PROTECTIVE EFFECT OF LEFLUNOMIDE ON THE NATURAL COURSE OF LEISHMANIA MAJOR-INDUCED DISEASE IN GENETICALLY SUSCEPTIBLE BALB C MICE/

Leflunomide has been reported as an immunomodulating agent which acts on a variety of cells including T- and B-lymphocytes. CD4(+) T-lymphoc ytes are essential for the type of disease that develops after infecti on with the protozoan parasite Leishmania major. A variety of immunolo gical interventions has been shown to modulate disease development. Th erefore, the effect of leflunomide on the development of parasite-indu ced lesions and the ensuing immune response was investigated in geneti cally susceptible BALB/c mice. Oral feeding for 7 to 10 days of leflun omide (30 mg/kg per day) beginning 2 days prior to or at the day of in fection led to the development of a stable resistant phenotype, i.e. t o long-lasting (> 13 months) regression of the lesions and clinical cu re. Starting leflunomide treatment 3 days after infection was ineffect ive. The main bioactive metabolite, 1726 B, did not inhibit viability or growth of L. major promastigotes and amastigotes in vitro. Quantita tive analysis of CD4(+) and CD8(+) cells in spleens and lymph nodes of parasite-infected animals treated with leflunomide for 5 days showed no significant effect. In vitro, 1726 B dose-dependently inhibited gro wth of stimulated T-cells, which could not be restored by saturating a mounts of exogenous IL-2 and IL-4. No effect was observed on the killi ng function of activated macrophages. Taken together, the data indicat e that leflunomide is a potent prophylactic agent to prevent an otherw ise lethal infection of BALB/c mice.