Skip to main content

Advertisement

Log in

Therapeutic effect of leflunomide on the development of experimental lupus nephritis in mice

  • Original Article
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

Mice with chronic graft-versus-host disease (cGVHD) induced by transferring parental BALB/C lymphocytes into (C57BL/6 × BALB/C) F1 (CBF1) hybrids, develop a syndrome characterized by B-cell hyperactivity, autoantibody production, and immune complex-mediated glomerulonephritis. In this model, we evaluated the role of leflunomide on the development of lupus nephritis in system autoimmunity. Daily administration of leflunomide (15 mg/kg/d) from 2 weeks after cGVHD induction can dramatically reduce the production of autoantibodies and immune complex deposition in the kidney, leading to relieved kidney damage and reduced mortality. The therapeutic effect of leflunomide on the lupus-prone mice was partially due to the inhibition of TLR9 signaling pathway, which was an important component of innate immune system.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Aurelia L, Philippe C, Isabelle A et al (2006) Role of TLR9 in anti-nucleosome and Anti-DNA antibody production in lpr mutation-induced murine lupus. J Immunol 177:1349–1354

    Google Scholar 

  2. Nagy G, Koncz A, Perl A (2005) T- and B-cell abnormalities in systemic lupus erythematosus. Crit Rev Immunol 25(2):123–140

    Article  PubMed  CAS  Google Scholar 

  3. Hahn BH, Ebling F, Singh RR et al (2005) Cellular and molecular mechanisms of regulation of autoantibody production in lupus. Ann N Y Acad Sci 1051:433–441

    Article  PubMed  CAS  Google Scholar 

  4. Christensen SR, Kashgarian M, Alexopoulou L et al (2005) Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med 202:321–331

    Article  PubMed  CAS  Google Scholar 

  5. Nakano S, Morimoto S, Suzuki J et al (2008) Role of pathogenic auto-antibody production by Toll-like receptor 9 of B cells in active systemic lupus erythematosus. Rheumatology 47:145–149

    Article  PubMed  CAS  Google Scholar 

  6. Laan RF, van Riel PL, van de Putte LB (2001) Leflunomide and methotrexate. Curr Opin Rheumatol 13(3):159–163

    Article  PubMed  CAS  Google Scholar 

  7. Vidic-Dankovic B, Kosec D, Damjanovic M et al (1995) Leflunomide prevents the development of experimentally induced myasthenia gravis. Int J Immunopharmacol 17:273–281

    Article  PubMed  CAS  Google Scholar 

  8. Bartlett RR, Anagnostopulos H, Zielinski T et al (1993) Effects of leflumomide on immune responses and models of inflammation. Springer Semin Immunopathol 14:381–394

    Article  PubMed  CAS  Google Scholar 

  9. Thomas K, Klaus T, Hans-Peter H, Stefan J (2001) Suppression of experimental autoimmune neuritis by leflunomide. Brain 124:1791–1802

    Article  Google Scholar 

  10. Wang HY, Cui TG, Hou FF et al (2008) Induction treatment of proliferative lupus nephritis with leflunomide combined with prednisone: a prospective multi-centre observational study. Lupus 17(7):638–644

    Article  PubMed  CAS  Google Scholar 

  11. Zhang FS, Nie YK, Jin XM et al (2009) The efficacy and safety of lefunomide therapy in lupus nephritis by repeat kidney biopsy. Rheumatol Int 29(11):1331–1335

    Article  PubMed  CAS  Google Scholar 

  12. Tam LS, Li EK, Wong CK et al (2004) Double-blind, randomized, placebo-controlled pilot study of leflunomide in systemic lupus erythematosus. Lupus 13(8):601–604

    Article  PubMed  CAS  Google Scholar 

  13. Wernick RM, Smith DL, Houghton DC et al (1993) Reliability of histologic scoring for lupus nephritis: a community-based evaluation. Ann Intern Med 119:805–811

    PubMed  CAS  Google Scholar 

  14. Trouw LA, Seelen MA, Duijs JM et al (2003) Glomerular deposition of C1q and anti-C1q antibodies in mice following injection of antimouse C1q antibodies. Clin Exp Immunol 132:32–39

