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Effect of Anti-C5a Therapy in a Murine Model of Early/Intermediate Dry Age-Related Macular Degeneration
- Source :
- Investigative Ophthalmology & Visual Science
- Publication Year :
- 2018
- Publisher :
- Association for Research in Vision and Ophthalmology (ARVO), 2018.
-
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.
- Subjects :
- Male
0301 basic medicine
genetic structures
age related macular degeneration
medicine.medical_treatment
Complement C5a
Enzyme-Linked Immunosorbent Assay
Retinal Pigment Epithelium
Cholesterol, Dietary
Pathogenesis
Mice
03 medical and health sciences
Immune system
Geographic Atrophy
Electroretinography
Animals
Medicine
complement
Antibodies, Blocking
Complement Activation
biology
business.industry
Immunotherapy
Macular degeneration
Flow Cytometry
medicine.disease
Choroidal Neovascularization
eye diseases
3. Good health
Complement system
Mice, Inbred C57BL
Disease Models, Animal
monocytosis
030104 developmental biology
Retinal Cell Biology
Factor H
Immunology
biology.protein
sense organs
Antibody
business
Complement component 5a
Injections, Intraperitoneal
Subjects
Details
- ISSN :
- 15525783
- Volume :
- 59
- Database :
- OpenAIRE
- Journal :
- Investigative Opthalmology & Visual Science
- Accession number :
- edsair.doi.dedup.....718af87bcbbaf83512bfb5cd996398a4