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NDT Advance Access published online on November 9, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp586
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© The Author 2009. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


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

Katarzyna Bocian1, Jan Borysowski2, Piotr Wierzbicki2, Janusz Wyzgal3, Danuta Klosowska2, Agata Bialoszewska4, Leszek Paczek3, Andrzej Górski2 and Grazyna Korczak-Kowalska1,2

1 Department of Immunology, Faculty of Biology, University of Warsaw 2 Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw 3 Transplantation Institute, Medical University of Warsaw 4 Department of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland

Correspondence and offprint requests to: Katarzyna Bocian; E-mail: kbocian{at}biol.uw.edu.pl



  Abstract

Background. A growing body of data shows that CD4+CD25+ regulatory T cells (Tregs) can induce transplantation tolerance by suppressing immune responses to allograft antigens. However, both the generation and the suppressive capacity of CD4+CD25+ Tregs can be substantially affected by different immunosuppressive drugs used in clinical transplantation. The goal of this study was to compare the effects of cyclosporine A and rapamycin on the induction and suppressive functions of human CD4+CD25+ Tregs in vitro.

Methods. CD4+CD25+ Tregs were induced in two-way mixed lymphocyte reaction (MLR) in the presence of rapamycin (Treg-Rapa) or cyclosporine A (Treg-CsA). Tregs were identified in MLR cultures by flow cytometry using anti-CD4, anti-CD25, anti-CTLA-4, anti-CD122, anti-GITR mAbs and ant-PE-FOXP3 staining sets. Suppressive capacity of induced Tregs was evaluated by their capability to inhibit anti-CD3 Ab-triggered proliferation of peripheral blood mononuclear cells (PBMCs), as measured by flow cytometry. The concentration of TGF-β1 in culture supernatants was measured by enzyme-linked immunosorbent assay.

Results. Although both rapamycin and cyclosporine A suppressed the induction of CD4+CD25+ Tregs during MLRs, this effect was significantly more pronounced in cells cultured with cyclosporine. On the other hand, only rapamycin significantly decreased the percentage of CD4+CD25+ Tregs which expressed GITR, a negative regulator of Treg’s suppressive capacity. Importantly, Treg-Rapa, unlike Treg-CsA, displayed significant suppressive activity and were capable of inhibiting the proliferation of anti-CD3 Ab-activated PBMCs. This activity was likely mediated by TGF-β1.

Conclusions. Rapamycin, unlike cyclosporine A, does not inhibit the function of CD4+CD25+ Tregs. This implies that rapamycin could contribute to the development of transplantation tolerance by promoting the induction of functional CD4+CD25+ Tregs. Moreover, our results suggest that rapamycin could be combined with functional Tregs.

Keywords: cyclosporine A; rapamycin; suppressive functions; TGF-β; Treg cells

Received for publication: 20. 2.09
Accepted in revised form: 13.10.09


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