Effect of anti-C5a therapy in a murine model of early/ intermediate dry age-related macular degeneration

Christopher B. Toomey, Michael Landowski, Mikael Klingeborn, Una Kelly, John Deans, Holly Dong, Ons Harrabi, Thomas van Blarcom, Yik Andy Yeung, Ruslan Grishanin, John C. Lin, Daniel R. Saban, Catherine Bowes Rickman

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE: A large body of evidence supports a central role for complement activation in the pathobiology of age-related macular degeneration (AMD), including plasma complement component 5a (C5a). Interestingly, C5a is a chemotactic agent for monocytes, a cell type also shown to contribute to AMD. However, the role monocytes play in the pathogenesis of "dry" AMD and the pharmacologic potential of targeting C5a to regulate these cells are unclear. We addressed these questions via C5a blockade in a unique model of early/intermediate dry AMD and large panel flow cytometry to immunophenotype monocytic involvement. METHODS: Heterozygous complement factor H (Cfh+/-) mice aged to 90 weeks were fed a high-fat, cholesterol-enriched diet (Cfh+/-∼HFC) for 8 weeks and were given weekly intraperitoneal injections of 30 mg/kg anti-C5a (4C9, Pfizer). Flow cytometry, retinal pigmented epithelium (RPE) flat mounts, and electroretinograms were used to characterize anti-C5a treatment. RESULTS: Aged Cfh+/-mice developed RPE damage, sub-RPE basal laminar deposits, and attenuation of visual function and immune cell recruitment to the choroid that was accompanied by expression of inflammatory and extracellular matrix remodeling genes following 8 weeks of HFC diet. Concomitant systemic administration of an anti-C5a antibody successfully inhibited local recruitment of mononuclear phagocytes to the choroid-RPE interface but did not ameliorate these AMD-like pathologies in this mouse model. CONCLUSIONS: These results show that immunotherapy targeting C5a is not sufficient to block the development of the AMD-like pathologies observed in Cfh+/-∼HFC mice and suggest that other complement components or molecules/mechanisms may be driving "early" and "intermediate" AMD pathologies.

Original languageEnglish (US)
Pages (from-to)662-673
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number2
DOIs
StatePublished - Feb 2018
Externally publishedYes

Keywords

  • Age related macular degeneration
  • Complement
  • Immunotherapy
  • Monocytosis

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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