title: Differing effects of rapamycin or calcineurin inhibitor on T-regulatory cells in pediatric liver and kidney transplant recipients.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Transplant Immunology, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Akimova
authors.forename: B M
authors.initials: BM
authors.lastname: Kamath
authors.forename: J W
authors.initials: JW
authors.lastname: Goebel
authors.forename: K E C
authors.initials: KE
authors.lastname: Meyers
authors.forename: E B
authors.initials: EB
authors.lastname: Rand
authors.forename: A
authors.initials: A
authors.lastname: Hawkins
authors.forename: M H
authors.initials: MH
authors.lastname: Levine
authors.forename: J C
authors.initials: JC
authors.lastname: Bucuvalas
authors.forename: W W
authors.initials: WW
authors.lastname: Hancock
mesh_terms: D000293:Adolescent; D019703:Calcineurin / Q000627:therapeutic use*; D016022:Case-Control Studies; D002648:Child; D003430:Cross-Sectional Studies; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D011379:Prognosis; D020123:Sirolimus / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D019703:Calcineurin; D020123:Sirolimus