Transgenic Expression of a Soluble Complement Inhibitor Decreases the Incidence and Severity of Murine Experimental Autoimmune Uveitis

Abstract

Abstract: : Purpose: Complement receptor-related protein (Crry) is a rodent membrane-bound molecule which serves the functions of complement inhibition carried out in humans by DAF and MCP. Crry has been demonstrated in the normal rat eye and neutralizing antibodies to Crry injected into the anterior chamber of rats have been shown to produce an acute anterior uveitis. This study was designed to demonstrate that astrocyte-targeted expression of the transgene product soluble complement receptor-related protein (sCrry) reduces the incidence and severity of EAU in mice. Methods: C57BL/6-background mice with transgenic expression of sCrry under the GFAP promoter were compared with wild-type mice. EAU was induced using a peptide consisting of residues 1-20 of human IRBP (GPTHLFQPSLVLDMAKVLLD). 500µg of peptide in CFA with M. tuberculosis H37RA (2.5 mg/ml) was injected subcutaneously in each animal with 1.5 µg of pertussis toxin IP. Eyes were obtained at day 21 post immunization, fixed in 10% neutral buffered formalin, paraffin embedded, and 5-6 µm sections H&E stained. Disease severity was graded on a scale of 0 to 4. Results: Comparison of EAU in WT versus sCrry mice are shown in Table 1. Conclusions: The significant reduction in incidence and severity of EAU in transgenic animals expressing soluble Crry implies a role for complement activation in the initiation and/or potentiation of EAU, and points to a potential therapeutic target in human uveitis. Table 1. Comparison of EAU incidence and severity between WT and sCrry mice  

Keywords: 612 uveitis-clinical/animal model • 327 autoimmune disease • 316 animal model