Topical application of methotrexate for inhibition of corneal angiogenesis

Joussen, Antonia M.; Kruse, Friedrich E.; Völcker, H. E.; Kirchhof, Bernd

doi:10.1007/s004170050387

Cited by 83 publications

(39 citation statements)

References 31 publications

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“…Antiangiogenic therapy may prove a promising direction to reduce graft failure (21). Various chemical compounds and drugs, such as steroids (22), methotrexate (23), heparin (24), and thalidomide (25), are reported to inhibit corneal neovascularization. Recently, anti-VEGF therapy targeting corneal angiogenesis showed successful results in animal experiments and clinical trials (26).…”

mentioning

confidence: 99%

Immunological Disruption of Antiangiogenic Signals by Recruited Allospecific T Cells Leads to Corneal Allograft Rejection

Tan

Cruz-Guilloty

Medina-Mendez

et al. 2012

The Journal of Immunology

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Corneal transplantation is the most common solid organ transplantation. The immunologically privileged nature of the cornea results in high success rates. However, T cell-mediated rejection is the most common cause of corneal graft failure. Using antiangiogenesis treatment to prevent corneal neovascularization, which revokes immune privilege, prevents corneal allograft rejection. Endostatin is an antiangiogenic factor that maintains corneal avascularity. In this study, we directly test the role of antiangiogenic and immunological signals in corneal allograft survival, specifically the potential correlation of endostatin production and T cell recruitment. We report that 75% of the corneal allografts of BALB/c mice rejected after postoperative day (POD) 20, whereas all syngeneic grafts survived through POD60. This correlates with endogenous endostatin, which increased and remained high in syngeneic grafts but decreased after POD10 in allografts. Immunostaining demonstrated that early recruitment of allospecific T cells into allografts around POD10 correlated with decreased endostatin production. In Rag−/− mice, both allogeneic and syngeneic corneal grafts survived; endostatin remained high throughout. However, after T cell transfer, the allografts eventually rejected, and endostatin decreased. Furthermore, exogenous endostatin treatment delayed allograft rejection and promoted survival secondary to angiogenesis inhibition. Our results suggest that endostatin plays an important role in corneal allograft survival by inhibiting neovascularization and that early recruitment of allospecific T cells into the grafts promotes destruction of endostatin-producing cells, resulting in corneal neovascularization, massive infiltration of effector T cells, and ultimately graft rejection. Therefore, combined antiangiogenesis and immune suppression will be more effective in maintaining corneal allograft survival.

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mentioning

confidence: 99%

Immunological Disruption of Antiangiogenic Signals by Recruited Allospecific T Cells Leads to Corneal Allograft Rejection

Tan

Cruz-Guilloty

Medina-Mendez

et al. 2012

The Journal of Immunology

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“…cyclosporin A, have been used for the treatment of corneal neovasculature, but established therapeutic methods are not currently available [16,17,18,19,20,21]. …”

Section: Discussionmentioning

confidence: 99%

Topical and Subconjunctival Bevacizumab for Corneal Neovascularization in an Experimental Rat Model

et al. 2012

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Aims: To evaluate and compare the inhibitory effects of topical and subconjunctival bevacizumab on corneal neovascularization in a rat model. Methods: Twenty corneas of 20 rats were chemically cauterized with silver nitrate sticks. Animals were randomized into four groups: a control group that received only topical artificial tear drops twice daily, a subconjunctival injection group that received 1.25 mg (0.05 ml) of bevacizumab on the 1st, 4th, and 7th day, and two topical bevacizumab groups that received instillation of 4 or 12.5 mg/ml bevacizumab twice daily. Digital photographs of the cornea were taken and analyzed using an image analysis software program. On the 10th day, corneas were excised and examined histologically. Results: The mean percentage of the vascularized corneal area (%) in the control group was 63.32 ± 13.10 (mean ± SD), compared with 30.22 ± 15.73 in the subconjunctival injection group, 26.76 ± 10.23 in the 4-mg/ml topical group, and 25.52 ± 12.45 in the 12.5-mg/ml group. The differences between the control and each treatment group were significant (all p < 0.01). Further, histological examination revealed that each treatment group had fewer vessels than the control group (all p < 0.01). Conclusions: Both subconjunctival injection and topical use of bevacizumab are effective and safe in controlling corneal neovascularization.

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“…These include medication, laser photocoagulation, and surgery. Several angiogenesis inhibitors have been identified and tried as medical treatment, including prolactin, 3 endostatin, 7 angiostatin, 8 somatostatin, 9 cyclosporin A, 18 TNP-470, 19 steroids, 20 nonsteroidal antiinflammatory drugs, 21 thalidomide, 22 methotrexate, 23 and culture supernatant of human amniotic cells. 24 Recently, targeted macrophage metalloelastase or angiostatin gene transfer has been tried to halt angiogenesis in a mouse tumor model, 25,26 and naked plasmids have been shown to be taken up by corneal epithelium.…”

Section: Discussionmentioning

confidence: 99%

Lipid-mediated delivery of brain-specific angiogenesis inhibitor 1 gene reduces corneal neovascularization in an in vivo rabbit model

et al. 2005

Gene Ther

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Corneal neovascularization, which occurs in many pathologic states of the cornea, reduces the visual acuity. Recently, we found that the extracellular region of brain-specific angiogenesis inhibitor 1 (BAI1-ECR) has antiproliferative activity through functional blocking of a v b 5 integrin in endothelial cells. In this study, we investigated the effects of lipidmediated subconjunctival injection of the BAI1-ECR gene on corneal angiogenesis induced by epithelial debridement by heptanol in the rabbit. When a pEGFP-BAI1-ECR plasmid was given subconjunctivally 1 week after epithelial debridement, green fluorescence was detected in the corneal stroma with expression persisting for 7 days. To test the effect of BAI1-ECR on neovascularization, rabbits were injected with the BAI1-ECR gene or empty vector two or three times at 1-week intervals beginning 1 week after debridement. When measured with biomicroscopy at 1 or 2 weeks after two weekly injections, BAI1-delivered eyes had significantly less neovascularized corneal area than vector-injected ones in both time periods. Similar microscopic results were obtained after three weekly injections of BAI1-ECR. In quantitative histological examination, the BAI1-receiving eyes showed significantly less neovascular area and number of vessels than vector-injected ones. Also, after two weekly injections, BAI1-delivered eyes had decreased neovascularized corneal area equivalent to that of anti-VEGF antibody-injected ones. These results indicate that BAI1-ECR gene delivery effectively reduces experimental corneal neovascularization and suggest that the BAI1-ECR protein can be used as an angiogenesis suppressor in the eye. Gene Therapy (2005) 12, 617-624.

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Topical application of methotrexate for inhibition of corneal angiogenesis

Abstract: The antiangiogenic mechanism of MTX might be due to inhibition of both macrophage invasion during early angiogenesis and endothelial cell proliferation. The high levels in the aqueous humor indicate a possible application of topical MTX for inflammations of the anterior segment of the eye.

Cited by 83 publications

References 31 publications

Immunological Disruption of Antiangiogenic Signals by Recruited Allospecific T Cells Leads to Corneal Allograft Rejection

Immunological Disruption of Antiangiogenic Signals by Recruited Allospecific T Cells Leads to Corneal Allograft Rejection

Topical and Subconjunctival Bevacizumab for Corneal Neovascularization in an Experimental Rat Model

Lipid-mediated delivery of brain-specific angiogenesis inhibitor 1 gene reduces corneal neovascularization in an in vivo rabbit model

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