title: Local targeting of the CD200-CD200R axis does not promote corneal graft survival.
abstract: Corneal graft rejection is primarily a CD4(+) T cell-mediated mechanism in which macrophages may play an important inflammatory role. CD200Fc fusion protein is an artificial agonist of CD200R1, a receptor expressed predominantly on myeloid cells, engagement of which is known to down-regulate macrophage function. We therefore wished to test whether CD200Fc could be used as a therapeutic agent to prolong corneal graft survival. The distribution of CD200R1 and CD200, its natural ligand, was examined by immunohistology in the cornea and conjunctiva of unoperated rats and rats that had received corneal allografts. Mouse CD200Fc was injected subconjunctivally into transplanted rats on six occasions from the day of surgery until day 10 after transplantation. Control groups received injections of mouse IgG or diluent PBS. Allo-transplants were also performed in CD200(-/-) and control mice. The ability of CD200Fc to bind rat macrophages in vitro and to inhibit nitric oxide production was tested. Mean day of rejection in CD200Fc, IgG and PBS-treated rats was 12, 10 and 9 respectively (p=0.24). Mean day of rejection in CD200(-/-) and wild type mice was 17.5 and 16.0 respectively (p=0.07). Mouse CD200Fc bound to rat macrophages in a dose-dependent manner, but was unable to inhibit nitric oxide production. The fact that treatment with CD200Fc did not inhibit graft rejection and the failure of CD200 deficiency to affect graft survival suggests that local targeting of the CD200-CD200R axis to suppress macrophage activation is not a useful therapeutic strategy in corneal graft rejection.
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, BS8 1TD, UK. Electronic address: s.m.nicholls@bris.ac.uk.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Nicholls
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, BS8 1TD, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Copland
authors.affiliation: Section of Immunity, Infection and Inflammation (Ocular Immunology), Division of Applied Medicine, School of Medicine and Dentistry, Institute of Medical Sciences, Foresterhill, University of Aberdeen, AB25 2ZD, Scotland, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vitova
authors.affiliation: Section of Immunity, Infection and Inflammation (Ocular Immunology), Division of Applied Medicine, School of Medicine and Dentistry, Institute of Medical Sciences, Foresterhill, University of Aberdeen, AB25 2ZD, Scotland, UK.
authors.forename: Lucia
authors.initials: L
authors.lastname: Kuffova
authors.affiliation: Section of Immunity, Infection and Inflammation (Ocular Immunology), Division of Applied Medicine, School of Medicine and Dentistry, Institute of Medical Sciences, Foresterhill, University of Aberdeen, AB25 2ZD, Scotland, UK; Ocular Immunology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Western Australia, 6009, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, 6009, Australia.
authors.forename: John V
authors.initials: JV
authors.lastname: Forrester
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, BS8 1TD, UK; School of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, UK; National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, EC1V 2PD, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Dick
mesh_terms: D064591:Allografts; D000818:Animals; D000867:Anterior Chamber / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism*; D003228:Conjunctiva / Q000378:metabolism; D003315:Cornea / Q000378:metabolism*; D016039:Corneal Transplantation; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D056965:Injections, Intraocular; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D064446:Orexin Receptors / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D011971:Receptors, Immunologic / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms
chemical_list: D015703:Antigens, CD; C529001:CD200-FC, mouse; C495490:Cd200 protein, rat; C501103:Cd200r1 protein, mouse; D007074:Immunoglobulin G; D064446:Orexin Receptors; D011971:Receptors, Immunologic; D009569:Nitric Oxide; C042739:antigens, CD200
keywords: CD200; Corneal transplantation; Graft rejection; Immunotherapy; Macrophage; Mouse; Rat