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.

  • Paper
  • Published:

Intra-articular IL-4 gene therapy in arthritis: anti-inflammatory effect and enhanced Th2activity

Abstract

Gene therapy has been explored as a potential method for treating chronic inflammatory diseases such as rheumatoid arthritis. To determine the efficacy of intra-articular IL-4 gene therapy in an animal model of arthritis using a retroviral vector, a retrovirus encoding rat IL-4 (DA-IL-4) was engineered, purified and concentrated to high titer (109 CFU/ml). Infectivity and expression levels were demonstrated in vitro using cultured fibroblast-like synoviocytes. Efficacy was evaluated in the rat adjuvant arthritis model. DA-IL-4 or DA-β-gal retrovirus was injected into the intra-articular joint space of the right ankle on day 12 after immunization. Three days after joint injection, the injected paw contained increased levels of IL-4 compared with control or with the contralateral uninjected paw, demonstrating successful transgene expression. Surprisingly, 8 days after treatment IL-4 levels continued to increase in the injected and contralateral paw compared with DA-β-gal-treated animals. Serum IL-4 levels were also elevated in DA-IL-4-treated rats. RT-PCR studies demonstrated that the transgene was expressed in the injected ankle but not in the contralateral joint. IL-4 gene therapy resulted in a significant reduction in paw swelling and decreased radiographic evidence of bone destruction. This is the first demonstration of successful intra-articular retroviral gene treatment using a therapeutic gene. In addition to its anti-inflammatory effect, this study supports the potential application of intra-articular gene therapy as a method for enhancing systemic Th2 function.

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. Firestein GS . Etiology and pathogenesis of rheumatoid arthritis. In: Kelley WN et al (eds). Textbook of Rheumatology, 5th edn WB Saunders Co: Philadelphia 1997 851–897

    Google Scholar 

  2. Firestein GS, Zvaifler NJ . How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum 1990 33: 768–773

    Article  CAS  PubMed  Google Scholar 

  3. Miossec P, van den Berg W . Th1/Th2 cytokine balance in arthritis Arthritis Rheum 1997 40: 2105–2115

    Article  CAS  PubMed  Google Scholar 

  4. Mauri C, Williams RO, Walmsley M, Feldmann M . Relationship between Th1/Th2 cytokine patterns and the arthritogenic response in collagen-induced arthritis Eur J Immunol 1996 26: 1511–1518

    Article  CAS  PubMed  Google Scholar 

  5. Doncarli A, Stasiuk LM, Fournier C, Abehsira-Amar O . Conversion in vivo from an early dominant Th0/Th1 response to a Th2 phenotype during the development of collagen-induced arthritis Eur J Immunol 1997 27: 1451–1458

    Article  CAS  PubMed  Google Scholar 

  6. Horsfall AC et al. Suppression of collagen-induced arthritis by continuous administration of IL-4 J Immunol 1997 159: 5687–5696

    CAS  PubMed  Google Scholar 

  7. Joosten LA et al. Role of interleukin-4 and interleukin-10 in murine collagen-induced arthritis. Protective effect of interleukin-4 and interleukin-10 treatment on cartilage destruction Arthritis Rheum 1997 40: 249–260

    Article  CAS  PubMed  Google Scholar 

  8. Bessis N et al. Attenuation of collagen-induced arthritis in mice by treatment with vector cells engineered to secrete interleukin-13 Eur J Immunol 1996 26: 2399–2403

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. Ghivizzani SC et al. Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor alpha 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 

  11. Parks E et al. Transient gene transfer of IL-12 regulates chemokine expression and disease severity in experimental arthritis J Immunol 1998 160: 4615–4619

    CAS  PubMed  Google Scholar 

  12. Le CH, Nicolson AG, Morales A, Sewell KL . Suppression of collagen-induced arthritis through adenovirus-mediated transfer of a modified tumor necrosis factor alpha receptor gene Arthritis Rheum 1997 40: 1662–1669

    Article  CAS  PubMed  Google Scholar 

  13. 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 

  14. Hung GL et al. Suppression of intra-articular responses to interleukin-1 by transfer of the interleukin-1 receptor antagonist gene to synovium Gene Therapy 1994 1: 64–69

    CAS  PubMed  Google Scholar 

  15. Otani K et al. Suppression of antigen-induced arthritis in rabbits by ex vivo gene therapy J Immunol 1996 156: 3558–3562

    CAS  PubMed  Google Scholar 

  16. Chernajovsky Y et al. Pathogenic lymphoid cells engineered to express TGF beta 1 ameliorate disease in a collagen-induced arthritis model Gene Therapy 1997 4: 553–559

    Article  CAS  PubMed  Google Scholar 

  17. Triantaphyllopoulos KA, Williams RO, Tailor H, Chernajovsky Y . Amelioration of collagen-induced arthritis and suppression of interferon-gamma, interleukin-12, and tumor necrosis factor alpha production by interferon-beta gene therapy Arthritis Rheum 1999 42: 90–99

