Subconjunctival antisense oligonucleotides targeting TNF-α influence immunopathology and viral replication in murine HSV-1 retinitis

• DOI: 10.1007/s00417-008-0839-y
• Publication Date: 2008-05-19T10:43:32Z
• Authors: Jin Li; Susanne Wasmuth; Dirk Bauer; Hanna Baehler; Maren Hennig; Arnd Heiligenhaus
• Keywords: Mice, Inbred BALB C; Tumor Necrosis Factor-alpha; Eye Infections, Viral; Enzyme-Linked Immunosorbent Assay; Herpes Simplex; Retinal Necrosis Syndrome, Acute; Herpesvirus 1, Human; Antibodies, Viral; Virus Replication; Injections; 3. Good health; Mice; 03 medical and health sciences; 0302 clinical medicine; Animals; Female; Hypersensitivity, Delayed; Lymph Nodes; RNA, Messenger; Conjunctiva; Oligoribonucleotides, Antisense

To investigate the role of tumor necrosis factor-alpha (TNF-alpha) in immunopathology and viral replication in the contralateral eye in the von Szily model of herpes simplex virus (HSV)-1 acute retinitis.In vivo distribution was analyzed after subconjunctival injection of FITC-labeled antisense oligonucleotides (ASON). After HSV-1 (KOS) was injected in the right anterior chamber (AC) in BALB/c mice, the course of the contralateral retinitis was evaluated. The left eyes were treated with either TNF-alpha ASON, sequence-unspecific control (CON), or buffer. The ocular TNF-alpha content was quantified by ELISA. The delayed-type hypersensitivity (DTH) reaction, uptake of [3H]thymidine from regional lymph nodes (rln)- and spleen cells, serum-neutralizing antibodies, and viral titer in the eyes were evaluated.After subconjunctival injection, FITC-labeled ASON were found in the choroid and retina. In the TNF-alpha ASON-treated eyes, TNF-alpha expression and the incidence and severity of retinitis were reduced on day 8 postinfection (PI) (p < 0.05). On day 10 PI, higher viral titers were only seen in the eyes of the TNF-alpha ASON group (p < 0.05), and retinitis was slightly more severe on day 12 PI. While the HSV-1 specific [3H]thymidine uptake from rln cells was higher in the TNF-alpha ASON mice (p < 0.05), the [3H]thymidine uptake from spleen cells, the DTH response, and the neutralizing-antibody titers did not differ between the groups.After regional blockade of TNF-alpha in experimental HSV-1 retinitis TNF-alpha seems to possess an antiviral capacity against HSV-1 in the contralateral eye and participates in the immunopathology of HSV-1-induced acute retinitis.