IN-VIVO MECHANISM BY WHICH LEFLUNOMIDE CONTROLS LYMPHOPROLIFERATIVE AND AUTOIMMUNE-DISEASE IN MRL MPJ-LPR/LPR MICE/

Citation
Xl. Xu et al., IN-VIVO MECHANISM BY WHICH LEFLUNOMIDE CONTROLS LYMPHOPROLIFERATIVE AND AUTOIMMUNE-DISEASE IN MRL MPJ-LPR/LPR MICE/, The Journal of immunology, 159(1), 1997, pp. 167-174
Citations number
41
Categorie Soggetti
Immunology
Journal title
The Journal of immunology
ISSN journal
00221767 → ACNP
Volume
159
Issue
1
Year of publication
1997
Pages
167 - 174
Database
ISI
SICI code
0022-1767(1997)159:1<167:IMBWLC>2.0.ZU;2-Y
Abstract
Two activities have been identified for the immunosuppressive metaboli te of leflunomide, A77 1726: inhibition of dihydroo rotate dehydrogena se (DHO-DHase), an enzyme involved in the biosynthesis of pyrimidine n ucleotides (PyN); and inhibition of protein tyrosine kinases. The in v itro potency of A77 1726 as a DHO-DHase inhibitor is reported to be 10 - to 500-fold greater than as a tyrosine kinase inhibitor. These obser vations suggested that the immunosuppressive efficacy of leflunomide i n vivo is related to inhibition of DHO-DHase. However, observations th at patients with disorders in the PyN synthetic pathway are not overtl y immunodeficient militate against this hypothesis. We investigated th e effects of leflunomide in vivo and report that amelioration of lymph oproliferative and autoimmune diseases in MRL/Mpj-lpr/lpr (lpr/lpr) mi ce by leflunomide is not accompanied by reduced PyN concentrations in lymph node cells. Our hypothesis that lymphocytes could salvage serum uridine to counter the effects of reduced PyN synthesis in vivo was su pported by in vitro studies. Finally, we observed that amelioration of disease correlated with a reduction of tyrosine phosphorylated protei ns in lymph node cells of lpr/lpr mice. These observations suggest tha t the primary mechanism by which leflunomide prevents autoimmune and l ymphoproliferative diseases in lpr/lpr mice is not depletion of PyN, b ut correlates with reduced tyrosine phosphorylation concentrations in lymph node cells.