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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.
Int Immunopharmacol. 2015 Feb; 24(2):276-284.II

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+Show Affiliations

Department of Life Sciences, University of Siena, Via Aldo Moro 2, Siena, Italy.Department of Medical Sciences, Surgery and Neurosciences, Policlinico Le Scotte, University of Siena, Viale Bracci, Siena, Italy. Electronic address: lazzerini7@unisi.it.Department of Medical Sciences, Surgery and Neurosciences, Policlinico Le Scotte, University of Siena, Viale Bracci, Siena, Italy.Department of Life Sciences, University of Siena, Via Aldo Moro 2, Siena, Italy.Department of Life Sciences, University of Siena, Via Aldo Moro 2, Siena, Italy.Department of Medical Sciences, Surgery and Neurosciences, Policlinico Le Scotte, University of Siena, Viale Bracci, Siena, Italy.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

25536542

Citation

Fanigliulo, Daniela, et al. "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." International Immunopharmacology, vol. 24, no. 2, 2015, pp. 276-284.
Fanigliulo D, Lazzerini PE, Capecchi PL, et al. 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. Int Immunopharmacol. 2015;24(2):276-284.
Fanigliulo, D., Lazzerini, P. E., Capecchi, P. L., Ulivieri, C., Baldari, C. T., & Laghi-Pasini, F. (2015). 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. International Immunopharmacology, 24(2), 276-284. https://doi.org/10.1016/j.intimp.2014.12.021
Fanigliulo D, et al. 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. Int Immunopharmacol. 2015;24(2):276-284. PubMed PMID: 25536542.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Fanigliulo,Daniela, AU - Lazzerini,Pietro Enea, AU - Capecchi,Pier Leopoldo, AU - Ulivieri,Cristina, AU - Baldari,Cosima Tatiana, AU - Laghi-Pasini,Franco, Y1 - 2014/12/20/ PY - 2014/06/07/received PY - 2014/12/11/revised PY - 2014/12/11/accepted PY - 2014/12/24/entrez PY - 2014/12/24/pubmed PY - 2016/2/24/medline KW - Cyclosporine KW - FoxP3 KW - Immunosuppressive drugs KW - Rapamycin KW - Regulatory T cell SP - 276 EP - 284 JF - International immunopharmacology JO - Int. Immunopharmacol. VL - 24 IS - 2 N2 - 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. SN - 1878-1705 UR - https://www.unboundmedicine.com/medline/citation/25536542/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1567-5769(14)00499-8 DB - PRIME DP - Unbound Medicine ER -