27
Views
6
CrossRef citations to date
0
Altmetric
REVIEW ARTICLE

Leflunomide: an immunosuppressive drug with multiple effects on T cell function

, &
Pages 195-200 | Received 13 Sep 2001, Accepted 28 Nov 2001, Published online: 02 Jan 2014

References

  • Popovic S, Bartlett RR. Disease-modifying activity of HWA 486 on the development of SLE in MRL/1 -mice. Agents Actions
  • Stosic-Grujicic S, Dimitrijevic M, Bartlett R. Leflunomide protects mice from multiple low-dose streptozotocin (MLD-SZ)-induced
  • Bartlett RR, Anagnostopulos H, Zielinski T, Mattar T, Schleyerbach R. Effects of leflunomide on immune responses and models of inflammation. Springer Semin Immunopathol
  • Bartlett RR. Immunopharmacological profile of HWA 486, a novel isoxazol derivative. II. In vivo immunomodulating effects differ from those of cyclophosphamide, prednisolone, or cyclosporin A. Int J Immunopharmacol 1986;8:199–204.
  • Williams JW, Xiao F, Foster PF, Chong A, Sharma S, Bartlett R, et al. Immunosuppressive effects of leflunomide in a cardiac allo-
  • Kuchle CC, Thoenes GH, Langer KH, Schorlemmer HU, Bartlett RR, Schleyerbach R. Prevention of kidney and skin graft rejection in rats by leflunomide, a new immunomodulating agent. Transplant
  • Cao WW, Kao PN, Chao AC, Gardner P, Ng J, Morris RE. Mechanism of the antiproliferative action of leflunomide. A77 1726, the active metabolite of leflunomide, does not block T-cell receptormediated signal transduction, but its antiproliferative effects are antagonized by pyrimidine nucleosides. J Heart Lung Transplant 1995;14: 1016�30.
  • Elder RT, Xu X, Williams JW, Gong H, Finnegan A, Chong AS. The immunosuppressive metabolite of leflunomide, A77 1726, affects murine T cells through two biochemical mechanisms. J Immunol 1997;159:22�7.
  • Cherwinski HM, Cohn RG, Cheung P, Webster DJ, Xu YZ, Caulfield JP, et al. The immunosuppressant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine biosynthesis. J Pharmacol Exp Ther 1995;275:1043�9.
  • Xu X, Williams JW, Gong H, Finnegan A, Chong AS. Two activities of the immunosuppressive metabolite of leflunomide, A77 1726. Inhibition of pyrimidine nucleotide synthesis and protein tyrosine phosphorylation. Biochem Pharmacol 1996;52: 527� 34.
  • Chong AS, Rezai K, Gebel HM, Finnegan A, Foster P, Xu X, et al. Effects of leflunomide and other immunosuppressive agents on T cell proliferation in vitro. Transplantation 1996;61:140–5.
  • Fox RI, Mahboubi A, Green D, Sang B, Langford M, Frangou CG, et al. Leflunomide inhibits de novo uridine synthesis and is depen-dent on p53 for arrest in G1 phase of cell cycle. Arthritis Rheum 1998;41:5137.
  • Herrmann ML, Frangou CG, Kirschbaum BJ. Cell cycle control of the de novo pyrimidine synthesis inhibitor leflunomide through the p53 and p21WAF-1 pathway. Arthritis Rheum 1997;40: 5177.
  • Oren M. Regulation of the p53 tumor suppressor protein. J Biol Chem 1999;274:36031–4.
  • Agarwal ML, Taylor WR, Chernov MV, Chernova OB, Stark GR. The p53 network. J Biol Chem 1998;273: 1–4.
  • Kern SE. p53: tumor suppression through control of the cell cycle. Gastroenterology 1994;106:1708–11.
  • Colic M, Popovic P, Vucevic D, Dimitrijevic M. Leflunomide in-duces apoptosis of thymocytes and T-cell hybridoma: differences in sensitivity and signaling pathways. Transplant Proc 2001;33:2344–6.
  • Vassilev A, Ozer Z, Navara C, Mahajan S, Uckun FM. Bruton's tyrosine kinase as an inhibitor of the Fas/CD95 death-inducing signaling complex. J Biol Chem 1999;274: 1646–56.
  • Williamson RA, Yea CM, Robson PA, Curnock AP, Gadher S, Hambleton AB, et al. Dihydroorotate dehydrogenase is a high affinity binding protein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compound. J Biol Chem 1995;270:22467–72.
  • Rawls J, Knecht W, Diekert K, Lill R, Loftier M. Requirements for the mitochondrial import and localization of dihydroorotate dehy-drogenase. Eur J Biochem 2000;267:2079–87.
  • Bruneau JM, Yea CM, Spinella-Jaegle S, Fudali C, Woodward K, Robson PA, et al. Purification of human dihydro-orotate dehydro-genase and its inhibition by A77 1726, the active metabolite of leflunomide. Biochem J 1998;336: 299–303.
  • Silva HT, Shorthouse R, Morris RE. Single- and multiple-dose pharmacokinetics and pharmacodynamics of leflunomide's active metabolite A77 1726 in normal Lewis rats. Transplant Proc 1996;28: 3092–4.
