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-lymphocytes are essential for the type of disease that develops after infection with the protozoan parasite Leishmania major. A variety of immunological interventions has been shown to modulate disease development. Therefore, the effect of leflunomide on the development of parasite-induced lesions and the ensuing immune response was investigated in genetically susceptible BALB/c mice. Oral feeding for 7 to 10 days of leflunomide (30 mg/kg per day) beginning 2 days prior to or at the day of infection led to the development of a stable resistant phenotype, i.e. to long-lasting (> 13 months) regression of the lesions and clinical cure. Starting leflunomide treatment 3 days after infection was ineffective. The main bioactive metabolite, 1726 B, did not inhibit viability or growth of L. major promastigotes and amastigotes in vitro. Quantitative 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 growth of stimulated T-cells, which could not be restored by saturating amounts of exogenous IL-2 and IL-4. No effect was observed on the killing function of activated macrophages. Taken together, the data indicate that leflunomide is a potent prophylactic agent to prevent an otherwise lethal infection of BALB/c mice.
D000818:Animals; D000977:Antiparasitic Agents; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D005260:Female; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D007555:Isoxazoles / Q000494:pharmacology*; D000077339:Leflunomide; D018320:Leishmania major / Q000187:drug effects* / Q000254:growth & development; D016773:Leishmaniasis, Cutaneous / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C
D000977:Antiparasitic Agents; D000981:Antiprotozoal Agents; D007555:Isoxazoles; D000077339:Leflunomide