Monoclonal Antibody-Mediated CD200 Receptor Signaling Suppresses Macrophage Activation and Tissue Damage in Experimental Autoimmune Uveoretinitis

Division of Infection and Immunity, Department of Clinical Science at South Bristol, University of Bristol, Bristol, United Kingdom.
American Journal Of Pathology (Impact Factor: 4.59). 09/2007; 171(2):580-8. DOI: 10.2353/ajpath.2007.070272
Source: PubMed


Macrophage responses are regulated by multiple secreted factors as well as by cell surface receptors, including the inhibitory signals resulting from ligation of myeloid CD200 receptors (CD200R) by the widely distributed CD200. In the absence of CD200, animals display increased susceptibility to autoimmunity and earlier onset aggressive autoimmune disease. In these current experiments, an agonist monoclonal rat anti-mouse CD200R (DX109) antibody delivered a negative signal to bone marrow-derived macrophages, which suppressed interferon (IFN)gamma-mediated nitric oxide (NO) and interleukin-6 production. Experimental autoimmune uveoretinitis (EAU) was used as a model of organ-specific autoimmunity in the eye, a tissue with extensive neuronal and endothelial CD200 expression. In mice lacking CD200 (CD200(-/-)), increased numbers of retina-infiltrating macrophages displaying heightened NO responses were observed during EAU. In addition, we aimed to suppress disease by maintaining tonic suppression of macrophage activation via CD200R. Systemically administered DX109 monoclonal antibody suppressed EAU despite maintained T-cell proliferation and IFNgamma production. Furthermore, locally administered DX109 monoclonal antibody resulted in an earlier resolution of disease. These experiments demonstrate that promoting CD200R-mediated signaling can successfully prevent full expression of IFNgamma-mediated macrophage activation and protect against tissue damage during autoimmune responses.

Download full-text


Available from: Maria C Jenmalm, Oct 04, 2015
30 Reads
  • Source
    • "In models of skin and renal transplantation, systemic treatment of allograft recipients with CD200Fc, a synthetic agonist of CD200R1, prolongs allograft survival (Gorczynski et al., 1999). These findings are further supported by in vitro mouse studies which demonstrate that production of cytokines IL-6 and TNF (Jenmalm et al., 2006) and nitric oxide (NO) (Copland et al., 2007) are inhibited by engagement of an antibody agonist of CD200R1. In mixed leucocyte cultures, particularly relevant to transplantation, CD200R1 engagement by CD200Fc is reported to convert cytokine secretion from Th1 to Th2 type (Gorczynski, 2001) (Gorczynski et al., 2002) and inhibit T cell proliferation (Gorczynski et al., 2000). "
    [Show abstract] [Hide abstract]
    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. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Experimental Eye Research 11/2014; 130C:1-8. DOI:10.1016/j.exer.2014.11.006 · 2.71 Impact Factor
  • Source
    • "Second, specific T cell responses may be suppressed directly [160–162], or indirectly by suppressing antigen presentation or augmenting regulatory T cell responses [163, 164]. Third, non-specific tissue damaging responses may be disarmed by inhibiting macrophage function [72, 73, 82], by inhibiting cytokines [97–99, 165, 166], and by inhibiting trafficking of cells [34, 35, 167]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders.
    Seminars in Immunopathology 05/2014; 36(5). DOI:10.1007/s00281-014-0433-9 · 7.75 Impact Factor
  • Source
    • "Alternatively activated macrophages, characterized by canonical arginase-1 (Arg-1) expression, also generate VEGF in response to various environmental signals, including Th2 cytokines (IL-4, IL-13)89 as well as immune-modulatory compounds such as PGE212. The inhibitory CD200R, expressed predominantly by cells of myeloid lineage provides a normal homeostatic control mechanism that serves to limit cell activation1923. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophages are rapidly conditioned by cognate and soluble signals to acquire phenotypes that deliver specific functions during inflammation, wound healing and angiogenesis. Whether inhibitory CD200R signaling regulates pro-angiogenic macrophage phenotypes with the potential to suppress ocular neovascularization is unknown. CD200R-deficient bone marrow derived macrophages (BMMΦ) were used to demonstrate that macrophages lacking this inhibitory receptor exhibit enhanced levels of Vegfa, Arg-1 and Il-1β when stimulated with PGE2 or RPE-conditioned (PGE2-enriched) media. Endothelial tube formation in HUVECs was increased when co-cultured with PGE2-conditioned CD200R(-/-) BMMΦ, and laser-induced choroidal neovascularization was enhanced in CD200R-deficient mice. In corroboration, signaling through CD200R results in the down-regulation of BMMΦ angiogenic and pro-inflammatory phenotypes. Translational potential of this pathway was investigated in the laser-induced model of choroidal neovascularization. Local delivery of a CD200R agonist mAb to target myeloid infiltrate alters macrophage phenotype and inhibits pro-angiogenic gene expression, which suppresses pathological angiogenesis and CNV development.
    Scientific Reports 10/2013; 3:3072. DOI:10.1038/srep03072 · 5.58 Impact Factor
Show more