title: Calcineurin inhibitor withdrawal in stable kidney transplant patients decreases the donor-specific cytotoxic T lymphocyte precursor frequency.
abstract: BACKGROUND
  In a prospective study, calcineurin inhibitors (CNI) were withdrawn in patients two years after kidney transplantation. We questioned whether stopping CNI had an effect on the donor-specific reactivity, as CNI might hinder immune responses leading to graft acceptance.
  
  
  METHODS
  We measured the donor-specific cytotoxic T lymphocyte (CTL) precursor frequency (CTLpf) in 54 patients before and after withdrawal of CNI. In addition, the T-cell reactivity of PBMC to donor and third-party antigens was tested in MLR, and in IFNgamma-Elispot. Reactivity to tetanus toxoid (TET) was studied as well.
  
  
  RESULTS
  Donor-specific CTLpf significantly decreased after CNI withdrawal (P=0.0001). In contrast, no difference was observed in third-party reactive CTLpf, donor and third-party reactive MLR and IFNgamma-Elispot. Proliferative responses and the number of IFNgamma-producing cells to TET also decreased after CNI withdrawal. The decrease in CTLpf correlated with the time between the two blood samples (before and after stopping CNI, P=0.05). This decrease was caused by stopping CNI, because there was no correlation between CTLpf and the duration of the CNI treatment after transplantation. Moreover, the percentage of regulatory T cells in the peripheral blood increased after CNI withdrawal.
  
  
  CONCLUSIONS
  We report here that after withdrawal of CNI the donor-specific CTLpf decreases. We hypothesize that CNI suppress regulatory mechanisms that have the potential to down-regulate donor-specific CTL responses and reactivity to TET.
authors.affiliation: Department of Internal Medicine-Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. b.j.van_der_mast@lumc.nl
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: van der Mast
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Rischen-Vos
authors.forename: Petronella
authors.initials: P
authors.lastname: de Kuiper
authors.forename: Lenard M B
authors.initials: LM
authors.lastname: Vaessen
authors.forename: Nicole M
authors.initials: NM
authors.lastname: van Besouw
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
mesh_terms: D065095:Calcineurin Inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D004334:Drug Administration Schedule; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis; D016030:Kidney Transplantation / Q000276:immunology*; D018655:Lymphocyte Count; D007959:Lymphocyte Culture Test, Mixed; D013234:Stem Cells / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000473:pathology; D013745:Tetanus Toxoid / Q000494:pharmacology; D014019:Tissue Donors
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D013745:Tetanus Toxoid; D007371:Interferon-gamma