title: Novel immunosuppressive agent, FK506. In vitro effects on the cloned T cell activation.
abstract: The present study shows the in vitro effects of a novel immunosuppressive agent, FK506, in comparison with cyclosporin A (CsA). FK506 inhibited concanavalin A response and allo-mixed lymphocyte reaction of murine splenic lymphocytes in a dose-dependent manner, and at 40- to 200-fold lower concentrations than CsA. Allo-cytolytic T lymphocyte induction from murine thymocytes was also inhibited by FK506, whereas the ability of cytolytic T lymphocyte to lyse targets was not affected by the agent. Immunosuppressive effects of FK506 were further characterized by using antigen specific-proliferative T lymphocyte clones, BC.21 and KO.6. FK506 inhibited the proliferation of T cell clones stimulated with specific antigens in a dose-dependent manner, and at about 100-fold lower concentrations than CsA. However, cloned T cells, once activated, were scarcely affected by the agent; interleukin-2 (IL-2) driven proliferation of cloned T cells was not inhibited. On the other hand, it was found that FK506 inhibited both IL-2 secretion and IL-2 receptor expression of BC.21 after stimulation with the specific antigen. FK506 also inhibited the proliferation of BC.21 stimulated with phorbol 12-myristate 13-acetate plus calcium ionophore, indicating that it directly affected the signaling pathway downward from the perturbation of the Ti/T3 complex. Finally, it was suggested that FK506 and CsA synergistically inhibited the antigen-driven proliferation of cloned T cells. These results indicate that the novel immunosuppressive agent, FK506, affects T cell activation with mechanisms similar to those of CsA but at considerably lower concentrations.
mesh_terms: D000818:Animals; D000941:Antigens; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D003208:Concanavalin A / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D004357:Drug Synergism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism; D007519:Isoantigens; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D011725:Pyridines / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism; D015375:Receptors, Interleukin-2; D013601:T-Lymphocytes / Q000187:drug effects*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016559:Tacrolimus; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000941:Antigens; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007519:Isoantigens; D011725:Pyridines; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D003208:Concanavalin A; D000001:Calcimycin; D013755:Tetradecanoylphorbol Acetate; D016559:Tacrolimus