Macular Degeneration: Ferguson TA

Ferguson TA, Apte RS. · Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid, P.O. Box 8096, St. Louis, MO 63110, USA. · Semin Immunopathol. · Pubmed #18297288 No free full text.

Abstract: The anti-inflammatory nature of the intraocular environment is critical to the immune privilege of the eye. An important part of immune privilege is the induction of apoptosis by two death-inducing ligands (FasL and TRAIL) that can limit the spread of inflammation and control tumor growth. While initial studies focused on control of inflammation and the impact of these molecules on the systemic immune response, more recent studies have extended this concept to pathogenic neovascularization. This process is an important component of several blinding eye disorders including age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and corneal disease. These studies showed that the mediators of immune privilege also regulate the extent of angiogenesis. In this article, we will develop the idea that constitutive expression of FasL in the eye, as well as inducible FasL on cells of the immune system, modulates neovascularization in ocular disease. Further, we will present the idea that macrophage participation in this process and their function during disease depends on the microenvironment and the cytokine milieu. These concepts challenge the idea that neovascular eye disease is simply an inflammatory process and support the idea that these diseases may result from the loss or dysfunction of important components of the cellular immune system.

Kelly J, Ali Khan A, Yin J, Ferguson TA, Apte RS. · Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, USA. · J Clin Invest. · Pubmed #17975672 links to  free full text

Abstract: Abnormal angiogenesis plays a key role in diseases of aging such as heart disease, certain cancers, and eye diseases including age-related macular degeneration. Macrophages have been shown previously to be both anti- and proangiogenic, and their role in regulating angiogenesis at sites of tissue injury is critical and complex. In this study, we analyzed cytokine gene expression patterns of mouse macrophages by real-time quantitative PCR and tested the functional effects of senescence on gene expression and macrophage polarization. Following laser injury to the retina, IL-10 was upregulated and Fas ligand (FasL), IL-12, and TNF-alpha were downregulated in ocular macrophages of old mice (>18 months of age). Downregulation of FasL on macrophages led to a loss of the antiangiogenic phenotype, as evidenced by the inability of these macrophages to inhibit vascular endothelial cells. Our results demonstrate that senescence, FasL, and IL-10 are key determinants of macrophage function that alter the growth of abnormal postdevelopmental blood vessels in disease processes including blinding eye disease.

Apte RS, Richter J, Herndon J, Ferguson TA. · Department of Ophthalmology, Washington University School of Medicine, St. Louis, Missouri, USA. · PLoS Med. · Pubmed #16903779 links to  free full text

Abstract: BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in people over 50 y of age in at least three continents. Choroidal neovascularization (CNV) is the process by which abnormal blood vessels develop underneath the retina. CNV develops in 10% of patients with AMD but accounts for up to 90% of the blindness from AMD. Although the precise etiology of CNV in AMD remains unknown, the macrophage component of the inflammatory response, which has been shown to promote tumor growth and support atherosclerotic plaque formation, is thought to stimulate aberrant angiogenesis in blinding eye diseases. The current theory is that macrophage infiltration promotes the development of neovascularization in CNV. METHODS AND FINDINGS: We examined the role of macrophages in a mouse model of CNV. IL-10(-/-) mice, which have increased inflammation in response to diverse stimuli, have significantly reduced CNV with increased macrophage infiltrates compared to wild type. Prevention of macrophage entry into the eye promoted neovascularization while direct injection of macrophages significantly inhibited CNV. Inhibition by macrophages was mediated by the TNF family death molecule Fas ligand (CD95-ligand). CONCLUSIONS: Immune vascular interactions can be highly complex. Normal macrophage function is critical in controlling pathologic neovascularization in the eye. IL-10 regulates macrophage activity in the eye and is an attractive therapeutic target in order to suppress or inhibit CNV in AMD that can otherwise lead to blindness.

Kaplan HJ, Leibole MA, Tezel T, Ferguson TA. · Washington University School of Medicine, Department of Ophthalmology and Visual Sciences, St. Louis, Missouri 63110, USA. · Nat Med. · Pubmed #10086384 No free full text.

Abstract: A principal cause of blindness is subretinal neovascularization associated with age-related macular degeneration. Excised neovascular membranes from patients with age-related macular degeneration demonstrated a pattern of Fas+ new vessels in the center of the vascular complex, surrounded by FasL+ retinal pigment epithelial cells. In a murine model, Fas (CD95)-deficient (Ipr) and FasL-defective (gld) mice had a significantly increased incidence of neovascularization compared with normal mice. Furthermore, in gld mice there is massive subretinal neovascularization with uncontrolled growth of vessels. We found that cultured choroidal endothelial cells were induced to undergo apoptosis by retinal pigment epithelial cells through a Fas-FasL interaction. In addition, antibody against Fas prevented vascular tube formation of choroidal endothelial cells derived from the eye in a three-dimensional in vitro assay. Thus, FasL expressed on retinal pigment epithelial cells may control the growth and development of new subretinal vessels that can damage vision.