  • Milbert U, Schorlemmer HU, Haun G, Wunschel M, Fudali CRE, Bartlett RR. Chromatographic separation with subsequent detec-tion of changes in conductivity as a useful tool to detect an increase in the -dihydroorotic acid (-DHO) content of cell lysates and serum. Int J Immunopharmacol 1998;14:223–32.
  • Davis JP, Cain GA, Pitts WJ, Magolda RL, Copeland RA. The immunosuppressive metabolite of leflunomide is a potent in-hibitor of human dihydroorotate dehydrogenase. Biochemistry 1996;35:1270–3.
  • Liu S, Neidhardt EA, Grossman TH, Ocain T, Clardy J. Structures of human dihydroorotate dehydrogenase in complex with anti-proliferative agents. Structure Fold Des 2000;8:25–33.
  • Dimitrova P, Skapenko A, Herrmann M, Schleyerbach R, Kalden JR, Schulze-Koops H. Restriction of de novo pyrimidine biosyn-thesis inhibits Thl cell activation and promotes Th2 cell differen-tiation. J Immunol. In press 2002.
  • Fairbanks LD, Bofill M, Ruckemann K, Simmonds HA. Impor-tance of ribonucleotide availability to proliferating T-lymphocytes from healthy humans. Disproportionate expansion of pyrimidine pools and contrasting effects of de novo synthesis inhibitors. J Biol Chem 1995;270:29682–9.
  • Cherwinski HM, Byars N, Ballaron SJ, Nakano GM, Young JM, Ransom JT. Leflunomide interferes with pyrimidine nucleotide biosynthesis. Inflamm Res 1995;44:317–22.
  • Silva HT Jr, Cao W, Shorthouse RA, Loftier M, Morris RE. In vitro and in vivo effects of leflunomide, brequinar, and cyclo-sporine on pyrimidine biosynthesis. Transplant Proc 1997;29:1292–3.
  • Jackowski S. Cell cycle regulation of membrane phospholipid me-tabolism. J Biol Chem 1996;271:20219–22.
  • Eugui EM, Almquist SJ, Muller CD, Allison AC. Lymphocyte-selective cytostatic and immunosuppressive effects of myco-phenolic acid in vitro: role of deoxyguanosine nucleotide depletion. Scand J Immunol 1991;33:161–73.
  • Sokoloski JA, Sartorelli AC. Inhibition of mannose incorporation into glycoproteins and dolichol-linked intermediates of Sarcoma 180 cells by 6-methylmercaptopurine ribonucleoside. Int J Cancer 1987;39:764–8.
  • Sasvari-Szekely M, Spasokukotskaja T, Staub M. Deoxyribo-cytidine is salvaged not only into DNA but also into phospholipid precursors. IV. Exogenous deoxyribocytidine can be used with the same efficacy as (ribo)cytidine for lipid activation. Biochem Biophys Res Commun 1993;194:966–72.
  • Kraan MC, de Koster BM, Elferink JG, Post WJ, Breedveld FC, Tak PP. Inhibition of neutrophil migration soon after initiation of treatment with leflunomide or methotrexate in patients with rheu-matoid arthritis: findings in a prospective, randomized, double-blind clinical trial in fifteen patients. Arthritis Rheum 2000;43: 1488–95.
  • Lin Y, Vandeputte M, Waer M. Accommodation and T-independent B cell tolerance in rats with long-term surviving hamster heart xenografts. J Immunol 1998;160:369–75.
  • Exton JH. Signaling through phosphatidylcholine breakdown. J Biol Chem 1990;265:1–4.
  • Ruckemann K, Fairbanks LD, Carrey EA, Hawrylowicz CM, Richards DF, Kirschbaum B, et al. Leflunomide inhibits pyrimi-dine de novo synthesis in mitogen-stimulated T-lymphocytes from healthy humans. J Biol Chem 1998;273:21682–91.
  • Weiss A, Littman DR. Signal transduction by lymphocyte antigen receptors. Cell 1994;76:263–74.
  • Hunter T. Signaling - 2000 and beyond. Cell 2000;100:113–27.
  • Xu X, Blinder L, Shen J, Gong H, Finnegan A, Williams JW, et al. In vivo mechanism by which leflunomide controls lymphopro-liferative and autoimmune disease in MRL/MpJ-lprftpr mice. J Immunol 1997;159:167–74.
  • Xu X, Williams JW, Bremer EG, Finnegan A, Chong AS. Inhibi-tion of protein tyrosine phosphorylation in T cells by a novel immunosuppressive agent, leflunomide. J Biol Chem 1995;270: 12398–403.
  • Straus DB, Weiss A. The CD3 chains of the T cell antigen receptor associate with the ZAP-70 tyrosine kinase and are tyrosine phos-phorylated after receptor stimulation. J Exp Med 1993;178:1523–30.
  • Degano M, Garcia KC, Apostolopoulos V, Rudolph MG, Teyton L, Wilson IA. A functional hot spot for antigen recognition in a superagonist TCR/MHC complex. Immunity 2000;12:251–61.
