Conversion From Calcineurin Inhibitor to Mycophenolate Mofetil-Based Immunosuppression Changes the Frequency and Phenotype of CD4+FOXP3+ Regulatory T Cells

  title={Conversion From Calcineurin Inhibitor to Mycophenolate Mofetil-Based Immunosuppression Changes the Frequency and Phenotype of CD4+FOXP3+ Regulatory T Cells},
  author={Ahmet Ender Demirkıran and Varsha D. K. D. Sewgobind and Joyce van der Weijde and Alice Kok and Carla C. Baan and Jaap Kwekkeboom and Hugo W. Tilanus and Herold Johnny Metselaar and Luc J.W. van der Laan},
Background. CD4+Foxp3+ regulatory T cells (Treg) depend on interleukin (IL)-2 for their function and survival. By interfering with the IL-2 production, calcineurin inhibitors (CNI) may negatively affect Treg. Here, we describe the effects of conversion from CNI to mycophenolate mofetil (MMF) monotherapy on renal function, and on Treg frequency and phenotype in liver transplant recipients. Methods. Patients (n=16) with renal impairment on CNI were converted to MMF and received a single dose of… 
Sirolimus vs mycophenolate moftile in Tacrolimus based therapy after induction with Antithymocyte globulin promote regulatory T cell expansion and inhibit RORγt and T-bet expression in kidney transplantation
It is suggested that regimen containing MMF despite increasing CD4+CD25+FOXP3+Tregs significantly, but cannot decrease RORγt and T-bet expression as well as the regimen containing SRL.
Effects of tacrolimus (FK506) and mycophenolate mofetil (MMF) on regulatory T cells and co-inhibitory receptors in the peripheral blood of human liver allograft patients
The application of FK506 combined with MMF may be superior to Fk506 monotherapy for the patients to further induce the immune tolerance after liver transplantation.
Characterization of Rabbit Antithymocyte Globulins-Induced CD25+ Regulatory T Cells From Cells of Patients With End-Stage Renal Disease
Background. Rabbit antithymocyte globulins (rATGs) are known to convert CD4+CD25−FoxP3− T cells from healthy individuals to CD4+CD25+FoxP3+ T cells. In this study, we investigated the effect of rATG
Different Immunosuppressive Combinations on T-Cell Regulation in Renal Transplant Recipients
Overall, immunosuppression lowers CD4+CD25highFoxP3± Treg levels significantly in the periphery in renal transplant recipients, a fact that may influence long-term allograft survival.
Inhibitory Effects of Belatacept on Allospecific Regulatory T-Cell Generation in Humans
BEL alone and in combination with agents used in transplant recipients inhibits the in vitro generation of human Tregs, suggesting that it might be a less optimal agent for tolerance induction in human organ transplantation.
Induction of bona fide regulatory T cells after liver transplantation – the potential influence of polyclonal antithymocyte globulin
  • D. Stauch, A. Yahyazadeh, K. Kotsch
  • Biology, Medicine
    Transplant international : official journal of the European Society for Organ Transplantation
  • 2012
Although in vitro experiments confirm that rATG primarily led to a conversion of CD4+ CD25− into CD4- CD25+ T cells displaying immunosuppressive capacities, these cells cannot be classified as bona fide Treg based on their FOXP3 demethylation pattern and therefore the potential clinical relevance of these cells for transplant outcome remains to be determined.
Unique Effects of Mycophenolate Mofetil on Cord Blood T Cells: Implications for GVHD Prophylaxis
Insight is provided into the effects of immunosuppressive drugs used after HSCT on resting and activated T-cell subsets from PB but especially from CB, which may explain the lower GvHD incidence observed in recipients of CB transplants.


Calcineurin Inhibitors, but not Rapamycin, Reduce Percentages of CD4+CD25+FOXP3+ Regulatory T Cells in Renal Transplant Recipients
CNI, but not Rapa, induce a decrease of circulating Tregs in stable renal transplant recipients, which may be a suitable tool to identify renal transplant patients who may be candidates for reduced immunosuppression.
Differential effect of calcineurin inhibitors, anti-CD25 antibodies and rapamycin on the induction of FOXP3 in human T cells.
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.
Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production.
The data indicate that RAPA and MMF rather than CSA preserve function of Treg cells in pathologic immune responses such as GVHD without weakening the GVT effect.
Differential effects of cyclosporine A, methylprednisolone, mycophenolate, and rapamycin on CD154 induction and requirement for NFkappaB: implications for tolerance induction.
The data suggest that ligation of surface-expressed CD154 provides an important signal that modulates T cell activation and thereby contributes to the effects of CD154 mAb, in addition to previously recognized actions involving blockade of CD40/CD154-dependent cellactivation and activation-induced cell death.
Regulatory T Cells Induced by 1α,25-Dihydroxyvitamin D3 and Mycophenolate Mofetil Treatment Mediate Transplantation Tolerance1
It is demonstrated that a short treatment with immunosuppressive agents, such as 1α,25-dihydroxyvitamin D3/mycophenolate mofetil, induces tolerance to islet allografts associated with an increased frequency of CD4+CD25+ regulatory cells that can adoptively transfer transplantation tolerance.
Impact of Immunosuppressive Drugs on CD4+CD25+FOXP3+ Regulatory T Cells: Does In Vitro Evidence Translate to the Clinical Setting?
A comprehensive overview of the current literature on the effects of immunosuppressive drugs on CD4+CD25+FOXP3+ Treg is provided and whether in vitro data are substantiated by in vivo evidence from the clinic is discussed.
Following Anti‐CD25 Treatment, A Functional CD4+CD25+ Regulatory T‐Cell Pool Is Present in Renal Transplant Recipients
It is shown that after daclizumab therapy a Treg population, normal in number and function, is present in the peripheral blood of renal transplant recipients, and functional analysis revealed that the Treg possessed a normal capacity to suppress mixed lymphocyte reactions in vitro.
Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+CD25+ regulatory T cells.
It is found that rapamycin and CsA do not interfere with the suppressive activity of human naturally occurring CD4+ CD25+ T cells, which may favor the use of rap amycin in tolerance-inducing strategies.
The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade.
It is found that the additional use of compatible immunosuppressive drugs allows the dose of TBI to be reduced, so that mixed chimerism and donor skin-graft acceptance can be achieved with 1 Gy using clinically feasible cell numbers, and this protocol of BMT with costimulation blockade can be safely combined with a clinically tested immunOSuppressive regimen to permit success with a lower dose of irradiation.
Mycophenolate Mofetil for Renal Dysfunction in Liver Transplant Recipients on Cyclosporine or Tacrolimus: Randomized, Prospective, Multicenter Pilot Study Results
These pilot studies show that in LTX recipients with renal dysfunction, MMF allows CNI dose reduction or discontinuation, improving or stabilizing GFR in most patients.