Abstract
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.
Highlights
Kidney transplantation is considered the treatment of choice for patients with end-stage renal failure
Within the CD4+CD25hiCD127lo/− region, we found that only patients under Cyclosporine A (CsA) treatment showed a reduced percentage of Forkhead box P3 (FOXP3)+ cells compared to controls (76.80 ± 2.83 versus 88.46 ± 1.20; p = 0.002); while the percentage of FOXP3+ cells within this region was not significantly altered in kidney transplant patients under BLT treatment compared to controls (83.29 ± 2.39 versus 88.46 ± 1.20; p = 0.07)
Regulatory T cells have been implicated in tolerance induction to allogeneic organ transplantation [13]
Summary
Kidney transplantation is considered the treatment of choice for patients with end-stage renal failure. A lower incidence of chronic allograft nephropathy, favoring BLT compared to patients under CsA treatment was documented by 12 months post-transplantation [4, 5]. It has been reported an increase of acute rejection episodes and post-transplant lymphoproliferative disorders in BLT-treated patients [4], clinical studies have shown that 7 years after transplantation kidney transplant patients under BLT treatment have a significantly better patient and graft survival, as well as mean estimated glomerular filtration rate than patients under CsA [6]
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