Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs.
Immunosuppressive drugs (ISD) are used for the prevention and treatment of graft rejection, graft-versus-host-disease (GVHD) and autoimmune disorders. The precise mechanisms by which ISD interfere with T cell activation and effector function or delete antigen-specific T cells are defined only partially. We analysed commonly used ISD such as dexamethasone (DEX), mycophenolic acid (MPA), FK506, cyclosporin A (CsA), rapamycin (RAP), methotrexate (MTX) and cyclophosphamide (CP) for apoptosis-induction and modulation of activation and effector function in human peripheral T cells, cytotoxic T cell lines (CTL) and Jurkat T cells. Of all drugs tested only CP and MTX prevented antigen-specific proliferation of T cells and decreased cytotoxicity of alloantigen specific CTL lines by direct induction of apoptosis. MTX and CP also slightly increased activation-induced cell death (AICD) and CD95-sensitivity. In contrast, all other drugs tested did not induce T cell apoptosis, increase CD95-sensitivity or AICD. CsA and FK506 even prevented AICD by down-modulation of CD95L. DEX, MPA, CsA, FK506 and RAP inhibited activation of naive T cells, but were not able to block proliferation of activated T cells nor decrease cytotoxic capacity of CTL lines. These results show that ISD can be classified according to their action on apoptosis-induction and inhibition of proliferation and would favour a rational combination therapy to delete existing reactive T cells and prevent further T cell activation.
Strauss
G
G
University Children's Hospital, Ulm, Germany.
Osen
W
W
Debatin
K-M
KM
D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology*; D003520:Cyclophosphamide / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008727:Methotrexate / Q000494:pharmacology; D009173:Mycophenolic Acid / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D016559:Tacrolimus / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D007166:Immunosuppressive Agents; D003907:Dexamethasone; D016572:Cyclosporine; D003520:Cyclophosphamide; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus; D008727:Methotrexate