Different Immunosuppressive Combinations on T-Cell Regulation in Renal Transplant Recipients

Fourtounas, Costas; Dousdampanis, Periklis; Sakellaraki, Panagiota; Rodi, Maria; Georgakopoulos, Tassos; Vlachojannis, John G.; Mouzaki, Αthanasia

doi:10.1159/000313940

Cited by 40 publications

(32 citation statements)

References 55 publications

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“…In liver transplant recipients, conversion from CNI to MMF with a 1-time dose of daclizumab showed an increase in the percentage of Treg from baseline 114 . Analysis of kidney transplant patients on stable immunosuppression regimens identified higher levels of CD4 + CD25 high FOXP3 + Treg in patients receiving MMF versus everolimus 115 . Overall, preclinical and clinical evidence thus far suggest that MMF is compatible with Treg homeostasis and function.…”

Section: Impact Of Approved Immunosuppressive Drugs On Tregmentioning

confidence: 98%

Impact of Immune-Modulatory Drugs on Regulatory T Cell

2016

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Immunosuppression strategies that selectively inhibit effector T cells while preserving and even enhancing CD4+FOXP3+ regulatory T cells (Treg) permit immune self-regulation and may allow minimization of immunosuppression and associated toxicities. Many immunosuppressive drugs were developed before the identity and function of Treg were appreciated. A good understanding of the interactions between Treg and immunosuppressive agents will be valuable to the effective design of more tolerable immunosuppression regimens. This review will discuss preclinical and clinical evidence regarding the influence of current and emerging immunosuppressive drugs on Treg homeostasis, stability, and function as a guideline for the selection and development of Treg-friendly immunosuppressive regimens.

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Section: Impact Of Approved Immunosuppressive Drugs On Tregmentioning

confidence: 98%

Impact of Immune-Modulatory Drugs on Regulatory T Cell

2016

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“…Previous reports have described how CNIs reduce regulatory T cells (Tregs) but increase IL-17-producing T helper cells (Th17) despite reducing the overall number of T cells. 5–12 The loss of Tregs, which secrete the anti-inflammatory cytokines TGFbeta and IL-10, kill pro-inflammatory immune cells, and promote immune tolerance, and the augmentation of Th17 cells that produce the potent pro-inflammatory and pro-hypertensive cytokine IL-17, together lead to organ dysfunction and hypertension. 8, 9 However, it is unknown whether targeting these effects can have vascular and renal protective effects and attenuate the hypertension caused by CNIs.…”

Section: Introductionmentioning

confidence: 99%

Regulatory T-Cell Augmentation or Interleukin-17 Inhibition Prevents Calcineurin Inhibitor–Induced Hypertension in Mice

et al. 2017

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The immunosuppressive calcineurin inhibitors cyclosporine A and tacrolimus alter T cell subsets and can cause hypertension, vascular dysfunction, and renal toxicity. We and others have reported that cyclosporine A and tacrolimus decrease anti-inflammatory regulatory T cells and increase pro-inflammatory interleukin-17-producing T cells, therefore we hypothesized that inhibition of these effects using non-cellular therapies would prevent the hypertension, endothelial dysfunction, and renal glomerular injury induced by calcineurin inhibitor therapy. Daily treatment of mice with cyclosporine A or tacrolimus for 1 week significantly decreased CD4+/FoxP3+ regulatory T cells in the spleen and lymph nodes, as well as induced hypertension, vascular injury and dysfunction, and glomerular mesangial expansion in mice. Daily co-treatment with all-trans retinoic acid, reported to increase regulatory T cells and decrease interleukin-17-producing T cells, prevented all of the detrimental effects of cyclosporine A and tacrolimus. All-trans retinoic acid also increased regulatory T cells and prevented the hypertension, endothelial dysfunction, and glomerular injury in genetically modified mice that phenocopy calcineurin inhibitor-treated mice (FKBP12-Tie2 KO). Treatment with an interleukin-17 neutralizing antibody also increased regulatory T cell levels and prevented the hypertension, endothelial dysfunction, and glomerular injury in cyclosporine A-treated and tacrolimus-treated mice as well as FKBP12-Tie2 KO mice, while an isotype control had no effect. Augmenting regulatory T cells and/or inhibiting interleukin-17 signaling using non-cellular therapies prevents the cardiovascular and renal toxicity of calcineurin inhibitors in mice.

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“…11,12 Conversely, corticosteroids have been reported to increase Treg frequency and FOXP3 expression in patients with autoimmune diseases. 13,14 Finally, renal transplant recipients receiving MMF show significantly higher CD4…”

Section: Introductionmentioning

confidence: 99%

“…12 Furthermore, studies on liver transplant patients with renal impairment on CsA and converted to MMF showed that the new treatment may reverse the negative effect of calcineurin inhibitors on Tregs. 15 This study has focused on the consequences of using drugs commonly applied in the treatment of transplant patients, namely TAC, MPA and mPr, for the viability, function and stability of ex vivo expanded Tregs.…”

Section: Introductionmentioning

confidence: 99%