Monoclonal antibody-mediated CD200 receptor signaling suppresses macrophage activation and tissue damage in experimental autoimmune uveoretinitis

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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)-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.

Calder, CJUniversity of Bristol (author)
Raveney, BJUniversity of Bristol (author)
Nicholson, LBUniversity of Bristol (author)
Phillips, JSP Biopharma, Palo Alto, California (author)
Cherwinski, HSP Biopharma, Palo Alto, California (author)
Jenmalm, Maria,1971-SP Biopharma, Palo Alto, California(Swepub:liu)marje18 (author)
Sedgewick, JDSP Biopharma, Palo Alto, California (author)
Dick, ADUniversity of Bristol (author)
University of BristolSP Biopharma, Palo Alto, California (creator_code:org_t)

In:American Journal of Pathology: Elsevier BV171:2, s. 580-5880002-94401525-2191

By the author/editor: Copland, DA; Calder, CJ; Raveney, BJ; Nicholson, LB; Phillips, J; Cherwinski, H; show more...; Jenmalm, Maria, ...; Sedgewick, JD; Dick, AD; show less...

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