    Article  CAS  PubMed  Google Scholar 

  18. Nguyen KHY et al. Direct synovial gene transfer with retroviral vectors in rat adjuvant arthritis J Rheumatol, 1998 25: 1118–1125

    CAS  Google Scholar 

  19. Evans CH et al. Gene therapy for rheumatic diseases Arthritis Rheum 1999 42: 1–16

    Article  CAS  PubMed  Google Scholar 

  20. Nita I et al. Direct gene delivery to synovium Arthritis Rheum 1996 39: 820–828

    Article  CAS  PubMed  Google Scholar 

  21. Bruder JT, Kovesdi I . Adenovirus infection stimulates the Raf/MAPK signaling pathway and induces interleukin-8 expression J Virol 1997 71: 398–404

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang Y, Su Q, Wilson JM . Role of viral antigens in destructive cellular immune responses to adenovirus vector-transduced cells in mouse lungs J Virol 1996 70: 7209–7212

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Knowles MR et al. A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis New Engl J Med 1995 333: 823–831

    Article  CAS  PubMed  Google Scholar 

  24. Vile RG, Tuszynski A, Castleden S . Retroviral vectors. From laboratory tools to molecular medicine Mol Biotechnol 1996 5: 139–158

    Article  CAS  PubMed  Google Scholar 

  25. Gojo S et al. Ex vivo gene transfer into myocardium using replication-defective retrovirus Cell Trans 1996 5 (Suppl. 1): S81–84

    Article  Google Scholar 

  26. Chomarat P, Banchereau J, Miossec P . Differential effects of interleukins 10 and 4 on the production of interleukin-6 by blood and synovium monocytes in rheumatoid arthritis Arthritis Rheum 1995 38: 1046–1054

    Article  CAS  PubMed  Google Scholar 

  27. Lacraz S et al. IL-10 inhibits metalloproteinase and stimulates TIMP-1 production in human mononuclear phagocytes J Clin Invest 1995 96: 2304–2310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nemoto O et al. Suppression of matrix metalloproteinase-3 synthesis by interleukin-4 in human articular chondrocytes J Rheumatol 1997 24: 1774–1779

    CAS  PubMed  Google Scholar 

  29. Dolhain RJ et al. Shift toward T lymphocytes with a T helper 1 cytokine-secretion profile in the joints of patients with rheumatoid arthritis Arthritis Rheum 1996 39: 1961–1969

    Article  CAS  PubMed  Google Scholar 

  30. Kusaba M, Honda J, Fukuda T, Oizumi K . Analysis of type 1 and type 2 T cells in synovial fluid and peripheral blood of patients with rheumatoid arthritis J Rheumatol 1998 25: 1466–1471

    CAS  PubMed  Google Scholar 

  31. Kotake S et al. In vivo gene expression of type 1 and type 2 cytokines in synovial tissues from patients in early stages of rheumatoid, reactive, and undifferentiated arthritis Proc Assoc Am Phys 1997 109: 286–301

    CAS  PubMed  Google Scholar 

  32. Irwin MJ et al. Direct injection of a recombinant retroviral vector induces human immunodeficiency virus-specific immune responses in mice and nonhuman primates J Virol 1994 68: 5036–5044

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Smiley WR et al. Establishment of parameters for optimal transduction efficiency and antitumor effects with purified high-titer HSV-TK retroviral vector in established solid tumors Hum Gene Ther 1997 8: 965–977

    Article  CAS  PubMed  Google Scholar 

  34. Miller AD, Buttimore C . Redesign of retrovirus packaging cell lines to avoid recombination leading to helper virus production Mol Cell Biol 1986 6: 2859–2902

    Article  Google Scholar 

  35. Arnett FC et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis Arthritis Rheum 1988 31: 315–324

    Article  CAS  PubMed  Google Scholar 

  36. Alvaro-Gracia JM, Zvaifler NJ, Firestein GS . Cytokines in chronic inflammatory arthritis. V. Mutual antagonism between IFN-gamma and TNF-alpha on HLA-DR expression, proliferation, collagenase production, and GM-CSF production by rheumatoid arthritis synoviocytes J Clin Invest 1990 86: 1790–1798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Firestein GS . Anti-inflammatory effects of adenosine kinase inhibitors in acute and chronic inflammation Drug Dev Res 1996 39: 371–376

    Article  CAS  Google Scholar 

Download references

Acknowledgements

These studies were supported in part by a University of California STAR Biotechnology grant and a grant from Chiron, Inc.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boyle, D., Nguyen, K., Zhuang, S. et al. Intra-articular IL-4 gene therapy in arthritis: anti-inflammatory effect and enhanced Th2activity. Gene Ther 6, 1911–1918 (1999). https://doi.org/10.1038/sj.gt.3301049

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301049

Keywords

This article is cited by

Search

Quick links