Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

Gene Therapy volume 15, pages 1478–1488 (2008)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Reeves SW, Sloan FA, Lee PP, Jaffe GJ . Uveitis in the elderly: epidemiological data from the national long-term care survey medicare cohort. Ophthalmology 2006; 113: 307.

    Article  PubMed  Google Scholar 

  2. Edelsten C, Reddy MA, Stanford MR, Graham EM . Visual loss associated with pediatric uveitis in English primary and referral centers. Am J Ophthalmol 2003; 135: 676–680.

    Article  PubMed  Google Scholar 

  3. Gritz DC, Wong IG . Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study. Ophthalmology 2004; 111: 491–500.

    Article  PubMed  Google Scholar 

  4. Imrie FR, Dick AD . Nonsteroidal drugs for the treatment of noninfectious posterior and intermediate uveitis. Curr Opin Ophthalmol 2007; 18: 212–219.

    Article  PubMed  Google Scholar 

  5. Broderick CA, Smith AJ, Balaggan KS, Georgiadis A, Buch PK, Trittibach PC et al. Local administration of an adeno-associated viral vector expressing IL-10 reduces monocyte infiltration and subsequent photoreceptor damage during experimental autoimmune uveitis. Mol Ther 2005; 12: 369–373.

    Article  CAS  PubMed  Google Scholar 

  6. Robertson M, Liversidge J, Forrester JV, Dick AD . Neutralizing tumor necrosis factor-alpha activity suppresses activation of infiltrating macrophages in experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci 2003; 44: 3034–3041.

    Article  PubMed  Google Scholar 

  7. Tynjala P, Lindahl P, Honkanen V, Lahdenne P, Kotaniemi K . Infliximab and etanercept in the treatment of chronic uveitis associated with refractory juvenile idiopathic arthritis. Ann Rheum Dis 2007; 66: 548–550.

    Article  CAS  PubMed  Google Scholar 

  8. Smith JR, Verwaerde C, Rolling F, Naud MC, Delanoye A, Thillaye-Goldenberg B et al. Tetracycline-inducible viral interleukin-10 intraocular gene transfer, using adeno-associated virus in experimental autoimmune uveoretinitis. Hum Gene Ther 2005; 16: 1037–1046.

    Article  CAS  PubMed  Google Scholar 

  9. Rosenbaum JT, McDevitt HO, Guss RB, Egbert PR . Endotoxin-induced uveitis in rats as a model for human disease. Nature 1980; 286: 611–613.

    Article  CAS  PubMed  Google Scholar 

  10. Forrester JV, Worgul BV, Merriam Jr GR . Endotoxin-induced uveitis in the rat. Albrecht Von Graefes Arch Klin Exp Ophthalmol 1980; 213: 221–233.

    Article  CAS  PubMed  Google Scholar 

  11. Baeuerle PA, Henkel T . Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 1994; 12: 141–179.

    Article  CAS  PubMed  Google Scholar 

  12. Baeuerle PA, Baltimore D . NF-kappa B: ten years after. Cell 1996; 87: 13–20.

    Article  CAS  PubMed  Google Scholar 

  13. de Vos AF, Klaren VN, Kijlstra A . Expression of multiple cytokines and IL-1RA in the uvea and retina during endotoxin-induced uveitis in the rat. Invest Ophthalmol Vis Sci 1994; 35: 3873–3883.

    CAS  PubMed  Google Scholar 

  14. Planck SR, Huang XN, Robertson JE, Rosenbaum JT . Cytokine mRNA levels in rat ocular tissues after systemic endotoxin treatment. Invest Ophthalmol Vis Sci 1994; 35: 924–930.

    CAS  PubMed  Google Scholar 

  15. Shen DF, Buggage RR, Eng HC, Chan CC . Cytokine gene expression in different strains of mice with endotoxin-induced uveitis (EIU). Ocul Immunol Inflamm 2000; 8: 221–225.

    Article  CAS  PubMed  Google Scholar 

  16. Tuaillon N, Shen DF, Berger RB, Lu B, Rollins BJ, Chan CC . MCP-1 expression in endotoxin-induced uveitis. Invest Ophthalmol Vis Sci 2002; 43: 1493–1498.

    PubMed  Google Scholar 

  17. Jacquemin E, De Kozak Y, Thillaye B, Courtois Y, Goureau O . Expression of inducible nitric oxide synthase in the eye from endotoxin-induced uveitis rats. Invest Ophthalmol Vis Sci 1996; 37: 1187–1196.

