title: Differential effects of the immunosuppressive agents cyclosporine and leflunomide in vivo. Leflunomide blocks clonal T cell expansion yet allows production of lymphokines and manifestation of T cell-mediated shock.
abstract: The effects of leflunomide and CsA on immune responses in vitro and in vivo were investigated. Like CsA, leflunomide inhibited mitogen- or antigen-driven T cell proliferation in vitro. However, leflunomide impaired neither the capability of T cells to produce IL-2 and IL-4, nor the expression of IL-2R, that is, the acquisition of competence. In contrast to CsA, the IL-2-driven growth of secondary T cells was blocked by leflunomide. Cell cycle analyses revealed that activated T cells did not enter S phase of the cell cycle in the presence of leflunomide. Next, the effects of leflunomide and CsA on the T cell response toward the bacterial superantigen (SAg) staphylococcal enterotoxin B (SEB) were analyzed in vivo. SEB-induced early deletion (apoptosis) of a fraction of SEB-reactive V beta 8+ T cells and IL-2R expression were not impaired by either CsA nor leflunomide. On the other hand, both CsA and leflunomide prevented V beta 8-selective clonal T cell expansion and generation of SEB-specific cytolytic activity. In contrast to CsA, leflunomide treatment permitted in vivo SEB-induced production of T cell-derived lymphokines (IL-2 and TNF). Further, leflunomide failed to protect D-galactosamine-sensitized mice from SEB-induced, T cell-mediated lethal shock, whereas CsA was fully protective. Manifestation of SEB-induced T cell anergy was not impaired by leflunomide. Our results provide evidence that CsA and leflunomide differ significantly in their functional properties to suppress immune responses in that both agents inhibit T cell functions linked to clonal expansion, while leflunomide does not inhibit lymphokine secretion and thus permits lymphokine-mediated immune functions.
authors.affiliation: Institute of Medical Microbiology and Hygiene, Technical University of Munich, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Lang
authors.forename: H
authors.initials: H
authors.lastname: Wagner
authors.forename: K
authors.initials: K
authors.lastname: Heeg
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D005434:Flow Cytometry; D007376:Interleukin-2 / Q000096:biosynthesis; D007555:Isoxazoles / Q000494:pharmacology*; D000077339:Leflunomide; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018089:Superantigens / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D007376:Interleukin-2; D007555:Isoxazoles; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine; D000077339:Leflunomide