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Vascular Endothelial Growth Factor Receptor 2-Based DNA Immunization Delays Development of Herpetic Stromal Keratitis by Antiangiogenic Effects¹

Bumseok Kim^*, Susmit Suvas^*, Pranita P. Sarangi^*, Sujin Lee, Ralph A. Reisfeld and Barry T. Rouse^2,*

^* Department of Microbiology and Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996; Department of Pediatric Infectious Disease, Vanderbilt University, Nashville, TN 37232; and Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

Stromal keratitis (SK) is an immunoinflammatory eye lesion caused by HSV-1 infection. One essential step in the pathogenesis is neovascularization of the normally avascular cornea, a process that involves the vascular endothelial growth factor (VEGF) family of proteins. In this report, we targeted the proliferating vascular endothelial cells expressing VEGFR-2 in the SK cornea by immunization with recombinant Salmonella typhimurium containing a plasmid encoding murine VEGFR-2. This form of DNA immunization resulted in diminished angiogenesis and delayed development of SK caused by HSV-1 infection and also reduced angiogenesis resulting from corneal implantation with rVEGF. CTL responses against endothelial cells expressing VEGFR-2 were evident in the VEGFR-2-immunized group and in vivo CD8⁺ T cell depletion resulted in the marked reduction of the antiangiogenic immune response. These results indicate a role for CD8⁺ T cells in the antiangiogenic effects. Our results may also imply that the anti-VEGFR-2 vaccination approach might prove useful to control pathological ocular angiogenesis and its consequences.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant RO1 EY05093 (to B.T.R.) and CA 83856 (to R.A.R.).

² Address correspondence and reprint requests to Dr. Barry T. Rouse, University of Tennessee, M409 Walters Life Sciences Building, Knoxville, TN 37996-0845. E-mail address: btr{at}utk.edu

³ Abbreviations used in this paper: SK, stromal keratitis; VEGF, vascular endothelial cell growth factor; HEV, high endothelial venule; m, mouse; p.i., postinfection.

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