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

Abstract

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 antimouse CD200R (DX109) antibody delivered a negative signal to bone marrow-derived macrophages, which suppressed interferon (IFN)␥-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 IFN␥ 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 IFN␥-mediated macrophage activation and protect against tissue damage during autoimmune responses. (Am J

Doyne lecture 2016: intraocular health and the many faces of inflammation

“…In support, we observe that tissue damage in experimental retinal inflammation is significantly attenuated when macrophages are removed 21,22 or macrophage/monocyte activation is blocked. 16,[23][24][25] Experimentally, we observe that the tissue is protected when TNF-alpha activity is neutralised (and indeed show the requisite requirement of TNF for macrophage activation in ocular inflammation [26][27][28] ), or by reprogramming macrophage activation threshold with CD200R treatment. These consistent observations have led to a pipeline for therapeutic opportunities to redress activation thresholds of immune cells.…”

“…CD200 is ubiquitously expressed on macrophages, neurons, and endothelium, [10][11][12][13] and perturbing their interaction results in an aggressive disease phenotype. 14,15 If we attempt to reconstitute and de-activate macrophage function (by direct ligation of CD200R with anti-CD200R monoclonal antibodies or by a CD200Fc), attenuation of retinal or CNS inflammation can be achieved 14,16 as well as regulation of other myeloid cells, including mast cells in the lung. [17][18][19][20] How do we keep the peace?…”

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

“…43,44 As a result, the retina's resident CD200R þ macrophages (microglia) remain tonically deactivated patrolling and governing retinal homeostasis. 45 On the other side of the fence, complement activation will also generate further macrophage activation via C5a, promoting and promulgating the pro-inflammatory macrophage status. 46 The benefits of keeping immune cell activation in check, particularly within tissues, is an effective means of inducing a rapid activation response when the constraint of the negative signal is removed, irrespective of whether this occurs in the context of autoimmunity or even in AMD.…”

An Interaction between CD200 and Monoclonal Antibody Agonists to CD200R2 in Development of Dendritic Cells That Preferentially Induce Populations of CD4+CD25+ T Regulatory Cells

“…The dominant (high avidity) interaction with CD200R1 results in direct suppression of both inflammation and graft rejection (3)(4)(5)(6). These interactions produce altered graft rejection and suppress inflammation in a mouse model of collagen-induced arthritis (7).…”