Differing effects of rapamycin or calcineurin inhibitor on T-Regulatory cells in pediatric liver and kidney transplant recipients

T. Akimova, B. M. Kamath, J. W. Goebel, K. E.C. Meyers, E. B. Rand, A. Hawkins, M. H. Levine, J. C. Bucuvalas, W. W. Hancock

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

In a cross-sectional study, we assessed effects of calcineurin inhibitor (CNI) or rapamycin on T-regulatory (Treg) cells from children with stable liver (n = 53) or kidney (n = 9) allografts several years posttransplant. We analyzed Treg number, phenotype, suppressive function, and methylation at the Treg-specific demethylation region (TSDR) using Tregs and peripheral blood mononuclear cells. Forty-eight patients received CNI (39 as monotherapy) and 12 patients received rapamycin (9 as monotherapy). Treg numbers diminished over time on either regimen, but reached significance only with CNI (r =-0.424, p = 0.017). CNI levels inversely correlated with Treg number (r =-0.371, p = 0.026), and positively correlated with CD127+ expression by Tregs (r = 0.437, p = 0.023). Patients with CNI levels >3.6 ng/mL had weaker Treg function than those with levels <3.6 ng/mL, whereas rapamycin therapy positively correlated with Treg numbers (r = 0.628, p = 0.029) and their expression of CTLA4 (r = 0.726, p = 0.041). Overall, CTLA4 expression, TSDR demethylation and an absence of CD127 were important for Treg suppressive function. We conclude that rapamycin has beneficial effects on Treg biology, whereas long-term and high dose CNI use may impair Treg number, function and phenotype, potentially acting as a barrier to attaining host hyporesponsiveness to an allograft. In a cross-sectional clinical study of pediatric liver and kidney transplant recipients, analysis of FOXP3+ Treg cells shows that rapamycin has beneficial effects on Treg parameters, whereas long-term and high-dose calcineurin inhibitor use may impair Treg number, function and phenotype, potentially acting as a barrier to attaining host hyporesponsiveness to an allograft.

Original languageEnglish
Pages (from-to)3449-3461
Number of pages13
JournalAmerican Journal of Transplantation
Volume12
Issue number12
DOIs
StatePublished - Dec 2012
Externally publishedYes

Keywords

  • Clinical transplantation
  • immunoregulation
  • immunosuppression

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