Corticosteroids do not reverse the inhibitory effect of cyclosporine on regulatory T-cell activity in contrast to mycophenolate mofetil.

Inevitable hepatitis C virus recurrence after liver transplantation, a major barrier to survival of the transplanted liver may be promoted by immunosuppression and by CD4(+)CD25(+) regulatory T cells (Treg). Treg cells are essential for the induction and maintenance of immunologic self-tolerance as well as transplant tolerance. Moreover, we have previously described low doses of cyclosporine (CsA) to inhibit Treg activity by inducing interleukin-2 and interfron-γ. We investigated here in, the effect of mycophenolate mofetil (MMF) and corticosteroids, usually used in combination with a calcineurin inhibitor on human CD4(+)CD25(+) Treg cells. Human CD4(+)CD25(+) cells isolated from healthy donors were cultured in the presence of CsA +/- corticoids or MMF. Suppressive activity of regulatory T cells was assessed in mixed leukocyte reactions including CD25(+) solvents with autologous activated peripheral blood mononuclear cells (PBMC). MMF and dexamethasone inhibited PBMC and Treg proliferation in dose-dependent fashing, maintaining the suppressive activity of Treg cells. However, the association of corticoids with CsA could not reverse the inhibitory effects of CsA on Treg activity, unlike the MMF and CsA combination. We have previously shown CsA to significantly impair the function of CD4(+)CD25(+) Treg cells. Herein we reports that corticoids were not able to reverse this effect, whereas MMF couterbalanced it, suggesting that the combination of MMF with CsA maintains regulatory T cells activity promoting tolerance.

Miroux C ，Morales O ，Ouaguia L ，Aoudjehane L ，Boleslawski E ，Pancré V ，de Launoit Y ，Calmus Y ，Conti F ，Delhem N ... -  《-》

Inhibitory effects of cyclosporine on human regulatory T cells in vitro.

Miroux C ，Moralès O ，Carpentier A ，Dharancy S ，Conti F ，Boleslowski E ，Podevin P ，Auriault C ，Pancré V ，Delhem N ... -  《-》

Peripheral CD4+ CD25+ Treg cell expansion in lung transplant recipients is not affected by calcineurin inhibitors.

Meloni F ，Morosini M ，Solari N ，Bini F ，Vitulo P ，Arbustini E ，Pellegrini C ，Fietta AM ... -  《INTERNATIONAL IMMUNOPHARMACOLOGY》

Rapamycin, unlike cyclosporine A, enhances suppressive functions of in vitro-induced CD4+CD25+ Tregs.

Bocian K ，Borysowski J ，Wierzbicki P ，Wyzgal J ，Klosowska D ，Bialoszewska A ，Paczek L ，Górski A ，Korczak-Kowalska G ... -  《-》

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.

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.

Fanigliulo D ，Lazzerini PE ，Capecchi PL ，Ulivieri C ，Baldari CT ，Laghi-Pasini F ... -  《-》