Targeting Immune Privilege to Prevent Pathogenic Neovascularization

Abstract

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.

Doxycycline Inhibits Polarization of Macrophages to the Proangiogenic M2-type and Subsequent Neovascularization

“…Doxycycline has also been reported to dose-dependently reduce laser-induced CNV lesions in mice, as shown in this study as well (9,11,12), and preliminary observations suggest a beneficial effect of doxycycline in treating neovascular AMD. One study suggests that this effect may be mediated by increased FasL expression by RPE cells after doxycycline treatment (11).…”

“…One study suggests that this effect may be mediated by increased FasL expression by RPE cells after doxycycline treatment (11). Taken together, doxycycline inhibits pathologic angiogenesis and is likely to do so through diverse mechanisms.…”

“…4B). Importantly, several studies have shown that doxycycline dose-dependently inhibits CNV lesion formation in this model, demonstrating a potent antiangiogenic activity of doxycycline (9,11,12). Thus, we hypothesized that inhibition of M2-type macrophage polarization by doxycycline results in reduced proangiogenic cytokine expression and subsequent neovascularization in this model.…”

Equine Luteal Function Regulation May Depend on the Interaction Between Cytokines and Vascular Endothelial Growth Factor: An In Vitro Study1

“…Besides inducing PGF 2a and inhibiting P 4 and PGE 2 secretion at the time of luteolysis, the present findings suggest that FASL may also suppress angiogenesis by reducing VEGF protein expression. This cytokine is known as a down-regulator of angiogenesis in different organs [68,69]. However, to the best of our knowledge, this is the first report on VEGF expression modulation by FASL in the equine CL.…”

Risk Factors, Pathogenesis and Diagnosis of Ocular Toxoplasmosis

“…FasL interacts with FasR (Fas receptor) carried by the inflammatory cells, inducing their apoptosis. This would control the entry of Fas-expressing lymphoid cells and limit the alteration of ocular cells by these cells [40,41]. Whereas the mechanisms that underlie retinal damage in OT are yet not fully understood, the immune response might directly affect the pathogenesis of toxoplasmic retinochoroiditis and some cytokines have been shown to be fundamental to either control or block a protective response against T. gondii in experimental models.…”