title: After discontinuation of calcineurin inhibitors, tapering of mycophenolate mofetil further impairs donor-directed cytotoxicity.
abstract: BACKGROUND
  Recently, we described a significant decrease in donor-specific cytotoxic T-lymphocyte precursor frequency (CTLpf) after discontinuation of calcineurin inhibitors (CNI), while the proliferative capacity in mixed lymphocyte culture (MLC), and the number of interferon-gamma (IFN-gamma) producing cells (pc) in Elispot remained unchanged.
  
  
  METHODS
  We tested T-cell reactivity in CNI free patients with stable renal graft function, on mycophenolate mofetil (MMF) or azathioprine (AZA) plus prednisone, who were tapered to 50% of their MMF or AZA dose.
  
  
  RESULTS
  Furthermore, tapering of the MMF or AZA dose resulted in a decrease of donor-reactive CTLpf in all patients with detectable CTLpf. Detectable numbers decreased from a median of 32 to 8 CTLp/10(6) peripheral blood mononuclear cell (PBMC). No effect on third-party reactive CTLpf was found, while the T-cell reactivity to donor and third-party cells as tested in MLC and in IFN-gamma Elispot was not affected either by tapering of immunosuppression. Third-party reactivity was significantly higher than donor-specific reactivity in all tests. A control group showed no changes in any of the in vitro assays.
  
  
  CONCLUSIONS
  Both withdrawal of CNI and tapering of MMF or AZA dose decreases the donor-specific CTLpf. Our data suggest that reduction of immunosuppression results in a specific decrease of donor-directed cytotoxic capacity of immunocompetent cells, while their proliferation and cytokine production capacity remained unchanged. Immunosuppression hinders development of cytotoxic non-responsiveness.
authors.affiliation: Department of Internal Medicine-Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. n.vanbesouw@erasmusmc.nl
authors.forename: Nicole M
authors.initials: NM
authors.lastname: van Besouw
authors.forename: Jacqueline
authors.initials: J
authors.lastname: van de Wetering
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: van der Mast
authors.forename: Ronella
authors.initials: R
authors.lastname: de Kuiper
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
mesh_terms: D001379:Azathioprine / Q000008:administration & dosage / Q000276:immunology; D019703:Calcineurin / Q000276:immunology; D065095:Calcineurin Inhibitors; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D006087:Graft vs Host Reaction / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology*; D007963:Leukocytes, Mononuclear; D007959:Lymphocyte Culture Test, Mixed; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D011241:Prednisone / Q000008:administration & dosage / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D019703:Calcineurin; D009173:Mycophenolic Acid; D001379:Azathioprine; D011241:Prednisone