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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Li
Jin
J
Department of Ophthalmology, Ophtha-Lab at St. Franziskus Hospital, Hohenzollernring 74, 48145 Muenster, Germany.
Wasmuth
Susanne
S
Bauer
Dirk
D
Baehler
Hanna
H
Hennig
Maren
M
Heiligenhaus
Arnd
A
D000818:Animals; D000914:Antibodies, Viral; D003228:Conjunctiva; D004797:Enzyme-Linked Immunosorbent Assay; D015828:Eye Infections, Viral / Q000276:immunology / Q000473:pathology / Q000821:virology*; D005260:Female; D006561:Herpes Simplex / Q000276:immunology / Q000473:pathology / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007267:Injections; D008198:Lymph Nodes; D051379:Mice; D008807:Mice, Inbred BALB C; D020320:Oligoribonucleotides, Antisense / Q000008:administration & dosage / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000187:drug effects; D015882:Retinal Necrosis Syndrome, Acute / Q000276:immunology / Q000473:pathology / Q000821:virology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects*
D000914:Antibodies, Viral; D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha