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Hiroshi Mochimaru, Tomohiko Usui, Tomonori Yaguchi, Yasuharu Nagahama, Go Hasegawa, Yoshihiko Usui, Shigeto Shimmura, Kazuo Tsubota, Shiro Amano, Yutaka Kawakami, Susumu Ishida; Suppression of Alkali Burn-Induced Corneal Neovascularization by Dendritic Cell Vaccination Targeting VEGF Receptor 2. Invest. Ophthalmol. Vis. Sci. 2008;49(5):2172-2177. doi: 10.1167/iovs.07-1396.
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purpose. To investigate whether the induction of cytotoxic T lymphocytes (CTLs) targeting VEGF receptor 2 inhibits corneal neovascularization caused by alkali injury.
methods. H-2Db-restricted peptide corresponding to amino acids 400 to 408 of VEGF receptor 2 (VEGFR2400–408) was used as an epitope peptide. Dendritic cells (DCs) were harvested from bone marrow progenitors of C57BL/6 mice. Six-week-old C57BL/6 mice received subcutaneous injections of VEGFR2400–408- or gp70-pulsed mature DCs three times at 6-day intervals. After the third immunization, corneal neovascularization was induced by alkali injury. Two weeks after the injury, the corneal vascularized area was evaluated by lectin angiography. To confirm the peptide-specific CTL activities in C57BL/6 mice, CD8+ T cells from immunized mice were subjected to ELISA for interferon (IFN)-γ and tumor necrosis factor (TNF)-α production and 51Cr-release cytotoxicity assay. To determine the in vivo effector T cells, the immunized mice were intraperitoneally injected with an anti-CD4 or -CD8 depletion antibody.
results. Corneal neovascularization was significantly attenuated in mice immunized with VEGFR2400–408 compared with those not immunized or immunized with gp70. VEGFR2400–408 or gp70, but not β-gal96–103, application led to dose-dependent induction of IFN-γ and TNF-α in the CD8+ T cells cocultured with stimulator cells. Cytotoxicity assays showed the specific lysis of major histocompatibility complex-matched cells expressing VEGFR2, but not β-gal96–103. In vivo depletion of CD8+, but not CD4+, T cells significantly reversed the suppressive effect of VEGFR2400–408 immunization on corneal neovascularization to the level observed in nonimmunized or gp70-immunized animals.
conclusions. These results indicate the possibility of DC vaccination targeting VEGFR2 as a novel therapeutic strategy for corneal chemical injury.
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