Inhibition of T-cell activation in vitro in human peripheral blood mononuclear cells by pimecrolimus and glucocorticosteroids and combinations thereof.
Pimecrolimus is an ascomycin macrolactam derivative that has been recently approved for the topical treatment of atopic dermatitis. In this study we report for the first time on a direct comparison of the inhibitory activity of pimecrolimus and the glucocorticosteroids betamethasone 17-valerate, dexamethasone and hydrocortisone at the level of T-cell proliferation and cytokine production. Stimulated human peripheral blood mononuclear cell (PBMC) systems were used that are either sensitive or resistant to calcineurin inhibitors or glucocorticosteroids. Pimecrolimus and the glucocorticosteroids inhibited dose-dependently T-cell proliferation and cytokine production in a sensitive system (anti-CD3 mAb-stimulated PBMC) with the following rank order of potency: pimecrolimus approximately betamethasone 17-valerate approximately dexamethasone > hydrocortisone. In resistant systems (anti-CD3 plus anti-CD28- or Staphylococcal enterotoxin B-stimulated PBMC), pimecrolimus or the glucocorticosteroids alone exerted either no effect, or only a partial inhibitory effect. However, combinations of pimecrolimus with a glucocorticosteroid synergistically and strongly inhibited T-cell proliferation. Taken together, the data indicate that medium potency glucocorticosteroids, such as betamethasone 17-valerate and dexamethasone, are as potent T-cell inhibitors as pimecrolimus. Furthermore, the experimental evidence suggests that combinations of glucocorticosteroids and pimecrolimus could be used clinically to achieve superior therapeutic efficacy, when monotherapy with the individual agents is unsatisfactory.
Winiski
Anthony
A
Novartis Institutes for BioMedical Research, Vienna, Austria. anthony.winiski@novartis.com
Wang
Shirley
S
Schwendinger
Brigitte
B
Stuetz
Anton
A
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D004768:Enterotoxins / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D004768:Enterotoxins; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; C031818:enterotoxin B, staphylococcal; C117268:pimecrolimus; D016559:Tacrolimus