Abstract
Everolimus (EVL) is a novel mTOR-inhibitor similar to sirolimus (SRL) that is used in organ transplant recipients, often in combination with tacrolimus (TAC) or mycophenolate (MPA). The current study aims to determine its effects on regulatory T cells. Increasing concentrations of EVL, MPA and TAC alone or in combination were added to MLRs of healthy volunteers. Lymphoproliferation by 3H-TdR incorporation and the percentage of newly generated CD4+CD127-CD25+FOXP3+ (total Treg) and CD4+CD127-CD25HighFOXP3+ (natural Treg) in CFSE labeled responder cells were assessed by flow cytometry. In comparison to medium controls, EVL and other agents dose-dependently inhibited 3H-TdR incorporation in HLA-2DR-matched and HLA-mismatched MLRs (n = 3–10). However, EVL significantly amplified newly generated total and natural Tregs in CFSE labeled responder cells (p<0.05) at all concentrations, while MPA and SRL did this only at sub-therapeutic concentrations and inhibited at therapeutic levels. In contrast, TAC inhibited newly generated Tregs at all concentrations. When tested in combination with TAC, EVL failed to reverse TAC inhibition of Treg generation. Combinations of EVL and low concentrations of MPA inhibited proliferation and amplified Treg generation in an additive manner when compared to medium controls or each drug tested alone (p<0.05). The relative tolerogenic effect from high to low was EVL > SRL> MPA > TAC. If the results from these in vitro studies are extrapolated to clinical transplantation, it would suggest EVL plus low concentrations of MPA may be the most tolerogenic combination.
Highlights
Immunosuppression (IS) is effective in preventing rejection after organ transplantation (Tx), the standard IS agents, calcineurin inhibitors (CNI) such as tacrolimus (TAC), often lead to chronic renal impairment and other long term adverse effects
We have studied the effects of EVL in inhibiting alloimmunity and enhancing Tregulatory cell (Treg) generation ex vivo using the Treg-mixed lymphocyte reaction (MLR) assay [7]
Everolimus (EVL) is a novel mTOR-inhibitor similar to sirolimus (SRL) that is used in organ transplant recipients, often in combination with other IS agents
Summary
Immunosuppression (IS) is effective in preventing rejection after organ transplantation (Tx), the standard IS agents, calcineurin inhibitors (CNI) such as tacrolimus (TAC), often lead to chronic renal impairment and other long term adverse effects. That EVL is being used clinically in LTx, one major question is if it has the same or greater in vitro and in vivo immunoregulatory properties well known for other mTOR inhibitors such as SRL [1, 8, 12, 13] If this were determined to be so, EVL might be used in clinical trials of CNI minimization or even full IS withdrawal especially in LTx. In the present report, we have studied the effects of EVL in inhibiting alloimmunity and enhancing Treg generation ex vivo using the Treg-MLR assay [7]
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