title: The effects of Cyclosporine A and azathioprine on human T cells activated by different costimulatory signals.
abstract: Immunosuppression is an important treatment modality in transplantation and human diseases that are associated with aberrant T cell activation. There are considerable differences regarding the cellular processes targeted by the immunosuppressive drugs that are in clinical use. Drugs like azathioprine (Aza) mainly act by halting proliferation of fast dividing cells, whereas others like cyclosporine A (CsA) specifically target signaling pathways in T cells. Since the outcome of T cell responses critically depends on the quality and strength of costimulatory signals, this study has addressed the interplay between costimulation and the immunosuppressive agents CsA and Aza during the in vitro activation of human T cells. We used an experimental system that allows analyzing T cells activated in the presence of selected costimulatory ligands to study T cells stimulated via CD28, CD2, LFA-1, ICOS or 4-1BB. The mean inhibitory concentrations (IC(50)) for Aza and CsA were determined for the proliferation of T cells receiving different costimulatory signals as well as for T cells activated in the absence of costimulation. CD28 signals but not costimulation via CD2, 4-1BB, ICOS or LFA-1 greatly increased the IC(50) for CsA. By contrast, the inhibitory effects of Aza were not influenced by T cell costimulatory signals. Our results might have implications for combining standard immunosuppressive drugs with CTLA-4Ig fusion proteins, which act by blocking CD28 costimulation.
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
authors.forename: Judith
authors.initials: J
authors.lastname: Leitner
authors.forename: Karin
authors.initials: K
authors.lastname: Drobits
authors.forename: Winfried F
authors.initials: WF
authors.lastname: Pickl
authors.forename: Otto
authors.initials: O
authors.lastname: Majdic
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zlabinger
authors.forename: Peter
authors.initials: P
authors.lastname: Steinberger
mesh_terms: D053330:4-1BB Ligand / Q000276:immunology / Q000378:metabolism; D001379:Azathioprine / Q000494:pharmacology*; D018801:CD2 Antigens / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D007165:Immunosuppression Therapy; D060889:Inducible T-Cell Co-Stimulator Protein / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D053330:4-1BB Ligand; D018801:CD2 Antigens; D018106:CD28 Antigens; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D016169:Lymphocyte Function-Associated Antigen-1; D016572:Cyclosporine; D001379:Azathioprine