Differing Effects of Rapamycin or Calcineurin Inhibitor on T-Regulatory Cells in Pediatric Liver and Kidney Transplant Recipients

Authors

  • T. Akimova,

    1. Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA
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  • B. M. Kamath,

    1. Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Canada
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  • J. W. Goebel,

    1. Division of Nephrology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
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  • K. E. C. Meyers,

    1. Department of Pediatrics, Division of Nephrology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA
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  • E. B. Rand,

    1. Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA
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  • A. Hawkins,

    1. Pediatric Liver Care Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
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  • M. H. Levine,

    1. Department of Surgery, Division of Transplant Surgery, Hospital of the University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, PA
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  • J. C. Bucuvalas,

    1. Pediatric Liver Care Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
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  • W. W. Hancock

    Corresponding author
    1. Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA
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Wayne W. Hancock, whancock@mail.med.upenn.edu

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.

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