    CAS  PubMed  Google Scholar 

  18. Bellot JL, Palmero M, Garcia-Cabanes C, Espi R, Hariton C, Orts A . Additive effect of nitric oxide and prostaglandin-E2 synthesis inhibitors in endotoxin-induced uveitis in the rabbit. Inflamm Res 1996; 45: 203–208.

    Article  CAS  PubMed  Google Scholar 

  19. Arend WP . The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev 2002; 13: 323–340.

    Article  CAS  PubMed  Google Scholar 

  20. Hill N, Sarvetnick N . Cytokines: promoters and dampeners of autoimmunity. Curr Opin Immunol 2002; 14: 791–797.

    Article  CAS  PubMed  Google Scholar 

  21. Riley JK, Takeda K, Akira S, Schreiber RD . Interleukin-10 receptor signaling through the JAK-STAT pathway. Requirement for two distinct receptor-derived signals for anti-inflammatory action. J Biol Chem 1999; 274: 16513–16521.

    Article  CAS  PubMed  Google Scholar 

  22. Hayashi S, Guex-Crosier Y, Delvaux A, Velu T, Roberge FG . Interleukin 10 inhibits inflammatory cells infiltration in endotoxin-induced uveitis. Graefes Arch Clin Exp Ophthalmol 1996; 234: 633–636.

    Article  CAS  PubMed  Google Scholar 

  23. Bainbridge JW, Stephens C, Parsley K, Demaison C, Halfyard A, Thrasher AJ et al. In vivo gene transfer to the mouse eye using an HIV-based lentiviral vector; efficient long-term transduction of corneal endothelium and retinal pigment epithelium. Gene Therapy 2001; 8: 1665–1668.

    Article  CAS  PubMed  Google Scholar 

  24. Demaison C, Brouns G, Blundell MP, Goldman JP, Levinsky RJ, Grez M et al. A defined window for efficient gene marking of severe combined immunodeficient-repopulating cells using a gibbon ape leukemia virus-pseudotyped retroviral vector. Hum Gene Ther 2000; 11: 91–100.

    Article  CAS  PubMed  Google Scholar 

  25. Tschernutter M, Schlichtenbrede FC, Howe S, Balaggan KS, Munro PM, Bainbridge JW et al. Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy. Gene Therapy 2005; 12: 694–701.

    Article  CAS  PubMed  Google Scholar 

  26. Yanez-Munoz RJ, Balaggan KS, MacNeil A, Howe SJ, Schmidt M, Smith AJ et al. Effective gene therapy with nonintegrating lentiviral vectors. Nat Med 2006; 12: 348–353.

    Article  CAS  PubMed  Google Scholar 

  27. Qin L, Ding Y, Pahud DR, Chang E, Imperiale MJ, Bromberg JS . Promoter attenuation in gene therapy: interferon-gamma and tumor necrosis factor-alpha inhibit transgene expression. Hum Gene Ther 1997; 8: 2019–2029.

    Article  CAS  PubMed  Google Scholar 

  28. Cominelli F, Nast CC, Clark BD, Schindler R, Lierena R, Eysselein VE et al. Interleukin 1 (IL-1) gene expression, synthesis, and effect of specific IL-1 receptor blockade in rabbit immune complex colitis. J Clin Invest 1990; 86: 972–980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cominelli F, Nast CC, Duchini A, Lee M . Recombinant interleukin-1 receptor antagonist blocks the proinflammatory activity of endogenous interleukin-1 in rabbit immune colitis. Gastroenterology 1992; 103: 65–71.

    Article  CAS  PubMed  Google Scholar 

  30. Thomas TK, Will PC, Srivastava A, Wilson CL, Harbison M, Little J et al. Evaluation of an interleukin-1 receptor antagonist in the rat acetic acid-induced colitis model. Agents Actions 1991; 34: 187–190.

    Article  CAS  PubMed  Google Scholar 

  31. McCall RD, Haskill S, Zimmermann EM, Lund PK, Thompson RC, Sartor RB . Tissue interleukin 1 and interleukin-1 receptor antagonist expression in enterocolitis in resistant and susceptible rats. Gastroenterology 1994; 106: 960–972.