  • Fraser JD, Straus D, Weiss A. Signal transduction events leading to T-cell lymphokine gene expression. Immunol Today 1993;14:357–62.
  • Manna SK, Mukhopadhyay A, Aggarwal BB. Leflunomide suppresses TNF-induced cellular responses: effects on NF-kappa B, activator protein-1, c-Jun N-terminal protein kinase, and apoptosis. J Immunol 2000;165: 5962–9.
  • Fuchs SY, Adler V, Pincus MR, Ronai Z. MEKK1/JNK signaling stabilizes and activates p53. Proc Natl Acad Sci USA 1998;95: 10541–6.
  • Siemasko K, Chong AS, Jack HM, Gong H, Williams JW, Finnegan A. Inhibition of JAK3 and STAT6 tyrosine phosphoryla-tion by the immunosuppressive drug leflunomide leads to a block in IgG1 production. J Immunol 1998;160:1581–8.
  • Ambach A, Saunus J, Konstandin M, Wesselborg S, Meuer SC, Samstag Y. The serine phosphatases PP1 and PP2A associate with and activate the actin-binding protein cofilin in human T lympho-cytes. Eur J Immunol 2000;30:3422–31.
  • Slauson SD, Silva HT, Sherwood SW, Morris RE. Flow cytometric analysis of the molecular mechanisms of immunosuppressive ac- tion of the active metabolite of leflunomide and its malononitril-amide analogues in a novel whole-blood assay. Immunol Lett 1999;67:179–83.
  • Van Parijs L, Refaeli Y, Lord JD, Nelson BH, Abbas AK, Baltimore D. Uncoupling IL-2 signals that regulate T cell proli-feration, survival, and Fas-mediated activation-induced cell death. Immunity 1999;11:281–8.
  • Fujii H, Ogasawara K, Otsuka H, Suzuki M, Yamamura K, Yokochi T, et al. Functional dissection of the cytoplasmic subre-gions of the IL-2 receptor betac chain in primary lymphocyte popu-lations. EMBO J 1998;17:6551–7.
  • Moriggl R, Berchtold S, Friedrich K, Standke GJ, Kammer W, Heim M, et al. Comparison of the transactivation domains of Stat5 and Stat6 in lymphoid cells and mammary epithelial cells. Mol Cell Biol 1997;17:3663–78.
  • Moriggl R, Sexl V, Piekorz R, Topham D, Ihle JN. Stat5 activation is uniquely associated with cytokine signaling in peripheral T cells. Immunity 1999;11: 225–30.
  • Zielinski T, Herrmann ML, Riedel N, Bartlett RR. The influence of leflunomide on cell cycle, IL-2-receptor (IL-2-R) and its gene expression. Agents Actions 1994;41:C204–5.
  • Lang R, Wagner H, Heeg K. Differential effects of the im-munosuppressive agents cyclosporine and leflunomide in vivo. Leflunomide blocks clonal T cell expansion yet allows production of lymphokines and manifestation of T cell-mediated shock. Trans-plantation 1995;59:382–9.
  • Richard M, Hoskin DW. Inhibition of anti-CD3 antibody-induced mouse T cell activation by pentoxifylline in combination with rapamycin or A77 1726 (leflunomide). Int J Immunopharmacol 1998;20:241–52.
  • Skapenko A, Wendler J, Lipsky PE, Kalden JR, Schulze-Koops H. Altered memory T cell differentiation in patients with early rheu-matoid arthritis. J Immunol 1999;163:491–9.
  • Van der Veen RC, Dietlin TA, Pen L, Gray JD, Hofman FM. Antigen presentation to Thl but not Th2 cells by macrophages results in nitric oxide production and inhibition of T cell prolifera-tion: interferon-gamma is essential but insufficient. Cell Immunol 2000;206:125–35.
  • Jankovic V, Samardzic T, Stosic-Grujicic S, Popadic D, Trajkovic V. Cell-specific inhibition of inducible nitric oxide synthase activa-tion by leflunomide. Cell Immunol 2000;199:73–80.
  • Siemasko KF, Chong AS, Williams JW, Bremer EG, Finnegan A. Regulation of B cell function by the immunosuppressive agent leflunomide. Transplantation 1996;61:635–42.
  • Schorlemmer HU, Seiler FR, Bartlett RR. Prolongation of al-logeneic transplanted skin grafts and induction of tolerance by leflunomide, a new immunosuppressive isoxazol derivative. Trans-plant Proc 1993;25:763–7.
  • Cao WW, Kao PN, Aoki Y, Xu JC, Shorthouse RA, Morris RE. A novel mechanism of action of the immunomodulatory drug leflunomide: augmentation of the immunosuppressive cytokine TGF-beta 1, and suppression of the immunostimulatory cytokine IL-2. Transplant Proc 1996;28:3079–80.
  • Feldmann M, Elliott MJ, Woody JN, Maini RN. Anti-tumor ne-crosis factor-alpha therapy of rheumatoid arthritis. Adv Immunol 1997;64:283–350.
  • Manna SK, Aggarwal BB. Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. J Immunol 1999;162: 2095–2102.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.