Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Jun 15;101(12):2615–2621. doi: 10.1172/JCI2480

Plasmid DNA encoding transforming growth factor-beta1 suppresses chronic disease in a streptococcal cell wall-induced arthritis model.

X Y Song 1, M Gu 1, W W Jin 1, D M Klinman 1, S M Wahl 1
PMCID: PMC508851  PMID: 9637694

Abstract

Transforming growth factor beta is a potent immunomodulator with both pro- and antiinflammatory activities. Based on its immunosuppressive actions, exogenous TGF-beta has been shown to inhibit autoimmune and chronic inflammatory diseases. To further explore the potential therapeutic role of TGF-beta, we administered a plasmid DNA encoding human TGF-beta1 intramuscularly to rats with streptococcal cell wall-induced arthritis. A single dose of 300 microg plasmid DNA encoding TGF-beta1, but not vector DNA, administered at the peak of the acute phase profoundly suppressed the subsequent evolution of chronic erosive disease typified by disabling joint swelling and deformity (articular index = 8.17+/-0. 17 vs. 1.25+/-0.76, n = 6, day 26, P < 0.01). Moreover, delivery of the TGF-beta1 DNA even as the chronic phase commenced virtually eliminated subsequent inflammation and arthritis. Both radiologic and histopathologic as well as molecular evidence supported the marked inhibitory effect of TGF-beta1 DNA on synovial pathology, with decreases in the inflammatory cell infiltration, pannus formation, cartilage and bone destruction, and the expression of proinflammatory cytokines that characterize this model. Increases in TGF-beta1 protein were detected in the circulation of TGF-beta1 DNA-treated animals, consistent with the observed therapeutic effects being TGF-beta1 dependent. These observations provide the first evidence that gene transfer of plasmid DNA encoding TGF-beta1 provides a mechanism to deliver this potent cytokine that effectively suppresses ongoing inflammatory pathology in arthritis.

Full Text

The Full Text of this article is available as a PDF (454.4 KB).