    Article  PubMed  CAS  Google Scholar 

  15. Van de Loosdrecht AA, Beelen RH, Ossenkoppele GJ et al (1994) A tetrazolium-based colorimetric MTT assay to quantitate human monocyte mediated cytotoxicity against leukemic cells from cell lines and patients with acute myeloid leukemia. J Immunol Methods 174:311–320

    Article  PubMed  Google Scholar 

  16. Popovich S, Bartletr RR (1987) The use of the murine chronic graft versus host (CGVH) disease, a model for systemic lupus erythematosus (SLE) for drug discovery. Agents Actions 21:284

    Article  Google Scholar 

  17. Bruijn JA, Van Elven EH, Hogendorn PCW et al (1988) Murine chronic graft versus host disease as a model for lupus nephritis. Am J Pathol 130:639

    PubMed  CAS  Google Scholar 

  18. Rolink AG, Radaszkiewicz T, Melchers F (1987) The autoantigen binding B cell repertoires of normal and of chronically graft versus host diseased mice. J Exp Med 165:1675

    Article  PubMed  CAS  Google Scholar 

  19. Vidic-Dankovic B, Kosec D, Damjanovic M et al (1995) Leflunomide prevents thedevelopment of experimentally induced myasthenia gravis. Int J Immunopharmacol 17(4):273–281

    Article  PubMed  CAS  Google Scholar 

  20. Means TK, Latz E, Hayashi F et al (2005) Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J Clin Invest 115:407–417

    PubMed  CAS  Google Scholar 

  21. Rifkin IR, Leadbetter EA, Busconi L et al (2005) Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol Rev 205:27–42

    Article  Google Scholar 

  22. Anders HJ, Banas B, Schlondorff D (2004) Signaling danger: toll-like receptors and their potential roles in kidney disease. J Am Soc Nephrol 15:854–867

    Article  PubMed  CAS  Google Scholar 

  23. Imai H, Hamai K, Komatsuda A et al (1997) IgG subclasses in patients with membranoproliferative glomerulonephritis, membranous nephropathy, and lupus nephritis. Kidney Int 51:270–276

    Article  PubMed  CAS  Google Scholar 

  24. Grootscholten C, van Bruggen MC, van der Pijl JW et al (2003) Deposition of nucleosomal antigens (histones and DNA) in the epidermal basement membrane in human lupus nephritis. Arthritis Rheum 48:1355–1362

    Article  PubMed  CAS  Google Scholar 

  25. Bootsma H, Spronk PE, Ter Borg EJ et al (1997) The predictive value of fluctuations in IgM and IgG class anti-dsDNA antibodies for relapses in systemic lupus erythematosus: a prospective long-term observation. Ann Rheum Dis 56:661–666

    Article  PubMed  CAS  Google Scholar 

  26. Clough JD, Valenzuela R (1980) Relationship of renal histopathology in SLE nephritis to immunoglobulin class of anti-DNA. Am J Med 68:80–85

    Article  PubMed  CAS  Google Scholar 

  27. Taki S, Hirose S, Kinoshita K et al (1992) Somatically mutated IgG anti-DNA antibody clonally related to germ-line encoded IgM anti-DNA antibody. Eur J Immunol 22:987–992

    Article  PubMed  CAS  Google Scholar 

  28. Pisetsky DS, Jelinek DF, McAnally LM et al (1990) In vitro autoantibody production by normal adult and cord blood B cells. J Clin Invest 85:899–903

    Article  PubMed  CAS  Google Scholar 

  29. Witte T, Hartung K, Sachse C et al (1998) IgM anti-dsDNA antibodies in systemic lupus erythematosus: negative association with nephritis. Rheumatol Int 18:85–91

    Article  PubMed  CAS  Google Scholar 

  30. Forger F, Matthias T, Oppermann M et al (2004) Clinical significance of anti-dsDNA antibody isotypes: IgG/IgM ratio of anti-dsDNA antibodies as a prognostic marker for lupus nephritis. Lupus 13:36–44

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge the Department of Molecular Biology, Norman Bethune Medical College, Jilin University for providing technical support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ping Luo.

Additional information

Chunyan He and Xuehong Lu contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

He, C., Lu, X., Yan, Z. et al. Therapeutic effect of leflunomide on the development of experimental lupus nephritis in mice. Rheumatol Int 32, 633–638 (2012). https://doi.org/10.1007/s00296-010-1630-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-010-1630-z

Keywords

Navigation