title: The immunosuppressive drug FK778 induces regulatory activity in stimulated human CD4+ CD25- T cells.
abstract: The induction of transplantation tolerance involves a T-cell-mediated process of immune regulation. In clinical transplantation, the use of immunosuppressive drugs that promote or facilitate this process would be highly desirable. Here, we investigated the tolerance-promoting potential of the immunosuppressive drug FK778, currently under development for clinical therapy. Using a human allogeneic in vitro model we showed that, upon T-cell receptor (TCR) triggering, FK778 induced a regulatory phenotype in CD4+ CD25- T cells. Purified CD4+ CD25- T cells primed in the presence of FK778 showed hyporesponsiveness upon restimulation with alloantigen in the absence of the drug. This anergic state was reversible by exogenous interleukin-2 (IL-2) and was induced independent of naturally occurring CD4+ CD25+ regulatory T cells. Pyrimidine restriction was a crucial requirement for the de novo induction of regulatory activity by FK778. The FK778-induced anergic cells showed suppressor activity in a cell-cell contact-dependent manner; were CD25(high), CD45RO+, CD27-, and CD62L-; and expressed cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), and FoxP3. The cells revealed delayed p27(kip1) degradation and enhanced phosphorylation of STAT3. In conclusion, the new drug FK778 shows tolerizing potential through the induction of a regulatory T-cell subset in CD4+ CD25- T cells.
authors.affiliation: Radboud University Nijmegen Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Kreijveld
authors.forename: Hans J P M
authors.initials: HJ
authors.lastname: Koenen
authors.forename: Luuk B
authors.initials: LB
authors.lastname: Hilbrands
authors.forename: Hans J P
authors.initials: HJ
authors.lastname: van Hooff
authors.forename: Irma
authors.initials: I
authors.lastname: Joosten
mesh_terms: D000328:Adult; D000480:Alkynes / Q000494:pharmacology*; D015703:Antigens, CD / Q000032:analysis; D000943:Antigens, Differentiation / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D060908:CTLA-4 Antigen; D002450:Cell Communication; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004353:Drug Evaluation, Preclinical; D051858:Forkhead Transcription Factors / Q000032:analysis; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology; D007555:Isoxazoles / Q000494:pharmacology*; D019041:L-Selectin / Q000032:analysis; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011743:Pyrimidines / Q000096:biosynthesis; D017475:Receptors, Nerve Growth Factor / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D014529:Uridine / Q000494:pharmacology
chemical_list: D000480:Alkynes; D015703:Antigens, CD; D000943:Antigens, Differentiation; C436291:CDKN1B protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D007519:Isoantigens; D007555:Isoxazoles; D009570:Nitriles; D011743:Pyrimidines; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C491405:TNFRSF18 protein, human; D019041:L-Selectin; D050760:Cyclin-Dependent Kinase Inhibitor p27; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; D014529:Uridine