Selected References

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

  1. Acsadi G., Dickson G., Love D. R., Jani A., Walsh F. S., Gurusinghe A., Wolff J. A., Davies K. E. Human dystrophin expression in mdx mice after intramuscular injection of DNA constructs. Nature. 1991 Aug 29;352(6338):815–818. doi: 10.1038/352815a0. [DOI] [PubMed] [Google Scholar]
  2. Allen J. B., Manthey C. L., Hand A. R., Ohura K., Ellingsworth L., Wahl S. M. Rapid onset synovial inflammation and hyperplasia induced by transforming growth factor beta. J Exp Med. 1990 Jan 1;171(1):231–247. doi: 10.1084/jem.171.1.231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barr E., Leiden J. M. Systemic delivery of recombinant proteins by genetically modified myoblasts. Science. 1991 Dec 6;254(5037):1507–1509. doi: 10.1126/science.1962212. [DOI] [PubMed] [Google Scholar]
  4. Border W. A., Ruoslahti E. Transforming growth factor-beta in disease: the dark side of tissue repair. J Clin Invest. 1992 Jul;90(1):1–7. doi: 10.1172/JCI115821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brandes M. E., Allen J. B., Ogawa Y., Wahl S. M. Transforming growth factor beta 1 suppresses acute and chronic arthritis in experimental animals. J Clin Invest. 1991 Mar;87(3):1108–1113. doi: 10.1172/JCI115073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chernajovsky Y., Adams G., Triantaphyllopoulos K., Ledda M. F., Podhajcer O. L. Pathogenic lymphoid cells engineered to express TGF beta 1 ameliorate disease in a collagen-induced arthritis model. Gene Ther. 1997 Jun;4(6):553–559. doi: 10.1038/sj.gt.3300436. [DOI] [PubMed] [Google Scholar]
  7. Clement L. T. Isoforms of the CD45 common leukocyte antigen family: markers for human T-cell differentiation. J Clin Immunol. 1992 Jan;12(1):1–10. doi: 10.1007/BF00918266. [DOI] [PubMed] [Google Scholar]
  8. Dhawan J., Pan L. C., Pavlath G. K., Travis M. A., Lanctot A. M., Blau H. M. Systemic delivery of human growth hormone by injection of genetically engineered myoblasts. Science. 1991 Dec 6;254(5037):1509–1512. doi: 10.1126/science.1962213. [DOI] [PubMed] [Google Scholar]
  9. Evans C., Robbins P. D. Prospects for treating arthritis by gene therapy. J Rheumatol. 1994 May;21(5):779–782. [PubMed] [Google Scholar]
  10. Fava R. A., Olsen N. J., Postlethwaite A. E., Broadley K. N., Davidson J. M., Nanney L. B., Lucas C., Townes A. S. Transforming growth factor beta 1 (TGF-beta 1) induced neutrophil recruitment to synovial tissues: implications for TGF-beta-driven synovial inflammation and hyperplasia. J Exp Med. 1991 May 1;173(5):1121–1132. doi: 10.1084/jem.173.5.1121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Giladi E., Raz E., Karmeli F., Okon E., Rachmilewitz D. Transforming growth factor-beta gene therapy ameliorates experimental colitis in rats. Eur J Gastroenterol Hepatol. 1995 Apr;7(4):341–347. [PubMed] [Google Scholar]
  12. Kekow J., Reinhold D., Pap T., Ansorge S. Intravenous immunoglobulins and transforming growth factor beta. Lancet. 1998 Jan 17;351(9097):184–185. doi: 10.1016/S0140-6736(05)78212-X. [DOI] [PubMed] [Google Scholar]
  13. Kopp J. B., Factor V. M., Mozes M., Nagy P., Sanderson N., Böttinger E. P., Klotman P. E., Thorgeirsson S. S. Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. Lab Invest. 1996 Jun;74(6):991–1003. [PubMed] [Google Scholar]
  14. Kozarsky K. F., Wilson J. M. Gene therapy: adenovirus vectors. Curr Opin Genet Dev. 1993 Jun;3(3):499–503. doi: 10.1016/0959-437x(93)90126-a. [DOI] [PubMed] [Google Scholar]
  15. Kuruvilla A. P., Shah R., Hochwald G. M., Liggitt H. D., Palladino M. A., Thorbecke G. J. Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2918–2921. doi: 10.1073/pnas.88.7.2918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Le C. H., Nicolson A. G., Morales A., Sewell K. L. Suppression of collagen-induced arthritis through adenovirus-mediated transfer of a modified tumor necrosis factor alpha receptor gene. Arthritis Rheum. 1997 Sep;40(9):1662–1669. doi: 10.1002/art.1780400916. [DOI] [PubMed] [Google Scholar]
  17. Lefer A. M., Tsao P., Aoki N., Palladino M. A., Jr Mediation of cardioprotection by transforming growth factor-beta. Science. 1990 Jul 6;249(4964):61–64. doi: 10.1126/science.2164258. [DOI] [PubMed] [Google Scholar]
  18. Letterio J. J., Roberts A. B. TGF-beta: a critical modulator of immune cell function. Clin Immunol Immunopathol. 1997 Sep;84(3):244–250. doi: 10.1006/clin.1997.4409. [DOI] [PubMed] [Google Scholar]
  19. McCartney-Francis N. L., Wahl S. M. Transforming growth factor beta: a matter of life and death. J Leukoc Biol. 1994 Mar;55(3):401–409. doi: 10.1002/jlb.55.3.401. [DOI] [PubMed] [Google Scholar]
  20. Miller K. L., Carlino J. A., Ogawa Y., Avis P. D., Carroll K. G. Alterations in erythropoiesis in TGF-beta 1-treated mice. Exp Hematol. 1992 Sep;20(8):951–956. [PubMed] [Google Scholar]
  21. Nita I., Ghivizzani S. C., Galea-Lauri J., Bandara G., Georgescu H. I., Robbins P. D., Evans C. H. Direct gene delivery to synovium. An evaluation of potential vectors in vitro and in vivo. Arthritis Rheum. 1996 May;39(5):820–828. doi: 10.1002/art.1780390515. [DOI] [PubMed] [Google Scholar]
  22. Quantin B., Perricaudet L. D., Tajbakhsh S., Mandel J. L. Adenovirus as an expression vector in muscle cells in vivo. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2581–2584. doi: 10.1073/pnas.89.7.2581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Racke M. K., Dhib-Jalbut S., Cannella B., Albert P. S., Raine C. S., McFarlin D. E. Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta 1. J Immunol. 1991 May 1;146(9):3012–3017. [PubMed] [Google Scholar]
  24. Raz E., Dudler J., Lotz M., Baird S. M., Berry C. C., Eisenberg R. A., Carson D. A. Modulation of disease activity in murine systemic lupus erythematosus by cytokine gene delivery. Lupus. 1995 Aug;4(4):286–292. doi: 10.1177/096120339500400409. [DOI] [PubMed] [Google Scholar]
  25. Raz E., Watanabe A., Baird S. M., Eisenberg R. A., Parr T. B., Lotz M., Kipps T. J., Carson D. A. Systemic immunological effects of cytokine genes injected into skeletal muscle. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4523–4527. doi: 10.1073/pnas.90.10.4523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sartor RB, Herfarth H, Van Tol EAF Bacterial Cell Wall Polymer-Induced Granulomatous Inflammation. Methods. 1996 Apr;9(2):233–247. doi: 10.1006/meth.1996.0030. [DOI] [PubMed] [Google Scholar]
  27. Tripathy S. K., Svensson E. C., Black H. B., Goldwasser E., Margalith M., Hobart P. M., Leiden J. M. Long-term expression of erythropoietin in the systemic circulation of mice after intramuscular injection of a plasmid DNA vector. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10876–10880. doi: 10.1073/pnas.93.20.10876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wahl S. M., Allen J. B., Costa G. L., Wong H. L., Dasch J. R. Reversal of acute and chronic synovial inflammation by anti-transforming growth factor beta. J Exp Med. 1993 Jan 1;177(1):225–230. doi: 10.1084/jem.177.1.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Wahl S. M. Transforming growth factor beta: the good, the bad, and the ugly. J Exp Med. 1994 Nov 1;180(5):1587–1590. doi: 10.1084/jem.180.5.1587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wolff J. A., Malone R. W., Williams P., Chong W., Acsadi G., Jani A., Felgner P. L. Direct gene transfer into mouse muscle in vivo. Science. 1990 Mar 23;247(4949 Pt 1):1465–1468. doi: 10.1126/science.1690918. [DOI] [PubMed] [Google Scholar]
  31. Yocum D. E., Esparza L., Dubry S., Benjamin J. B., Volz R., Scuderi P. Characteristics of tumor necrosis factor production in rheumatoid arthritis. Cell Immunol. 1989 Aug;122(1):131–145. doi: 10.1016/0008-8749(89)90154-8. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES