Clinical Significance of Monitoring Circulating CD4⁺CD25⁺Regulatory T Cells in Kidney Transplantation during the Early Posttransplant Period

Abstract

The CD4+CD25+ T regulatory cells (Tregs) play an important role in immune tolerance in experimental transplantation but the clinical significance of circulating Tregs in the peripheral blood is undetermined. In 50 kidney transplant (KT) recipients, 29 healthy controls and 32 liver transplant (LT) recipients, the frequency of Tregs was measured with flow cytometry before and after transplantation. In the KT recipients, IL-10 secretion was measured with an enzyme-linked immunospot (ELISPOT) assay. The median frequency of circulating Tregs before KT was similar to that in healthy controls but significantly lower than that in LT patients before transplantation. The frequency of Tregs was significantly decreased in patients with subclinical acute rejection compared with those without subclinical acute rejection. Calcineurin inhibitors (CNIs) and anti-CD25 antibody decreased the frequency of Tregs but mTOR inhibitor did not. The frequency of donor-specific IL-10 secreting cells did not correlate with the number of Tregs. The frequency of circulating Tregs in KT recipients is strongly affected by CNIs and anti-CD25 antibody, and a low frequency of Tregs is associated with subclinical acute rejection during the early posttransplant period.

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“…24 In addition, a significant difference was found between healthy control and chronic graft rejection patients in the current study, which agrees with findings of Karczewski and coworkers. 13 However, there was no significant Abbreviations: CSA, cyclosporine; Prog, prograf (tacrolimus); RAPA, rapamycin; stab, stable 6 but not with findings of other studies that found an increase in patients with graft acceptance 13,25 or a significant decrease of Tregs in transplant patients compared with healthy controls. 23 The variation between the different studies could be explained by the heavy immunosuppressive regimen posttransplant that may differ from 1 center to another and that affects Tregs.…”

“…The results of our study revealed that neither the type of donor nor the presence of infection had an effect on circulating Tregs; this also was reported in other studies. 6,13,23 Regarding the effect of sex, we found no significant difference in Treg percentage between male and female patients. To study the effect of duration posttransplant on Tregs, we divided the patients according to the period posttransplant into 3 subgroups: < 5 years; 5 to 10 years; and > 10 years.…”

“…29 According to Kim and associates, who studied patients before and after kidney transplant and healthy matched individuals, the median frequency of Tregs in the recipients was 4.2% (range, 2.5% to 9.7%) and healthy controls was 2.7% (range, 1.6% to 5.7%). 6 However, there was no significant difference between the recipients and healthy controls before transplant. They further compared the median frequencies of Tregs in patients with different underlying diseases and found no significant differences based on the underlying disease in kidney transplanted patients.…”

“…They reported the median frequency of circulating Tregs as 2% (1% to 3.6%) at 1 week, 1.6% (0.5% to 3.3%) at 2 weeks, and 2.5% (1.7% to 3.7%) at 8 weeks. 6 To study the effect of immunosuppressive drugs on Tregs, we divided our patients into 3 subgroups according to the therapy taken: RAPA, cyclosporine, or tacrolimus. Patients with stable graft on RAPA had a significantly higher level of Tregs than control subjects, and patients on cyclosporine had significantly lower levels.…”

“…5 The Tregs that represent 5% to 10% peripheral circulating CD4 + T cells in humans and rodents are observed in lymphoid tissue and at the graft site and can be isolated from the peripheral blood of recipients. 6 Interleukin 10 (IL-10) is required for the generation and suppressor functions of Tregs. 7 It was reported by van den Boogaardt and colleagues that more IL-10-producing cells were observed in kidney recipients with stable graft function than rejection.…”