBS in both upper and lower conjunctivae or with IgG2a control antibody or with PBS alone on the day of transplantation (day 0) and on alternate days until day 10. Survival of BALB/c strain mouse grafts in CD200-/- (n=12) and normal (n=10) C57BL/6 strain recipients was compared. Survival data were tested for normal distribution and analysed by ANOVA or student T-test, as appropriate.
CD200 was expressed on blood vessel endothelium in the conjunctiva and limbus of normal rats, as well as in stromal, conjunctival and iris neurons and CD200R was expressed on scattered CD163+ cells. During rejection some cells expressed CD200 and large numbers of macrophages expressed CD200R. However, treatment with CD200-Fc did not suppress rejection, median day to rejection being: CD200Fc group 11.5 (range 8-17 days), control IgG2a group 10.5 (range 6-13 days) and PBS group 9.5 (range 6-11 days) (p=0.24 by ANOVA). Graft rejection in CD200-/- mice, in which macrophages are constitutively activated, was not accelerated in comparison with wild type mice (median day to rejection 17.5 and 16 respectively, p=0.07 by T-test).
Despite widespread expression of CD200R on infiltrating macrophages, neither local CD200R agonist treatment nor genetic deficiency in CD200 altered the clinical course of corneal graft rejection. Targeting macrophages through the CD200R is unlikely to have clinical benefit in corneal graft rejection.
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