Journal Article

Lentiviral-vector-mediated expression of murine IL-1 receptor antagonist or IL-10 reduces the severity of endotoxin-induced uveitis

Smith, A J, Robbie, S J, Ali, R R, Barker, S E, Natkunarajah, M, Dick, A D, Sarra, G-M, Duran, Y, Trittibach, P, Broderick, C A, Bainbridge, J W B

2008

Overview

Uveitis is a sight threatening inflammatory disorder that remains a significant cause of visual loss. We investigated lentiviral gene delivery of interleukin 1 receptor antagonist (IL-1ra) or interleukin (IL)-10 to ameliorate murine endotoxin-induced uveitis (EIU). An human immunodeficiency virus-1-based vector containing the mIL-1ra or mIL-10 cDNA demonstrated high expression of biologically active cytokine. Following administration of Lenti.GFP into the anterior chamber, transgene expression was observed in corneal endothelial cells, trabecular meshwork and iris cells. To treat EIU, mice were injected with Lenti.IL-1ra, Lenti.IL-10 or a combination of these. EIU was induced 14 days after vector administration and mice were culled 12 h following disease induction. Lenti.IL-1ra or Lenti.IL-10-treated eyes showed significantly lower mean inflammatory cell counts in the anterior and posterior chambers compared with controls. The aqueous total protein content was also significantly lower in treated eyes, demonstrating better preservation of the blood-ocular barrier. Furthermore, the treated eyes showed less in vivo fluorescein leakage from inner retinal vessels compared with controls. The combination of both IL-1ra and IL-10 had no additive effect. Thus, lentiviral gene delivery of IL-1ra or IL-10 significantly reduces the severity of experimental uveitis, suggesting that lentiviral-mediated expression of immunomodulatory genes in the anterior chamber offers an opportunity to treat uveitis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Animals / Anterior chamber / Applied cell therapy and gene therapy / Biological activity / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Biotechnology / Blood vessels / Care and treatment / Cell Biology / Cell receptors / Cell structures and functions / Cornea / Cytokines / Endothelial cells / Eye / Female / Fluorescein / Fundamental and applied biological sciences. Psychology / Gene Expression / Gene Therapy / Gene transfer / Genetic aspects / Genetic Therapy - methods / Genetic vectors / Genetic Vectors - administration & dosage / Genetic Vectors - genetics / Health. Pharmaceutical industry / HIV / HIV-1 - genetics / Human Genetics / Human immunodeficiency virus / Humans / Immunomodulation / Industrial applications and implications. Economical aspects / Inflammatory diseases / Injections / Interleukin 1 / Interleukin 1 receptor antagonist / Interleukin 1 Receptor Antagonist Protein - genetics / Interleukin 1 Receptor Antagonist Protein - immunology / Interleukin 1 Receptor Antagonist Protein - metabolism / Interleukin 10 / Interleukin-10 - genetics / Interleukin-10 - immunology / Interleukin-10 - metabolism / Interleukins / Lipopolysaccharides / Medical sciences / Mice / Mice, Inbred C57BL / Miscellaneous / Models, Animal / Molecular and cellular biology / Nanotechnology / Ophthalmology / original-article / Physiological aspects / Rodents / Transduction, Genetic - methods / Transfusions. Complications. Transfusion reactions. Cell and gene therapy / Transgenes / Uvea - immunology / Uveitis / Uveitis - immunology / Uveitis - therapy