TableEdit

Bora, NS, Kaliappan, S, Jha, P, Xu, Q, Sivasankar, B, Harris, CL, Morgan, BP and Bora, PS (2007) CD59, a complement regulatory protein, controls choroidal neovascularization in a mouse model of wet-type age-related macular degeneration. J. Immunol. 178:1783-90

We have shown that membrane attack complex (MAC) formation via the activation of the alternative pathway plays a central role in the laser-induced choroidal neovascularization (CNV). This study was undertaken to understand the role of a complement regulatory protein, CD59, which controls MAC assembly and function, in this model. CNV was induced by laser photocoagulation in C57BL/6 and Cd59a(-/-) mice using an argon laser. Animals from each group were sacrificed on day 1, 3, 5, and 7 postlaser. Retinal pigment epithelium-choroid-scleral tissue was examined to determine the incidence and size of CNV complex, and semiquantitative RT-PCR and Western blot analysis for CD59a was studied. Recombinant soluble mouse CD59a-IgG2a fusion (rsCD59a-Fc) protein was injected via i.p. or intravitreal routes 24 h before laser. Our results demonstrated that CD59a (both mRNA and protein) was down-regulated during laser-induced CNV. Cd59a(-/-) mice developed CNV complex early in the disease process. Increased MAC deposition was also observed in these Cd59a(-/-) mice. Administration of rsCD59a-Fc inhibited the development of CNV complex in the mouse model by blocking MAC formation and also inhibited expression of angiogenic growth factors. These data provide strong evidence that CD59a plays a crucial role in regulating complement activation and MAC formation essential for the release of growth factors that drive the development of laser-induced CNV in mice. Thus, our results suggest that the inhibition of complement by soluble CD59 may provide a novel therapeutic alternative to current treatment.

PubMed

Animals; Antigens, CD59/analysis; Antigens, CD59/genetics; Antigens, CD59/physiology; Antigens, CD59/therapeutic use; Choroidal Neovascularization/drug therapy; Choroidal Neovascularization/etiology; Complement Activation; Complement Membrane Attack Complex; Disease Models, Animal; Down-Regulation; Immunoglobulin G/genetics; Intercellular Signaling Peptides and Proteins; Lasers/adverse effects; Macular Degeneration/etiology; Macular Degeneration/pathology; Macular Degeneration/therapy; Mice; Mice, Knockout; Recombinant Fusion Proteins/administration & dosage; Recombinant Fusion Proteins/pharmacology