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Susanne Wasmuth, Dirk Bauer, Yanning Yang, Klaus-Peter Steuhl, Arnd Heiligenhaus; Topical Treatment with Antisense Oligonucleotides Targeting Tumor Necrosis Factor-α in Herpetic Stromal Keratitis. Invest. Ophthalmol. Vis. Sci. 2003;44(12):5228-5234. doi: 10.1167/iovs.03-0312.
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purpose. Tumor necrosis factor (TNF)-α is a pleiotropic factor that is critical for the development of inflammation. The authors investigated whether topical application of TNF-α-antagonizing molecules, antisense oligonucleotides (ASON), might be an effective way of modifying the course of immune-mediated herpetic stromal keratitis (HSK).
methods. ASON targeting TNF-α mRNA were examined for their efficiency in interfering with the production of this cytokine in vitro. In vivo uptake was determined by FITC-labeled ASON. HSV-1 corneally infected mice were injected three times with ASON. Mice from the control groups received unrelated control oligonucleotides (CON) or buffer. The clinical course of HSK, the delayed-type hypersensitivity (DTH) reaction, the uptake of [3H]thymidine from cells derived from the spleen, virus-neutralizing antibody titers in the serum, and viral replication in the infected eyes were determined. The eyes were examined histologically. The corneal TNF-α content was measured by ELISA.
results. The TNF-α ASON reduced the lymphocytic cytokine expression in vitro. In vivo, the FITC-labeled molecules were detected in the cornea even after 10 days. In the TNF-α ASON mice the incidence of HSK decreased, and the severity of the disease was diminished. The corneal content of TNF-α was reduced, and the number of inflammatory cells was decreased. The other investigated parameters were not significantly altered by TNF-α ASON treatment.
conclusions. The data suggest that TNF-α ASON diminishes the release of TNF-α from cultured lymphocytes and from lymphocytes in the HSV-1–infected cornea. This topical treatment mitigates the course of HSK, whereas the systemic antiviral effector functions were not impaired.
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