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
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.