September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Ocular complement activation and inhibition in rodent models of endotoxin-induced uveitis
Author Affiliations & Notes
  • Maura Crowley
    Novartis, Cambridge, Massachusetts, United States
  • Omar Delgado
    Novartis, Cambridge, Massachusetts, United States
  • Karen Anderson
    Novartis, Cambridge, Massachusetts, United States
  • Wei Zheng
    Novartis, Cambridge, Massachusetts, United States
  • Holger Sellner
    Novartis, Cambridge, Massachusetts, United States
  • Nello Mainolfi
    Novartis, Cambridge, Massachusetts, United States
  • Muneto Mogi
    Novartis, Cambridge, Massachusetts, United States
  • Bruce D Jaffee
    Novartis, Cambridge, Massachusetts, United States
  • Sha-Mei Liao
    Novartis, Cambridge, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Maura Crowley, Novartis (E); Omar Delgado, Novartis (E); Karen Anderson, Novartis (E); Wei Zheng, Novartis (E); Holger Sellner, Novartis (E); Nello Mainolfi, Novartis (E); Muneto Mogi, Novartis (E); Bruce Jaffee, Novartis (E); Sha-Mei Liao, Novartis (E)
  • Footnotes
    Support  none
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 482. doi:
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    • Get Citation

      Maura Crowley, Omar Delgado, Karen Anderson, Wei Zheng, Holger Sellner, Nello Mainolfi, Muneto Mogi, Bruce D Jaffee, Sha-Mei Liao; Ocular complement activation and inhibition in rodent models of endotoxin-induced uveitis. Invest. Ophthalmol. Vis. Sci. 2016;57(12):482.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Polymorphisms in multiple complement pathway components have been found to associate with age related macular degeneration (AMD). We developed rodent models of systemic and ocular complement activation to identify complement inhibitors for the potential treatment of AMD.

Methods : C57Bl/6 mice (wild type, C3 or Factor B (FB) deficient) or Lewis rats received an intraperitoneal injection of lipopolysaccharide (LPS) at 2.5 or 1 mg/kg, respectively. At various time points after low molecular weight FB inhibitors were administered, plasma and eyes were collected. Complement activation was assessed by measuring the generation of complement C3 and FB breakdown products via Western blots in plasma and eye lysates. Levels of complement mRNAs were measured by TaqMan or microarray.

Results : Intraperitoneal injection of LPS increased the levels of C3 and FB breakdown products C3d, iC3b, and Ba in both plasma and eye tissues. LPS-induced complement activation was time-dependent, peaking at 24 hours. LPS-challenged C3 and FB deficient mice exhibited diminished complement activation in blood and ocular tissues. C3 and FB mRNA levels in the eye were also increased by systemic LPS in a time dependent manner, peaking at 16-24 hours post LPS. Administration of FB inhibitors effectively inhibited LPS-induced complement activation in a dose dependent manner up to 100% inhibition.

Conclusions : Challenge with LPS induces a time-dependent ocular synthesis and breakdown of complement proteins C3 and Factor B in rodents. Absence of complement breakdown products in C3 and FB deficient mice in response to LPS indicates that the alternative pathway is responsible for the complement activation in this model system. Low molecular weight Factor B inhibitors potently inhibit both ocular and systemic complement activation. These inhibitors may be efficacious for treating complement-mediated diseases such as AMD.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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