Targeting immune privilege to prevent pathogenic neovascularization.
PURPOSE. Current studies suggest that the immune system plays a critical role in blinding eye disorders. The eye is an immune-privileged site, and FasL expression is a major part of that mechanism because Fas/FasL interactions regulate inflammation and neovascularization, preventing damage to delicate ocular structures. These studies were undertaken to test the idea that modulating immune privilege might be an effective therapeutic approach to pathogenic angiogenesis in the eye. METHODS. C57BL/6 mice or FasL-defective B6-gld mice were laser treated to induce choroidal neovascularization (CNV). Mice were injected with cytotoxic FasL in the vitreous cavity or were treated with oral doxycycline in the drinking water. They were evaluated for CNV 7 days later. In some experiments eye tissue was harvested and evaluated for FasL expression, macrophage influx by immunohistochemistry, and release of sFasL. RESULTS. Injection of cytotoxic FasL successfully prevented neovascularization in a mouse model of CNV. Oral doxycycline increased functional FasL in the eye and substantially inhibited neovascularization. Doxycycline treatment increased FasL expression on the RPE cells and reduced circulating and tissue-associated sFasL. Treatment was ineffective in B6-gld mice, demonstrating that CNV inhibition was mediated by FasL. CONCLUSIONS. Targeting immune privilege using cytotoxic molecules or by increasing expression of the proapoptotic protein FasL may be a viable approach to treating neovascular eye disease.
Roychoudhury
Jayeeta
J
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA.
Herndon
John M
JM
Yin
Jiyi
J
Apte
Rajendra S
RS
Ferguson
Thomas A
TA
D000284:Administration, Oral; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004318:Doxycycline / Q000008:administration & dosage*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein / Q000008:administration & dosage* / Q000097:blood; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression; D007107:Immune System / Q000187:drug effects; D007267:Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use; D014822:Vitreous Body
D039481:CD11b Antigen; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D004318:Doxycycline