Inhibition of murine IgE and immediate cutaneous hypersensitivity responses to ovalbumin by the immunomodulatory agent leflunomide

Leflunomide has been identified as an immunoregulatory and anti-inflammator y compound. Allergic disease is characterized by elevated serum IgE levels, production of allergen-specific IgE and the release of inflammatory mediat ors from mast cells and granulocytes. Here we demonstrate, using an in vivo murine model, the ability of leflunomide to down-regulate levels of total and allergen-specific serum IgE production. Mice receiving leflunomide (45 mg/kg) orally at the time of primary immunization with ovalbumin adsorbed t o aluminium hydroxide adjuvant, showed a reduction in total serum IgE level s of 95%, 41% and 32% following primary, secondary and tertiary immunizatio ns, respectively (P < 0.05). When leflunomide was administered both at the time of primary and subsequent immunizations, reductions in total and speci fic serum IgE levels of >80% and >38%, respectively, were observed (P < 0.0 5). Administration of leflunomide to mice which had already developed an Ig E response resulted in reductions in total and specific serum IgE levels of >80% and >45%, respectively (P < 0.05). Following leflunomide treatment, a nimals failed to develop immediate cutaneous hypersensitivity responses whe n challenged intradermally with allergen. Down- regulation of immunoglobuli n production was not restricted to IgE, since levels of allergen-specific I gG1 and IgG2a in serum were also reduced. The finding of significant reduct ions in total and allergen-specific IgM suggests that the mechanism of acti on does not involve selective inhibition of immunoglobulin class switching. A loss in production of the T helper cell-derived B cell differentiation f actor IL-5 may account for the reduction in immunoglobulin levels. In adopt ive transfer experiments leflunomide did not induce tolerance in allergen-r eactive Th2 populations, contrary to animal disease models of transplantati on and autoimmunity, where leflunomide was shown to induce tolerance in the effector T cell population.