title: Soluble CD59 expressed from an adenovirus in vivo is a potent inhibitor of complement deposition on murine liver vascular endothelium.
abstract: Inappropriate activation of complement on the vascular endothelium of specific organs, or systemically, underlies the etiology of a number of diseases. These disorders include atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, atherosclerosis, age-related macular degeneration, diabetic retinopathy, and transplant rejection. Inhibition of the terminal step of complement activation, i.e. formation of the membrane attack complex, using CD59 has the advantage of retaining the upstream processes of the complement cascade necessary for fighting pathogens and retaining complement's crucial role in tissue homeostasis. Previous studies have shown the necessity of membrane targeting of soluble CD59 in order for it to prove an effective inhibitor of complement deposition both in vitro and in vivo. In this study we have generated an in vivo model of human complement activation on murine liver vascular endothelium. This model should prove useful for the development of anti-complement therapies for complement-induced pathologies of vascular endothelium. Using this model, we have demonstrated the viability of a non membrane-targeted soluble CD59 to significantly inhibit complement deposition on the endothelium of murine liver vasculature when expressed in vivo from an adenovirus. This result, unanticipated based on prior studies, suggests that the use of non membrane-targeted sCD59 as an anti-complement therapy be re-visited.
authors: Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors: Jarel
authors: J
authors: Gandhi
authors: Siobhan M
authors: SM
authors: Cashman
authors: Rajendra
authors: R
authors: Kumar-Singh
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology; D001011:Aorta / Q000276:immunology; D001808:Blood Vessels / Q000166:cytology / Q000276:immunology; D018957:CD59 Antigens / Q000276:immunology*; D003167:Complement Activation / Q000276:immunology*; D015938:Complement Membrane Attack Complex / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007274:Injections, Intraperitoneal; D008099:Liver / Q000098:blood supply* / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity / Q000276:immunology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology; D011485:Protein Binding; D044967:Serum / Q000276:immunology; D012995:Solubility
chemical_list: D000906:Antibodies; D018957:CD59 Antigens; D015938:Complement Membrane Attack Complex; D019408:Platelet Endothelial Cell Adhesion Molecule-1