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.

  • Research Article
  • Published:

The contralateral effect conferred by intra-articular adenovirus-mediated gene transfer of viral IL-10 is specific to the immunizing antigen

Abstract

We have demonstrated previously that local, adenoviral-mediated gene transfer of vIL-10 to a single joint of rabbits and mice with experimental arthritis can suppress disease in both the treated and untreated contralateral joints. These therapeutic effects observed in distant untreated joints following local intra-articular gene delivery have been termed the ‘contralateral effect’. To begin to understand the underlying immunologic mechanism that confers this effect, a dual-antigen model of antigen-induced arthritis (AIA) in rabbit knee joints was utilized. Rabbits were immunized against two antigens, ovalbumin and keyhole limpet hemocyanin, and AIA generated by intra-articular injection of each antigen into contralateral knees. Intra-articular adenovirus-mediated gene transfer of vIL-10 significantly reduced intra-articular leukocytosis and cartilage matrix degradation, while preserving near normal levels of cartilage matrix synthesis within treated joints. However, no antiarthritic effect was conferred in the contralateral control joints that received only a marker gene, in contrast to the results seen in a single-antigen AIA model. These results suggest that the distant antiarthritic effects associated with local gene delivery to joints are antigen-specific, and not due to vIL-10-induced generalized immunosuppression of the animal.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

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

Similar content being viewed by others

References

  1. Bresnihan B et al. Treatment of rheumatoid arthritis with recombinant human interelukin-1 receptor antagonist. Arthritis Rheum 1998; 41: 2196–2204.

    CAS  PubMed  Google Scholar 

  2. Jiang Y et al. A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larson scores. Arthritis Rheum 2000; 43: 1001–1009.

    CAS  PubMed  Google Scholar 

  3. Moreland LW et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997; 337: 141–147.

    CAS  PubMed  Google Scholar 

  4. Elliott MJ et al. Randomized double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor [alpha](cA2) versus placebo in rheumatoid arthritis. Lancet 1994; 244: 1105–1110.

    Google Scholar 

  5. Lechman ER et al. Direct adenoviral gene transfer of viral IL-10 to rabbit knees with experimental arthritis ameliorates disease in both injected and contralateral control knees. J Immunol 1999; 163: 2202–2208.

    CAS  PubMed  Google Scholar 

  6. Whalen JD et al. Adenoviral transfer of the viral IL-10 gene periarticularly to mouse paws suppresses development of collagen-induced arthritis in both injected and uninjected paws. J Immunol 1999; 162: 3625–3632.

    CAS  PubMed  Google Scholar 

  7. Ghivizzani SC et al. Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor α soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects. Proc Natl Acad Sci USA 1998; 95: 4613–4618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Boyle DL et al. Intra-articular IL-4 gene therapy in arthritis: anti-inflammatory effect and enhanced th2 activity. Gene Therapy 1999; 6: 1911–1918.

    Article  CAS  PubMed  Google Scholar 

  9. Kim SH et al. Ex vivo gene delivery of IL-1Ra and soluble TNF receptor confers a distal synergistic therapeutic effect in antigen-induced arthritis. Mol Ther 2002; 6: 591–600.

    Article  CAS  PubMed  Google Scholar 

  10. Miagkov AV et al. NF-kappaB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc Natl Acad Sci USA 1998; 95: 13859–13864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Watanabe S et al. On the mechanism of protection of distal joints after local gene transfer in collagen-induced arthritis. Hum Gene Ther 2000; 11: 751–758.

    Article  CAS  PubMed  Google Scholar 

  12. Lubbert E et al. Intra-articular IL-10 gene transfer regulates the expression of collagen-induced arthritis (CIA) in the knee and ipsilateral paw. Clin Exp Immunol 2000; 120: 375–383.

    Article  Google Scholar 

  13. Yeh P, Perricaudet M . Advances in adenoviral vectors: from genetic engineering to their biology. FASEB J 1997; 11: 615–623.

    Article  CAS  PubMed  Google Scholar 

  14. Graham FL, Van der Eb AJ . A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology 1973; 52: 456–467.

    Article  CAS  PubMed  Google Scholar 

  15. Mittereder N, March KL, Trapnell BC . Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy. J Virol 1996; 70: 7498–7509.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Glynn LE . The chronicity of inflammation and its significance in rheumatoid arthritis. Ann Rheum Dis 1968; 27: 105–121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Taskiran D, Stefanovic-Racic M, Georgescu HI, Evans CH . Nitric-oxide mediates suppression of cartilage proteoglycan synthesis by interelukin-1. Biochem Biophys Res Commun 1994; 200: 142–148.

    Article  CAS  PubMed  Google Scholar 

  18. Farndale RW, Buttle DJ, Barnette AJ . Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylene blue. Biochem Biophys Acta 1986; 883: 173–177.

    Article  CAS  PubMed  Google Scholar 

  19. Kim SH et al. Gene therapy for established murine collagen-induced arthritis by local and systemic adenovirus-mediated delivery of interleukin-4. Arthritis Res 2000; 2: 293–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang H et al. Amelioration of collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer. J Clin Invest 1997; 100: 1951–1957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Whalen JD et al. Viral IL-10 gene transfer inhibits DTH responses to soluble antigens: evidence for involvement of genetically modified dendritic cells and macrophages. Mol Ther 2001; 4: 543–550.

    Article  CAS  PubMed  Google Scholar 

  22. Kim S-H et al. Effective treatment of established murine collagen-induced arthritis by systemic administration of dendritic cells genetically modified to express IL-4. J Immunol 2001; 166: 3499–3505.

    Article  CAS  PubMed  Google Scholar 

  23. Kim SH, Kim S, Oligino TJ, Robbins PD . Effective treatment of established mouse collagen-induced arthritis by systemic administration of dendritic cells genetically modified to express FasL. 2002; 6: 584–590.

  24. Sack U et al. Systemic characteristics of chronic arthritis induced by transfer of human rheumatoid synovial membrane into SCID mice (human/murine SCID arthritis). J Autoimmun 1999; 13: 335–346.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Steve Ghivizzani, Tom Oligino and Chris Evans for helpful discussions. We would especially like to thank Jeff Mai for his technical expertise. The work was supported in part by Grants AR-6-2225 and DK44935 from the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lechman, E., Keravala, A., Nash, J. et al. The contralateral effect conferred by intra-articular adenovirus-mediated gene transfer of viral IL-10 is specific to the immunizing antigen. Gene Ther 10, 2029–2035 (2003). https://doi.org/10.1038/sj.gt.3302109

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302109

Keywords

This article is cited by

Search

Quick links