    Article  CAS  PubMed  Google Scholar 

  32. Lim WK, Fujimoto C, Ursea R, Mahesh SP, Silver P, Chan CC et al. Suppression of immune-mediated ocular inflammation in mice by interleukin 1 receptor antagonist administration. Arch Ophthalmol 2005; 123: 957–963.

    Article  CAS  PubMed  Google Scholar 

  33. Teoh SC, Sharma S, Hogan A, Lee R, Ramanan AV, Dick AD . Tailoring biological treatment: anakinra treatment of posterior uveitis associated with the CINCA syndrome. Br J Ophthalmol 2007; 91: 263–264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Grool TA, van Dullemen H, Meenan J, Koster F, ten Kate FJ, Lebeaut A et al. Anti-inflammatory effect of interleukin-10 in rabbit immune complex-induced colitis. Scand J Gastroenterol 1998; 33: 754–758.

    Article  CAS  PubMed  Google Scholar 

  35. Apparailly F, Verwaerde C, Jacquet C, Auriault C, Sany J, Jorgensen C . Adenovirus-mediated transfer of viral IL-10 gene inhibits murine collagen-induced arthritis. J Immunol 1998; 160: 5213–5220.

    CAS  PubMed  Google Scholar 

  36. Fang IM, Lin CP, Yang CH, Chiang BL, Yang CM, Chau LY et al. Inhibition of experimental autoimmune anterior uveitis by adenovirus-mediated transfer of the interleukin-10 gene. J Ocul Pharmacol Ther 2005; 21: 420–428.

    Article  CAS  PubMed  Google Scholar 

  37. De Kozak Y, Thillaye-Goldenberg B, Naud MC, Da Costa AV, Auriault C, Verwaerde C . Inhibition of experimental autoimmune uveoretinitis by systemic and subconjunctival adenovirus-mediated transfer of the viral IL-10 gene. Clin Exp Immunol 2002; 130: 212–223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Makarov SS, Olsen JC, Johnston WN, Anderle SK, Brown RR, Baldwin Jr AS et al. Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist cDNA. Proc Natl Acad Sci USA 1996; 93: 402–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pan RY, Chen SL, Xiao X, Liu DW, Peng HJ, Tsao YP . Therapy and prevention of arthritis by recombinant adeno-associated virus vector with delivery of interleukin-1 receptor antagonist. Arthritis Rheum 2000; 43: 289–297.

    Article  CAS  PubMed  Google Scholar 

  40. Huhn RD, Radwanski E, O'Connell SM, Sturgill MG, Clarke L, Cody RP et al. Pharmacokinetics and immunomodulatory properties of intravenously administered recombinant human interleukin-10 in healthy volunteers. Blood 1996; 87: 699–705.

    CAS  PubMed  Google Scholar 

  41. Gouze JN, Gouze E, Palmer GD, Liew VS, Pascher A, Betz OB et al. A comparative study of the inhibitory effects of interleukin-1 receptor antagonist following administration as a recombinant protein or by gene transfer. Arthritis Res Ther 2003; 5: R301–R309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Barbara G, Xing Z, Hogaboam CM, Gauldie J, Collins SM . Interleukin 10 gene transfer prevents experimental colitis in rats. Gut 2000; 46: 344–349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fukumoto T, Matsukawa A, Ohkawara S, Takagi K, Yoshinaga M . Administration of neutralizing antibody against rabbit IL-1 receptor antagonist exacerbates lipopolysaccharide-induced arthritis in rabbits. Inflamm Res 1996; 45: 479–485.

    Article  CAS  PubMed  Google Scholar 

  44. Seely AJ, Pascual JL, Christou NV . Science review: cell membrane expression (connectivity) regulates neutrophil delivery, function and clearance. Crit Care 2003; 7: 291–307.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Ikeda M, Ikeda U, Shimada K, Minota S, Kano S . Regulation of ICAM-1 expression by inflammatory cytokines in rat mesangial cells. Cytokine 1996; 8: 109–114.

    Article  CAS  PubMed  Google Scholar 

  46. Dinarello CA . The IL-1 family and inflammatory diseases. Clin Exp Rheumatol 2002; 20: S1–13.

    CAS  PubMed  Google Scholar 

  47. Becker MD, Garman K, Whitcup SM, Planck SR, Rosenbaum JT . Inhibition of leukocyte sticking and infiltration, but not rolling, by antibodies to ICAM-1 and LFA-1 in murine endotoxin-induced uveitis. Invest Ophthalmol Vis Sci 2001; 42: 2563–2566.

