Skip to main content
SpringerLink
Log in

Immunomodulation of rat antigen-induced arthritis by leflunomide alone and in combination with cyclosporin A

  • Original Research Papers
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

The effects of the new immunomodulating isoxazol derivative leflunomide, in comparison with cyclosporin A, on established antigen-induced arthritis in rats as well as serum antibody levels were determined. When treatment with leflunomide, at concentrations from 2.5 to 10 mg/kg/d, was started on day 3 of arthritis, the acute and chronic phases of arthritis were effectively inhibited. This was demonstrated by decreased joint swelling and reduced histopathological arthritis score at the end of experiment (day 26). Furthermore, the treatment resulted in a significantly reduced level of serum antibodies to the matrix components collagen type I, type II and proteoglycans. Neither leflunomide nor cyclosporin A, at doses of 1 mg/kg/d, had an effect on the severity of arthritis and antibody levels. However, when both drugs were used together, at these non-effective doses, the histopathological score of chronic arthritis was significantly reduced. The results of our experiments demonstrate that leflunomide has a strong suppressive effect on both acute and chronic phases of antigen-induced arthritis and formation of autoantibodies in rats. Furthermore, orally administered doses of leflunomide were as effective as doses of cyclosporin A given intraperitoneally. The combination of sub-effective doses of leflunomide and cyclosporin A resulted in significant inhibition of chronic arthritis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bartlett RR, Schleyerbach R. Immunopharmacological profile of a novel isoxazol derivative, HWA 486, with potential antirheumatic activity. I. Disease modifying action on adjuvant arthritis of the rat. Int J Immunopharmacol 1985;7:7–18.

    Google Scholar 

  2. Pasternak RD, Wadopian NS, Wright RN, Siminoff P, Gylys JA, Buyniski JP. Disease modifying activity of HWA 486 in rat adjuvant-induced arthritis. Agents Actions 1987;21:241–3.

    Google Scholar 

  3. Hambleton P, McMahon S. Drug actions on delayed-type hypersensitivity in rats with developing and established adjuvant arthritis. Agents Actions 1990;29:328–32.

    Google Scholar 

  4. Glant TT, Mikecz K, Bartlett RR, Deak F, Thonar EJMA, Williams JM, et al. Immunomodulation of proteoglycan-induced progressive polyarthritis by leflunomide. Immunopharmacology 1992;23:105–16.

    Google Scholar 

  5. Seifert H, Misikic P, Oed C, Löw-Friedrich I, Campion G. Clinical experience with leflunomide in patients with rheumatoid arthritis (RA). In: Bartlett RR, editor. Leflunomide. Proc Vienna Symp. Basel: Birkhäuser, 1993: p A5.

    Google Scholar 

  6. Dumonde DC, Glynn LE. The production of arthritis in rabbits by an immunological reaction to fibrin. Br J Exp Pathol 1962;43:373–83.

    Google Scholar 

  7. Brackertz D, Mitchell GF, Mackay IR. Antigen-induced arthritis in mice. I: Induction of arthritis in various strains of mice. Arthr Rheum 1977;20:841–50.

    Google Scholar 

  8. Dijkstra CD, Döpp EA, Vogels IMC, van Noorden CJF. Macrophages and dentritic cells in antigen-induced arthritis. An immunohistochemical study using cryostat sections of the whole knee joint of rat. Scand J Immunol 1987;26:513–23.

    Google Scholar 

  9. Griffith RJ. Characterisation and pharmacological sensitivity of antigen arthritis induced by methylated bovine serum albumin in the rat. Agents Actions 1992;35:88–95.

    Google Scholar 

  10. van den Berg WB, van de Putte LBA, Zwarts WA, Joosten LAB. Electrical charge of the antigen determines intraarticular antigen handling and chronicity of arthritis in mice. J Clin Invest 1984;74:1850–9.

    Google Scholar 

  11. Bräuer R, Kittlick PD, Thoss K, Henzgen S. Different immunological mechanisms contribute to cartilage destruction in antigen-induced arthritis. Exp Toxic Pathol 1994;46:383–8.

    Google Scholar 

  12. Hunneyball IM. The use of experimental arthritis in the rabbit for the development of antiarthritic drugs. Adv Inflamm Res 1984;7:249–62.

    Google Scholar 

  13. Bartlett RR, Anagnostopulos H, Zielinski T, Mattar T, Schleyerbach R. Effects of leflunomide on immune responses and models of inflammation. Springer Semin Immunopathol 1993;14:381–94.

    Google Scholar 

  14. Feutren G. Cyclosoprin A: recent developments in the mechanism of action and clinical application. Curr Opin Immunol 1989;2:239–45.

    Google Scholar 

  15. Blackham A, Griffith RJ. The effect of FK506 and cyclosporin A on antigen-induced arthritis. Clin Exp Immunol 1991;86: 224–8.

    Google Scholar 

  16. Bräuer R, Kette H, Henzgen S, Thoss K. Influence of cyclosporin A on cytokine levels in synovial fluid and serum of rats with antigen-induced arthritis. Agents Actions 1994;41:96–8.

    Google Scholar 

  17. Williams JW, Xiao F, Foster P, Clardy C, McChesney L, Sankary H, et al. Leflunomide in experimental transplantation. Control of rejection and alloantibody production, reversal of acute rejection, and interaction with cyclosporine. Transplantation 1994;57:1223–31.

    Google Scholar 

  18. McChesney LP, Xiao F, Sankary HN, Foster PF, Sharma S, Haklin M, et al. An evaluation of leflunomide in the canine renal transplantation model. Transplantation 1994;57:1717–22.

    Google Scholar 

  19. Xiao F, Chong AS Foster P, Sankary H, McChesney L, Koukoulis G, et al. Leflunomide controls rejection in hamster to rat cardiac xenografts. Transplantation 1994;58:828–34.

    Google Scholar 

  20. Bräuer R, Thoss K, Henzgen S. Humoral and cell-mediated sensitivity to cartilage constituents in mice with antigen-induced arthritis. In: van den Berg WB, van der Kraan PM, van Lent PLEM, editors. Joint Destruction in Arthritis and Osteoarthritis. Agents and Actions Suppl. Vol. 39. Basel: Birkhäuser, 1993:69–73.

    Google Scholar 

  21. Mattar T, Kochhar K, Bartlett R, Bremer EG, Finnegan A. Inhibition of the epidermal growth factor receptor tyrosine kinase activity by leflunomide. FEBS Letts 1993;334:161–4.

    Google Scholar 

  22. Zielinski T, Zeitter D, Müllner S Bartlett RR. Leflunomide, a reversible inhibitor of pyrimidine biosynthesis? Inflamm Res 1995;44:S207–8.

    Google Scholar 

  23. Cherwinski HM, Byars N, Ballaron SJ, Nakano GM, Young JM, Ransom JT. Leflunomide interferes with pyrimidine nucleotide biosynthesis. Inflamm Res 1995;44:317–22.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Pathology, Friedrich Schiller University, D-07740, Jena, Germany

    K. Thoss, S. Henzgen, P. K. Petrow, D. Katenkamp & R. Bräuer

Authors
  1. K. Thoss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Henzgen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. K. Petrow
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. Katenkamp
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. Bräuer
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

accepted by M. J. Parnham

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thoss, K., Henzgen, S., Petrow, P.K. et al. Immunomodulation of rat antigen-induced arthritis by leflunomide alone and in combination with cyclosporin A. Inflamm Res 45, 103–107 (1996). https://doi.org/10.1007/BF02265123

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02265123

Key words

Search

Navigation