title: Mycophenolic acid is a potent inhibitor of the expression of tumour necrosis factor- and tumour necrosis factor-receptor superfamily costimulatory molecules.
abstract: The tumour necrosis factor (TNF) ligands CD154, CD70 and TNF receptors CD134 and CD137 are all involved in allograft rejection. Because these molecules are not present on resting T cells, we investigated whether immunosuppressive drugs could inhibit their induction. Expression was induced in vitro on T cells by phorbol 12-myristate 13-acetate and ionomycin or by allogeneic dendritic cells in the presence or absence of cyclosporin A (CsA), tacrolimus (TAC), rapamycin derivative (SDZ RAD), or mycophenolic acid (MPA), and determined by flow cytometry. To study the effect of in vivo exposure to immunosuppressive drugs on these molecules, immunohistochemistry was performed on human lymph nodes from patients treated with TAC or TAC and MMF. The calcineurin inhibitors (CI) CsA and TAC strongly suppressed the induction of CD70, CD137 and CD154, but not of CD134, upon pharmacological stimulation of T cells in vitro. In allogeneic stimulations only CD137 and CD154 were inhibited by CI. SDZ RAD did not inhibit pharmacological induction, but in allogeneic stimulations all the investigated molecules were partially suppressed. Both in pharmacological and in allogeneic stimulations, MPA inhibited induction of all tested molecules on T cells nearly completely at 4 micro g/ml. However, in lymph nodes obtained from patients chronically treated with MMF and TAC no reduction of the expression of these molecules was observed. This was possibly caused by trough levels which were in vivo lower (mean: 2.3 micro g/ml) than the concentration giving complete inhibition in vitro. In conclusion, in contrast to CsA, TAC and SDZ RAD, MPA is a potent inhibitor of the induction of TNF- and TNF-receptor superfamily molecules on T cells. To obtain long-term suppression of these molecules in vivo, a plasma trough level of 4 micro g/ml is indicated.
authors.affiliation: Department of Gastroenterology & Hepatology, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Miranda M L
authors.initials: MM
authors.lastname: Van Rijen
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.forename: Martijn
authors.initials: M
authors.lastname: Hommes
authors.forename: Jan N M
authors.initials: JN
authors.lastname: Ijzermans
authors.forename: Hugo W
authors.initials: HW
authors.lastname: Tilanus
authors.forename: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D053282:CD27 Ligand; D023201:CD40 Ligand / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015759:Ionomycin / Q000037:antagonists & inhibitors / Q000276:immunology; D008198:Lymph Nodes; D008213:Lymphocyte Activation / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D009173:Mycophenolic Acid / Q000494:pharmacology*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D053282:CD27 Ligand; C505771:CD70 protein, human; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D017475:Receptors, Nerve Growth Factor; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; C505714:TNFRSF9 protein, human; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D015759:Ionomycin; D009173:Mycophenolic Acid; D013755:Tetradecanoylphorbol Acetate; D016559:Tacrolimus