    CAS  PubMed  Google Scholar 

  48. Whitcup SM, DeBarge LR, Rosen H, Nussenblatt RB, Chan CC . Monoclonal antibody against CD11b/CD18 inhibits endotoxin-induced uveitis. Invest Ophthalmol Vis Sci 1993; 34: 673–681.

    CAS  PubMed  Google Scholar 

  49. Koizumi K, Poulaki V, Doehmen S, Welsandt G, Radetzky S, Lappas A et al. Contribution of TNF-alpha to leukocyte adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis in vivo. Invest Ophthalmol Vis Sci 2003; 44: 2184–2191.

    Article  PubMed  Google Scholar 

  50. Yang GY, Mao Y, Zhou LF, Gong C, Ge HL, Betz AL . Expression of intercellular adhesion molecule 1 (ICAM-1) is reduced in permanent focal cerebral ischemic mouse brain using an adenoviral vector to induce overexpression of interleukin-1 receptor antagonist. Brain Res Mol Brain Res 1999; 65: 143–150.

    Article  CAS  PubMed  Google Scholar 

  51. Sarra GM, Stephens C, Schlichtenbrede FC, Bainbridge JW, Thrasher AJ, Luthert PJ et al. Kinetics of transgene expression in mouse retina following sub-retinal injection of recombinant adeno-associated virus. Vision Res 2002; 42: 541–549.

    Article  CAS  PubMed  Google Scholar 

  52. Lai YK, Shen WY, Brankov M, Lai CM, Constable IJ, Rakoczy PE . Potential long-term inhibition of ocular neovascularisation by recombinant adeno-associated virus-mediated secretion gene therapy. Gene Therapy 2002; 9: 804–813.

    Article  CAS  PubMed  Google Scholar 

  53. Abordo-Adesida E, Follenzi A, Barcia C, Sciascia S, Castro MG, Naldini L et al. Stability of lentiviral vector-mediated transgene expression in the brain in the presence of systemic antivector immune responses. Hum Gene Ther 2005; 16: 741–751.

    Article  CAS  PubMed  Google Scholar 

  54. Muhaya M, Calder VL, Towler HM, Jolly G, McLauchlan M, Lightman S . Characterization of phenotype and cytokine profiles of T cell lines derived from vitreous humour in ocular inflammation in man. Clin Exp Immunol 1999; 116: 410–414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Symons JA, Dickens EM, Di Giovine F, Duff GW . Measurement of Interleukin-1 activity. In: Clemens MJ, Morris AG, Gearing AJH (eds). Lymphokines and interferons, a practical approach. IRL Press: Oxford, UK, 1987, pp270–272.

Download references

Acknowledgements

This work was supported by The Sir Jules Thorn Charitable Trust, Moorfields Eye Hospital Special Trustees, the UK Department of Health and the Department of Health's National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and the UCL Institute for Ophthalmology. Personal support was provided to PT by the Swiss National Science Foundation, the Alfred A Vogt Foundation and the Swiss Fund for Preventing and Fight of the Blindness.

Author information

Authors and Affiliations

  1. Division of Molecular Therapy, Institute of Ophthalmology, University College London, London, UK

    P Trittibach, S E Barker, C A Broderick, M Natkunarajah, Y Duran, S J Robbie, J W B Bainbridge, A J Smith & R R Ali

  2. Department of Ophthalmology, University of Bern, Inselspital, Bern, Switzerland

    P Trittibach & G-M Sarra

  3. Academic Unit of Ophthalmology, Bristol Eye Hospital, University of Bristol, Bristol, UK

    A D Dick

Authors
  1. P Trittibach
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S E Barker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C A Broderick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Natkunarajah
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Duran
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S J Robbie
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J W B Bainbridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A J Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G-M Sarra
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A D Dick
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. R R Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R R Ali.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Trittibach, P., Barker, S., Broderick, C. et al. Lentiviral-vector-mediated expression of murine IL-1 receptor antagonist or IL-10 reduces the severity of endotoxin-induced uveitis. Gene Ther 15, 1478–1488 (2008). https://doi.org/10.1038/gt.2008.109

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2008.109

Keywords

This article is cited by

Search

Advanced search

Quick links