title: Intravitreal treatment with antisense oligonucleotides targeting tumor necrosis factor-α in murine herpes simplex virus type 1 retinitis.
abstract: BACKGROUND
  Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine known to participate in intraocular inflammatory disease. This study investigated whether treatment with intravitreal antisense-oligonucleotides (ASON) targeting TNF-α mRNA affects the progression of herpes simplex virus 1 (HSV-1) retinitis in mice.
  
  
  METHODS
  The in vivo uptake of the oligonucleotid after intravitreal injection was determined with FITC-labeled TNF-α ASON. HSV-retinitis was induced on day 0 by the injection of HSV-1 (KOS strain) into the anterior chamber (AC) of the right eyes of BALB/c mice (von Szily model). The left contralateral eyes were injected intravitreally on day 7 with TNF-α ASON, sequence-unspecific control ASON (CON), or buffer. The clinical course of retinitis, ocular inflammatory cell-infiltration, TNF-α expression in the eye by ELISA, delayed-type hypersensitivity (DTH) reaction, virus-neutralizing antibody titers in the serum, uptake of [3H]thymidine from regional lymph node (rln) cells, and viral content in the eyes were determined.
  
  
  RESULTS
  In vivo, strong fluorescence of FITC- TNF-α ASON was detected in the choroid and retina up to 3 days after intravitreal injection, but none in the rln. After treatment of eyes with ASON, decreased expression of TNF-α in the eye, and reduced incidence and severity of retinitis on day 10 after infection (P < 0.05) could be found. The other parameters were not significantly influenced after TNF-α ASON treatment.
  
  
  CONCLUSIONS
  TNF-α participates in the pathology of HSV-1 retinitis. Local inhibition of TNF-α mRNA by intraocular TNF-α ASON injection did not influence the systemic HSV-specific immune response or the antiviral response in the eye, but reduced ocular inflammatory bystander damage.
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Rafael S
authors.initials: RS
authors.lastname: Grajewski
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Susanne
authors.initials: S
authors.lastname: Wasmuth
authors.forename: Maren
authors.initials: M
authors.lastname: Hennig
authors.forename: Dirk
authors.initials: D
authors.lastname: Bauer
authors.forename: Arnd
authors.initials: A
authors.lastname: Heiligenhaus
mesh_terms: D000818:Animals; D000867:Anterior Chamber / Q000821:virology; D057134:Antibodies, Neutralizing; D004797:Enzyme-Linked Immunosorbent Assay; D015828:Eye Infections, Viral / Q000473:pathology / Q000628:therapy* / Q000821:virology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005904:Glial Fibrillary Acidic Protein; D006561:Herpes Simplex / Q000473:pathology / Q000628:therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006968:Hypersensitivity, Delayed / Q000276:immunology; D058449:Intravitreal Injections; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D015882:Retinal Necrosis Syndrome, Acute / Q000473:pathology / Q000628:therapy* / Q000821:virology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D010948:Viral Plaque Assay
chemical_list: D057134:Antibodies, Neutralizing; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C528900:glial fibrillary astrocytic protein, mouse
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