Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Jan 9;93(1):402–406. doi: 10.1073/pnas.93.1.402

Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist cDNA.

S S Makarov 1, J C Olsen 1, W N Johnston 1, S K Anderle 1, R R Brown 1, A S Baldwin Jr 1, J S Haskill 1, J H Schwab 1
PMCID: PMC40246  PMID: 8552648

Abstract

Restoration of the impaired balance between pro- and antiinflammatory cytokines should provide effective treatment of rheumatoid arthritis. Gene therapy has been proposed as an approach for delivery of therapeutic proteins to arthritic joints. Here, we examined the efficacy of antiinflammatory gene therapy in bacterial cell wall-induced arthritis in rats. Human secreted interleukin 1 receptor antagonist (sIL-1ra) was expressed in joints of rats with recurrent bacterial cell wall-induced arthritis by using ex vivo gene transfer. To achieve this, primary synoviocytes were transduced in culture with a retroviral vector carrying the sIL-1ra cDNA. Transduced cells were engrafted in ankle joints of animals prior to reactivation of arthritis. Animals in control groups were engrafted with synoviocytes transduced with lacZ and neo marker genes. Cells continued to express transferred genes for at least 9 days after engraftment. We found that gene transfer of sIL-1ra significantly suppressed the severity of recurrence of arthritis, as assessed by measuring joint swelling and by the gross-observation score, and attenuated but did not abolish erosion of cartilage and bone. The effect of intraarticularly expressed sIL-1ra was essentially local, as there was no significant difference in severity of recurrence between unengrafted contralateral joints in control and experimental groups. We estimate that locally expressed sIL-1ra was about four orders of magnitude more therapeutically efficient than systemically administered recombinant sIL-1ra protein. These findings provide experimental evidence for the feasibility of antiinflammatory gene therapy for arthritis.

