title: Clinically-relevant cyclosporin and rapamycin concentrations enhance regulatory T cell function to a similar extent but with different mechanisms: an in-vitro study in healthy humans.
abstract: Evidence indicates that regulatory T cells (Tregs) are profoundly involved in promoting allograft tolerance after organ transplantation. Since a successful transplantation currently still requires a long-term immunosuppressive treatment, clarifying the specific impact of these drugs on Tregs may be of high clinical relevance. Conflicting results arise from the literature, particularly as concerns cyclosporine (CsA). The specific aim of this work was to evaluate in-vitro the direct effects of clinically-relevant drug concentrations of three widely used immunosuppressive drugs, i.e. CsA, rapamycin (RAPA) and mycophenolic acid (MPA), on Treg activity, number and forkhead/winged helix transcription factor (FoxP3) expression in humans. Tregs (CD4(+)CD25(+)) isolated from healthy donors were cultured in the presence of different concentrations of CsA, RAPA or MPA. The suppressive activity of Tregs was evaluated in mixed lymphocyte reactions with CD4(+)CD25(-) T cells. Phenotype analysis and FoxP3 expression were assessed by flow cytometry. Clinically-relevant CsA and RAPA concentrations significantly enhanced to a similar extent the suppressive activity of Tregs. Although this effect was associated with an increase in Treg number as well as in FoxP3 expression with both drugs, the driving mechanism seemed to be primarily quantitative (i.e. increase of the cell number) for RAPA, whereas mainly qualitative (i.e. increase in FoxP3 levels) for CsA, respectively. Conversely, MPA did not show any effect on Treg function and number. These findings suggest that both RAPA and CsA may be beneficial in promoting Treg-dependent allograft tolerance after organ transplantation.
authors.affiliation: Department of Life Sciences, University of Siena, Via Aldo Moro 2, Siena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fanigliulo
authors.affiliation: Department of Medical Sciences, Surgery and Neurosciences, Policlinico Le Scotte, University of Siena, Viale Bracci, Siena, Italy. Electronic address: lazzerini7@unisi.it.
authors.forename: Pietro Enea
authors.initials: PE
authors.lastname: Lazzerini
authors.affiliation: Department of Medical Sciences, Surgery and Neurosciences, Policlinico Le Scotte, University of Siena, Viale Bracci, Siena, Italy.
authors.forename: Pier Leopoldo
authors.initials: PL
authors.lastname: Capecchi
authors.affiliation: Department of Life Sciences, University of Siena, Via Aldo Moro 2, Siena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ulivieri
authors.affiliation: Department of Life Sciences, University of Siena, Via Aldo Moro 2, Siena, Italy.
authors.forename: Cosima Tatiana
authors.initials: CT
authors.lastname: Baldari
authors.affiliation: Department of Medical Sciences, Surgery and Neurosciences, Policlinico Le Scotte, University of Siena, Viale Bracci, Siena, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Laghi-Pasini
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D009173:Mycophenolic Acid / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D023001:Transplantation Tolerance
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus
keywords: Cyclosporine; FoxP3; Immunosuppressive drugs; Rapamycin; Regulatory T cell