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Soluble CD59 Expressed from an Adenovirus In Vivo Is a Potent Inhibitor of Complement Deposition on Murine Liver Vascular Endothelium

By Jarel Gandhi, Siobhan M. Cashman and Rajendra Kumar-Singh

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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3123367
Provided by: PubMed Central

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Citations

  1. (2011). A Non Membrane-Targeted Human Soluble CD59 Attenuates Choroidal Neovascularization in a Model of Age Related Macular Degeneration. PLoS One,
  2. (2002). A role for local inflammation in the formation of drusen in the aging eye.
  3. (1998). A simplified system for generating recombinant adenoviruses.
  4. (1997). Acquired C3 deficiency in patients with alcoholic cirrhosis predisposes to infection and increased mortality.
  5. (2009). Adenovirus activates complement by distinctly different mechanisms in vitro and in vivo: indirect complement activation by virions in vivo.
  6. (2011). Adenovirus-mediated delivery of CD46 attenuates the alternative complement pathway on RPE: implications for age-related macular degeneration. Gene Ther,
  7. (1999). Assessment of complement deficiency in patients with meningococcal disease in The Netherlands.
  8. (1992). Association of murine CD31 with transmigrating lymphocytes following antigenic stimulation.
  9. (1989). CD59, an LY-6-like protein expressed in human lymphoid cells, regulates the action of the complement membrane attack complex on homologous cells.
  10. (1996). Characterization of 911: a new helper cell line for the titration and propagation of early region 1-deleted adenoviral vectors.
  11. (1998). Characterization of Neisseria meningitidis strains causing disease in complement-deficient and complement-sufficient patients.
  12. (2003). Complement receptor 2-mediated targeting of complement inhibitors to sites of complement activation.
  13. (2009). Complement regulator CD59 protects against atherosclerosis by restricting the formation of complement membrane attack complex.
  14. (2010). Complement: a key system for immune surveillance and homeostasis.
  15. (2010). Decay accelerating factor (CD55)-mediated attenuation of complement: therapeutic implications for age-related macular degeneration.
  16. (2006). Differential biodistribution of adenoviral vector in vivo as monitored by bioluminescence imaging and quantitative polymerase chain reaction.
  17. (2008). Evaluation of adenovirusdelivered human CD59 as a potential therapy for AMD in a model of human membrane attack complex formation on murine RPE.
  18. (2002). Extensive deposits of complement C3d and C5b-9 in the choriocapillaris of eyes of patients with diabetic retinopathy.
  19. (2009). Generation and phenotyping of mCd59a and mCd59b double-knockout mice.
  20. (2003). Generation of a recombinant, membrane-targeted form of the complement regulator CD59: activity in vitro and in vivo.
  21. (2001). Hemolytic uremic syndrome: how do factor H mutants mediate endothelial damage?
  22. (2009). Hereditary and acquired complement dysregulation in membranoproliferative glomerulonephritis.
  23. (1996). Human decay accelerating factor expressed on endothelial cells of transgenic pigs affects complement activation in an ex vivo liver perfusion model.
  24. (1990). Human protectin (CD59), an 18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers.
  25. (2007). Improved retinal transduction in vivo and photoreceptor-specific transgene expression using adenovirus vectors with modified penton base.
  26. (2001). Lifetime correction of genetic deficiency in mice with a single injection of helper-dependent adenoviral vector.
  27. (2001). Membrane complement regulators protect against the development of type II collagen-induced arthritis in rats.
  28. (1997). Molecular cloning, chromosomal localization, expression, and functional characterization of the mouse analogue of human CD59.
  29. (2003). Neuroprotection by complement (C1) inhibitor in mouse transient brain ischemia.
  30. (2010). Recombinant membrane-targeted form of CD59 inhibits the growth of choroidal neovascular complex in mice.
  31. (1994). Recombinant soluble CD59 inhibits reactive haemolysis with complement.
  32. (2011). Role of complement and perspectives for intervention in ischemia-reperfusion damage. Ann Med epub ahead of print.
  33. (1999). Targeting of functional antibody-CD59 fusion proteins to a cell surface.
  34. (1990). The complement-inhibitory activity of CD59 resides in its capacity to block incorporation of C9 into membrane C5b-9.
  35. (2010). The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited.
  36. (2007). The role of complement in inflammatory diseases from behind the scenes into the spotlight.
  37. (2009). The role of the anaphylatoxins in health and disease.
  38. (2010). Therapeutic complement inhibition: new developments.
  39. (2008). Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals.