Differential Effect of Calcineurin Inhibitors, Anti-CD25 Antibodies and Rapamycin on the Induction of FOXP3 in Human T Cells

Abstract

The high FOXP3 mRNA levels during allogeneic responses in vivo and in vitro suggests that regulatory activities of CD25 T cells or the generation of these cells is an intrinsic part of activation. CNI and alphaCD25 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.

Immunosuppressive Drugs and Tregs

“…Upon transfer, these in vivo-converted Tregs potently suppress the rejection of donor but not third-party skin grafts (49). In humans, comparative in vitro studies showed that the CNIs and anti-IL-2R significantly inhibit Foxp3 mRNA expression upon third-party cell stimulation, whereas rapamycin merely delays it from 5 to 7 d (50). Available in vivo human data suggest that, on the one hand, CNIs lead to lower circulating levels of Tregs than does rapamycin (51,52) and to CNI tapering (53) but, on the other hand, higher levels than in healthy donors (46).…”

Immune Phenotype Predicts Risk for Posttransplantation Squamous Cell Carcinoma

“…31 The addition of sirolimus to CD4 ϩ T cells in vitro increases the number of FOXP3 ϩ cells, 32 whereas cyclosporine decreases the number of Tregs. 33 Despite the effect of immunosuppression on Treg number and the relationship of immunosuppression with the development of cancer in OTRs, Tregs have not been assessed in relation to cancer after transplantation. We therefore investigated the hypothesis that SCC in kidney transplant recipients (KTRs) would be associated with an increased number of Tregs by determining the immune phenotype of leukocytes present in the peripheral blood and at the site of the SCC lesion.…”

After Moving of Regulatory T-Cell Therapy to the Clinic: Will We Need a New Tregs Source?

“…Several studies have shown that the use of CNIs during adoptive Treg therapy may link with progressive decline in Treg numbers, 55 fail to support the differentiation of the highly suppressive CD4+CD25+CD27+ Treg subset upon alloantigen stimulation, 56 reduce FOXP3 expression in nTregs, 57,58 and diminishes the frequencies of CD4+CD25+FOXP3+ T cells. 59 On the other hand, MMF and lowdose tacrolimus had an induction of CD4+CD25+FOXP3+ Tregs as showed in kidney transplanted recipients treated with these drugs that permit Tregs expansion in the periphery and accumulation in the allograft and the maintenance of their suppressive function which was confirmed by in vitro analysis of these cells.…”