Targeting immune privilege to prevent pathogenic neovascularization.

Immune privilege is a term applied to organs that have a unique relationship with the immune response. These sites prohibit the spread of inflammation at the expense of immune effector mechanisms because even minor episodes can threaten organ integrity. Once thought to be a passive process relying on physical barriers, immune privilege is now viewed as an active process that uses multiple anti-inflammatory mechanisms to maintain organ function (reviewed in Refs. 1, 2). The prototypic organ of immune privilege is the eye, in which the spread of inflammation can lead to blindness. An important part of immune privilege is the constitutive expression of the death-inducing ligands FasL and TNF-related apoptosis inducing ligand (TRAIL), which inhibit inflammation and tumor growth by inducing apoptosis in cells expressing the Fas or TRAIL receptors.3–5 Although initial studies focused on the control of inflammation3 and the impact of these molecules on the systemic immune response,6,7 more recent studies have extended this concept to pathogenic neovascularization. These studies demonstrated an important role for FasL in controlling neovascular diseases of the cornea,8 retina,9 and choroid.10 It is now known that FasL expression on the parenchymal tissues of the eye regulates the extent of neovascularization by inducing apoptosis in Fas+ endothelial cells.10,11 In the eye, neovascularization is a major component of several ocular disorders, including diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration (AMD).12 In these diseases, the growth of new vessels can impair vision and threaten quality of life. AMD is a progressive disease that causes irreversible visual impairment and blindness in nearly 50 million people globally.13,14 Neovascular AMD is the more aggressive form and accounts for 90% of blindness from this disease. It is characterized by choroidal neovascularization (CNV), which is the development of abnormal blood vessels under the retina. Neovascular AMD is a progressive disease that can eventually result in blindness. Consequently, identifying therapies that can control neovascularization and prevent progression to vision loss is an area of intense study. Presently, only anti-VEGF therapy has proven effective at slowing the progression of neovascular AMD15 but may not permanently prevent blindness from this disease. Recent work16–18 has focused on the role of chronic inflammation in the development of pathologic processes such as cancer, heart disease, and eye disorders. Because inflammation can promote angiogenesis there is considerable discussion of the role of inflammation in promoting ocular angiogenesis, particularly in neovascular AMD.12,13,18–22 Investigations into the role of inflammation and neovascular eye disease often overlook the principles of immune privilege whereby the ocular environment is not proinflammatory but tends to prohibit inflammation at the expense of certain immune effector mechanisms.1 It has been suggested that the loss of immune privilege as the eye ages may contribute to the increases in neovascular disease,1,10,23 but this has not been studied. Given that FasL expression is an important component of immune privilege, we tested the idea that targeting this molecule would have therapeutic value in the treatment of eye disease. Our results showed that injection of a cytotoxic form of FasL can successfully prevent the progression of blood vessels into the eye. In addition, we showed that augmenting FasL expression by oral treatment with doxycycline leads to ablation of the neovascular response. Thus, modulation of immune privilege may be a successful adjunct therapy for blinding neovascular eye disorders.