Monoclonal antibody-mediated CD200 receptor signaling suppresses macrophage activation and tissue damage in experimental autoimmune uveoretinitis.
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.
Copland
David A
DA
Division of Infection and Immunity, Department of Clinical Science at South Bristol, University of Bristol, Bristol, United Kingdom.
Calder
Claudia J
CJ
Raveney
Ben J E
BJ
Nicholson
Lindsay B
LB
Phillips
Joseph
J
Cherwinski
Holly
H
Jenmalm
Maria
M
Sedgwick
Jonathon D
JD
Dick
Andrew D
AD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000473:pathology / Q000517:prevention & control*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D012173:Retinitis / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000276:immunology; D013997:Time Factors; D051193:Toll-Like Receptors / Q000378:metabolism; D014605:Uveitis / Q000473:pathology / Q000517:prevention & control*
D000911:Antibodies, Monoclonal; C492346:CD200 receptor, mouse; C522598:DX109; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009573:Nitrites; D051193:Toll-Like Receptors; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse