Immunophenotyping of peripheral immunoregulatory as well as Th17A and Th22 cell subpopulations in kidney transplant recipients under belatacept or cyclosporine treatment

Furuzawa‐Carballeda, Janette; Bostock, Ian C.; Lima, Guadalupe; Mancilla-Urrea, Eduardo; Mondragón, G.; Reyes‐Acevedo, Rafael; Chevaile, Alejandro; Morales‐Buenrostro, Luis E.; Llórente, Luis; Alberú, Josefina

doi:10.1016/j.trim.2014.02.002

Cited by 10 publications

(13 citation statements)

References 43 publications

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“…T cells were significantly higher in the belatacept group (after renal transplantation) when compared to those under cyclosporine and controls. Moreover, a difference was also found when the cyclosporine group was compared with controls, being higher in the latter group (Furuzawa-Carballeda et al 2014).…”

Section: Discussionmentioning

confidence: 88%

Suppressor Properties of Human CD8+CD28− T Cells in Mixed Leukocyte Reaction are not Affected by CsA and RAPA

Korecka-Polak

Bocian

Pachówka

et al. 2016

Arch. Immunol. Ther. Exp.

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Human CD8(+)CD28(-) T suppressor cells were previously shown to be involved in the control of the immune response to transplanted allografts. It seems essential to examine how immunosuppressive drugs influence these cells. However, the CD8(+)CD28(-) population contains both suppressor (Ts) and cytotoxic (Tc) T cells, and the phenotype of the Ts subpopulation has not been identified explicitly. It is proposed that the transcription factor FOXP3 may be helpful in distinguishing the Ts and Tc subpopulations. The aim of this study was to evaluate the influence of the immunosuppressive drugs cyclosporine A (CsA) and rapamycin (RAPA) on the level, suppressor properties, and phenotype of human CD8(+)CD28(-) T cells in vitro. The model used was the mixed leukocyte reaction performed with peripheral blood mononuclear cells from healthy volunteers. It was observed that CD8(+)CD28(-) T cells from cultures with CsA or RAPA had similar suppressor properties to cells from control cultures, although the drugs influenced the expression of FOXP3. CsA and RAPA did not interfere with the suppressor properties of human CD8(+)CD28(-) T cells in vitro, although they affected the expression of the FOXP3 molecule.

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Section: Discussionmentioning

confidence: 88%

Suppressor Properties of Human CD8+CD28− T Cells in Mixed Leukocyte Reaction are not Affected by CsA and RAPA

Korecka-Polak

Bocian

Pachówka

et al. 2016

Arch. Immunol. Ther. Exp.

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“…This was supported by studies showing an increase of CD16 + IDO + cells and Tregs in peripheral blood and in intragraft FOXP3 + cells, proposed to generate a tolerant profile to renal allograft in those patients (8, 9). Other studies showed no differences in the percentage of CD4 + CD25 hi and in FOXP3 levels in the CD4 + subpopulation between BLT and CsA patients after 6 months of treatment (10) or showed no long-term negative impact of BLT on circulating Tregs (11).…”

Section: Introductionmentioning

confidence: 74%

“…In this study, we used, besides the CD25 + and FOXP3 + markers, the low expression of CD127 to identify Tregs that were evaluated in 35 patients with a mean time of 7 years since transplantation. By contrast, analysis of Tregs in other studies was based on CD25 and FOXP3 expression (9), two markers that are transiently expressed in activated humans T cells (22), and other results were limited by the small numbers of patients included in the study (21). …”

Section: Discussionmentioning

confidence: 97%

“…Studies have reported that kidney transplant patients under BLT treatment show a better renal function and less chronic nephropathy in comparison to those under CsA treatment (4, 6, 20). Some studies claim that Treg frequency in peripheral blood and transplanted organs are increased in patients under BLT treatment (9, 21); however, other studies claim the opposite (12). Such differences may be caused by inconsistent parameters used for the characterization of the total Treg pool, different gating strategies and small numbers of participants in many studies.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, a recent study showed BLT-treated patients have increased cellular populations with regulatory function such that IL-10 + B cells and IDO + cells (9, 47), which could promote tolerance during transplantation and facilitate the long-term survival and function of allografts.…”

Section: Discussionmentioning

confidence: 99%

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Methylation of FOXP3 TSDR Underlies the Impaired Suppressive Function of Tregs from Long-term Belatacept-Treated Kidney Transplant Patients

et al. 2017

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Regulatory T cells (Tregs) are considered key players in the prevention of allograft rejection in transplanted patients. Belatacept (BLT) is an effective alternative to calcineurin inhibitors that appears to preserve graft survival and function; however, the impact of this drug in the homeostasis of Tregs in transplanted patients remains controversial. Here, we analyzed the phenotype, function, and the epigenetic status of the Treg-specific demethylated region (TSDR) in FOXP3 of circulating Tregs from long-term kidney transplant patients under BLT or Cyclosporine A treatment. We found a significant reduction in the proportion of CD4+CD25hiCD127lo/−FOXP3+ T cells in all patients compared to healthy individual (controls). Interestingly, only BLT-treated patients displayed an enrichment of the CD45RA+ “naïve” Tregs, while the expression of Helios, a marker used to identify stable FOXP3+ thymic Tregs remained unaffected. Functional analysis demonstrated that Tregs from transplanted patients displayed a significant reduction in their suppressive capacity compared to Tregs from controls, which is associated with decreased levels of FOXP3 and CD25. Analysis of the methylation status of the FOXP3 gene showed that BLT treatment results in methylation of CpG islands within the TSDR, which could be associated with the impaired Treg suppression function. Our data indicate that analysis of circulating Tregs cannot be used as a marker for assessing tolerance toward the allograft in long-term kidney transplant patients. Trial registration number IM103008.

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Pharmacologic Targeting of Regulatory T Cells for Solid Organ Transplantation: Current and Future Prospects

Safa

Chandran

Wojciechowski

2015

Drugs

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The last three decades have witnessed significant advances in the development of immunosuppressive medications used in kidney transplantation leading to a remarkable gain in short-term graft function and outcomes. Despite these major breakthroughs, improvements in long-term outcomes lag behind due to a stalemate between drug-related nephrotoxicity and chronic rejection typically due to donor-specific antibodies. Regulatory T cells (Tregs) have been shown to modulate the alloimmune response and can exert suppressive activity preventing allograft rejection in kidney transplantation. Currently available immunosuppressive agents impact Tregs in the alloimmune milieu with some of these interactions being deleterious to the allograft while others may be beneficial. Variable effects are seen with common antibody induction agents such that basiliximab, an IL-2 receptor blocker, decreases Tregs while lymphocyte depleting agents such as antithymocyte globulin increase Tregs. Calcineurin inhibitors, a mainstay of maintenance immunosuppression since the mid-1980s, seem to suppress Tregs while mammalian targets of rapamycin (less commonly used in maintenance regimens) expand Tregs. The purpose of this review is to provide an overview of Treg biology in transplantation, identify in more detail the interactions between commonly used immunosuppressive agents and Tregs in kidney transplantation and lastly describe future directions in the use of Tregs themselves as therapy for tolerance induction.

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Immunophenotyping of peripheral immunoregulatory as well as Th17A and Th22 cell subpopulations in kidney transplant recipients under belatacept or cyclosporine treatment

Cited by 10 publications

References 43 publications

Suppressor Properties of Human CD8+CD28− T Cells in Mixed Leukocyte Reaction are not Affected by CsA and RAPA

Suppressor Properties of Human CD8+CD28− T Cells in Mixed Leukocyte Reaction are not Affected by CsA and RAPA

Methylation of FOXP3 TSDR Underlies the Impaired Suppressive Function of Tregs from Long-term Belatacept-Treated Kidney Transplant Patients

Pharmacologic Targeting of Regulatory T Cells for Solid Organ Transplantation: Current and Future Prospects

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