Differential effect of calcineurin inhibitors, anti-CD25 antibodies and rapamycin on the induction of FOXP3 in human T cells

Background. The transcription factor FOXP3 has been identified as the molecule associated with the regulatory function of CD25+ T cells. Methods. To understand the biology of FOXP3 + T cells in allogeneic reactions, we measured FOXP3 mRNA expression levels in allostimulated CD25 bright+ cells and CD25 intermediate(int)/- cells and in peripheral blood mononuclear cells (PBMC). The effect of immunosuppressive drugs on FOXP3 expression was studied in mixed lymphocyte reactions (MLR) in the presence and absence of calcineurin inhibitors (CNI), αCD25 mAb, and Rapamycin (Rapa), and analyzed in biopsies from cardiac allograft recipients during acute rejection by quantitative (Q)-PCR. Results. FOXP3 mRNA expression was restricted to the CD25 bright+ population that inhibited the proliferation of allostimulated CD25 int/- cells. In the MLR FOXP3 was readily induced after allostimulation. Kinetic examination of the MLR showed a 10-20-fold higher FOXP3 mRNA expression level after 5 days of culture. The CNI Cyclosporin and Tacrolimus, and aCD25 mAb inhibited in vitro induced FOXP3 gene transcription (range 70%-90%), whereas Rapa did not inhibit the induction. After clinical heart transplantation the highest FOXP3 mRNA expression levels were measured in biopsies during acute rejection (P=0.03). Conclusions. The high FOXP3 mRNA levels during allogeneic responses in vivo and in vitro suggests that regulatory activities of CD25 bright+ T cells or the generation of these cells is an intrinsic part of activation. CNI and αCD25 mAb in contrast to Rapa, did interfere with this immunosuppressive counter-mechanism and as a result might have an inhibitory effect to tolerance induction after transplantation. Copyright

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