Oral Administration of Leflunomide (HWA486) Results in Prominent Suppression of Immunoglobulin E Formation in a Rat Type 1 Allergy Model

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 288; no. 2; pp. 849 - 857
• Main Authors: Mizushima, Y, Amano, Y, Kitagawa, H, Ogata, K
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.02.1999
• Subjects: Administration, Oral; Aniline Compounds - metabolism; Aniline Compounds - pharmacology; Animals; Antibody Specificity; Disease Models, Animal; Drug Administration Schedule; Female; Hydroxybutyrates - metabolism; Hydroxybutyrates - pharmacology; Hypersensitivity, Immediate - drug therapy; Hypersensitivity, Immediate - immunology; Hypersensitivity, Immediate - metabolism; Immunoglobulin E - biosynthesis; Immunoglobulin E - blood; Immunoglobulin G - blood; Immunoglobulin M - blood; Immunosuppressive Agents - metabolism; Immunosuppressive Agents - pharmacology; Isoxazoles - pharmacology; Lymphocyte Activation - drug effects; Ovalbumin - immunology; Ovalbumin - pharmacology; Rats; Rats, Inbred BN; Uridine - pharmacology
• ISSN: 0022-3565; 1521-0103

Leflunomide, a drug being developed for use in the treatment of rheumatoid arthritis, was evaluated in an ovalbumin (OVA)-induced rat type 1 allergy model. In a dose of 1 mg/kg/day, it strongly suppressed the formation of OVA-specific IgE, thus preventing the elevation of the plasma histamine level and induction of anaphylactic shock observed after i.v. challenge with OVA. Studies on leflunomide’s effects on the secondary antibody response showed that administration during the primary immune response remarkably diminished the secondary antibody responses, except IgM, even without further drug administration. Furthermore, when administered during the secondary response after rechallenge, both the total IgE and OVA-specific IgE serum levels declined rapidly to nearly baseline levels. Although OVA-specific IgG1, IgG2a, and IgM did not decrease from their primary response levels, these classes’ secondary responses were strongly suppressed. In an in vitro study, the proliferation and antibody production of OVA-stimulated spleen cells, derived from Brown Norway rats, were strongly inhibited by A77 1726 , leflunomide’s active metabolite. When uridine was added to the cell culture, this molecule’s effect on cell proliferation was completely restored, whereas the antibody production was partially restored. These findings are consistent with data indicating that leflunomide is a dihydroorotate dehydrogenase inhibitor. Taken together, the above findings suggest the therapeutic potential of leflunomide against type 1 allergic diseases.