Full text

PDF
405

Images in this article

404Fig. 1
on p.404
404Fig. 2
on p.404
405Fig. 5
on p.405

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adam M. A., Ramesh N., Miller A. D., Osborne W. R. Internal initiation of translation in retroviral vectors carrying picornavirus 5' nontranslated regions. J Virol. 1991 Sep;65(9):4985–4990. doi: 10.1128/jvi.65.9.4985-4990.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arend W. P., Dayer J. M. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum. 1995 Feb;38(2):151–160. doi: 10.1002/art.1780380202. [DOI] [PubMed] [Google Scholar]
  3. Arend W. P. Interleukin-1 receptor antagonist. Adv Immunol. 1993;54:167–227. doi: 10.1016/s0065-2776(08)60535-0. [DOI] [PubMed] [Google Scholar]
  4. Baeuerle P. A., Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–179. doi: 10.1146/annurev.iy.12.040194.001041. [DOI] [PubMed] [Google Scholar]
  5. Bandara G., Mueller G. M., Galea-Lauri J., Tindal M. H., Georgescu H. I., Suchanek M. K., Hung G. L., Glorioso J. C., Robbins P. D., Evans C. H. Intraarticular expression of biologically active interleukin 1-receptor-antagonist protein by ex vivo gene transfer. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10764–10768. doi: 10.1073/pnas.90.22.10764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bandara G., Robbins P. D., Georgescu H. I., Mueller G. M., Glorioso J. C., Evans C. H. Gene transfer to synoviocytes: prospects for gene treatment of arthritis. DNA Cell Biol. 1992 Apr;11(3):227–231. doi: 10.1089/dna.1992.11.227. [DOI] [PubMed] [Google Scholar]
  7. Bomsztyk K., Toivola B., Emery D. W., Rooney J. W., Dower S. K., Rachie N. A., Sibley C. H. Role of cAMP in interleukin-1-induced kappa light chain gene expression in murine B cell line. J Biol Chem. 1990 Jun 5;265(16):9413–9417. [PubMed] [Google Scholar]
  8. Cromartie W. J., Craddock J. G., Schwab J. H., Anderle S. K., Yang C. H. Arthritis in rats after systemic injection of streptococcal cells or cell walls. J Exp Med. 1977 Dec 1;146(6):1585–1602. doi: 10.1084/jem.146.6.1585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dinarello C. A. Interleukin-1. Adv Pharmacol. 1994;25:21–51. doi: 10.1016/s1054-3589(08)60429-9. [DOI] [PubMed] [Google Scholar]
  10. Dinarello C. A., Thompson R. C. Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro. Immunol Today. 1991 Nov;12(11):404–410. doi: 10.1016/0167-5699(91)90142-G. [DOI] [PubMed] [Google Scholar]
  11. Eisenberg S. P., Evans R. J., Arend W. P., Verderber E., Brewer M. T., Hannum C. H., Thompson R. C. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature. 1990 Jan 25;343(6256):341–346. doi: 10.1038/343341a0. [DOI] [PubMed] [Google Scholar]
  12. Esser R. E., Stimpson S. A., Cromartie W. J., Schwab J. H. Reactivation of streptococcal cell wall-induced arthritis by homologous and heterologous cell wall polymers. Arthritis Rheum. 1985 Dec;28(12):1402–1411. doi: 10.1002/art.1780281213. [DOI] [PubMed] [Google Scholar]
  13. Evans C., Robbins P. D. Prospects for treating arthritis by gene therapy. J Rheumatol. 1994 May;21(5):779–782. [PubMed] [Google Scholar]
  14. Granowitz E. V., Porat R., Mier J. W., Pribble J. P., Stiles D. M., Bloedow D. C., Catalano M. A., Wolff S. M., Dinarello C. A. Pharmacokinetics, safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans. Cytokine. 1992 Sep;4(5):353–360. doi: 10.1016/1043-4666(92)90078-6. [DOI] [PubMed] [Google Scholar]
  15. Hannum C. H., Wilcox C. J., Arend W. P., Joslin F. G., Dripps D. J., Heimdal P. L., Armes L. G., Sommer A., Eisenberg S. P., Thompson R. C. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990 Jan 25;343(6256):336–340. doi: 10.1038/343336a0. [DOI] [PubMed] [Google Scholar]
  16. Haskill S., Martin G., Van Le L., Morris J., Peace A., Bigler C. F., Jaffe G. J., Hammerberg C., Sporn S. A., Fong S. cDNA cloning of an intracellular form of the human interleukin 1 receptor antagonist associated with epithelium. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3681–3685. doi: 10.1073/pnas.88.9.3681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hung G. L., Galea-Lauri J., Mueller G. M., Georgescu H. I., Larkin L. A., Suchanek M. K., Tindal M. H., Robbins P. D., Evans C. H. Suppression of intra-articular responses to interleukin-1 by transfer of the interleukin-1 receptor antagonist gene to synovium. Gene Ther. 1994 Jan;1(1):64–69. [PubMed] [Google Scholar]
  18. Iwasaki T., Sims J. E., Grabstein K., Dower S. K., Rachie N., Bomsztyk K. Comparison of IL-1 alpha effectiveness in activating murine pre-B and T cell lines. Cytokine. 1993 Sep;5(5):416–426. doi: 10.1016/1043-4666(93)90031-y. [DOI] [PubMed] [Google Scholar]
  19. Makarov S. S., Olsen J. C., Johnston W. N., Schwab J. H., Anderle S. K., Brown R. R., Haskill J. S. Retrovirus mediated in vivo gene transfer to synovium in bacterial cell wall-induced arthritis in rats. Gene Ther. 1995 Aug;2(6):424–428. [PubMed] [Google Scholar]
  20. Miller A. D., Rosman G. J. Improved retroviral vectors for gene transfer and expression. Biotechniques. 1989 Oct;7(9):980-2, 984-6, 989-90. [PMC free article] [PubMed] [Google Scholar]
  21. Miller L. C., Lynch E. A., Isa S., Logan J. W., Dinarello C. A., Steere A. C. Balance of synovial fluid IL-1 beta and IL-1 receptor antagonist and recovery from Lyme arthritis. Lancet. 1993 Jan 16;341(8838):146–148. doi: 10.1016/0140-6736(93)90006-3. [DOI] [PubMed] [Google Scholar]
  22. Morgan R. A., Cornetta K., Anderson W. F. Applications of the polymerase chain reaction in retroviral-mediated gene transfer and the analysis of gene-marked human TIL cells. Hum Gene Ther. 1990 Summer;1(2):135–149. doi: 10.1089/hum.1990.1.2-135. [DOI] [PubMed] [Google Scholar]
  23. Roessler B. J., Allen E. D., Wilson J. M., Hartman J. W., Davidson B. L. Adenoviral-mediated gene transfer to rabbit synovium in vivo. J Clin Invest. 1993 Aug;92(2):1085–1092. doi: 10.1172/JCI116614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Roessler B. J., Hartman J. W., Vallance D. K., Latta J. M., Janich S. L., Davidson B. L. Inhibition of interleukin-1-induced effects in synoviocytes transduced with the human IL-1 receptor antagonist cDNA using an adenoviral vector. Hum Gene Ther. 1995 Mar;6(3):307–316. doi: 10.1089/hum.1995.6.3-307. [DOI] [PubMed] [Google Scholar]
  25. Scheinman R. I., Beg A. A., Baldwin A. S., Jr NF-kappa B p100 (Lyt-10) is a component of H2TF1 and can function as an I kappa B-like molecule. Mol Cell Biol. 1993 Oct;13(10):6089–6101. doi: 10.1128/mcb.13.10.6089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schwab J. H., Anderle S. K., Brown R. R., Dalldorf F. G., Thompson R. C. Pro- and anti-inflammatory roles of interleukin-1 in recurrence of bacterial cell wall-induced arthritis in rats. Infect Immun. 1991 Dec;59(12):4436–4442. doi: 10.1128/iai.59.12.4436-4442.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sporn S. A., Eierman D. F., Johnson C. E., Morris J., Martin G., Ladner M., Haskill S. Monocyte adherence results in selective induction of novel genes sharing homology with mediators of inflammation and tissue repair. J Immunol. 1990 Jun 1;144(11):4434–4441. [PubMed] [Google Scholar]
  28. Stimpson S. A., Dalldorf F. G., Otterness I. G., Schwab J. H. Exacerbation of arthritis by IL-1 in rat joints previously injured by peptidoglycan-polysaccharide. J Immunol. 1988 May 1;140(9):2964–2969. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES