1. Department of Ophthalmology & Visual Science,
2. Department of Physiology, University of Kentucky, Lexington, Kentucky 40506, USA
3. Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
4. Department of Ophthalmology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
5. Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA
6. Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
7. Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah 84148, USA
8. Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
9. Department of Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA
10. Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97239, USA
11. Department of Ophthalmology, University of Luebeck, D-23538 Lübeck, Germany
12. These authors contributed equally to this work.
13. Present address: Respiratory, Inflammation and Autoimmunity, Medimmune, Inc., Gaithersburg, Maryland 20878, USA.

Correspondence to: Jayakrishna Ambati^1,2 Correspondence and requests for materials should be addressed to J.A. (Email: jamba2@email.uky.edu).

Abstract

Age-related macular degeneration (AMD), a leading cause of blindness worldwide, is as prevalent as cancer in industrialized nations. Most blindness in AMD results from invasion of the retina by choroidal neovascularisation (CNV). Here we show that the eosinophil/mast cell chemokine receptor CCR3 is specifically expressed in choroidal neovascular endothelial cells in humans with AMD, and that despite the expression of its ligands eotaxin-1, -2 and -3, neither eosinophils nor mast cells are present in human CNV. Genetic or pharmacological targeting of CCR3 or eotaxins inhibited injury-induced CNV in mice. CNV suppression by CCR3 blockade was due to direct inhibition of endothelial cell proliferation, and was uncoupled from inflammation because it occurred in mice lacking eosinophils or mast cells, and was independent of macrophage and neutrophil recruitment. CCR3 blockade was more effective at reducing CNV than vascular endothelial growth factor A (VEGF-A) neutralization, which is in clinical use at present, and, unlike VEGF-A blockade, is not toxic to the mouse retina. In vivo imaging with CCR3-targeting quantum dots located spontaneous CNV invisible to standard fluorescein angiography in mice before retinal invasion. CCR3 targeting might reduce vision loss due to AMD through early detection and therapeutic angioinhibition.

1. Department of Ophthalmology & Visual Science,
2. Department of Physiology, University of Kentucky, Lexington, Kentucky 40506, USA
3. Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
4. Department of Ophthalmology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
5. Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA
6. Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
7. Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah 84148, USA
8. Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
9. Department of Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA
10. Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97239, USA
11. Department of Ophthalmology, University of Luebeck, D-23538 Lübeck, Germany
12. These authors contributed equally to this work.
13. Present address: Respiratory, Inflammation and Autoimmunity, Medimmune, Inc., Gaithersburg, Maryland 20878, USA.

Correspondence to: Jayakrishna Ambati^1,2 Correspondence and requests for materials should be addressed to J.A. (Email: jamba2@email.uky.edu).

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