title: CD154 is expressed during treatment with calcineurin inhibitors after organ transplantation.
abstract: BACKGROUND
  CD154 (CD40 ligand) monoclonal antibody prevents allograft rejection in rodents and monkeys. Inasmuch as calcineurin inhibitors (CI) inhibit CD154 expression by pharmacologic agents in vitro, we investigated whether CD154 is also inhibited by CI in vivo and in vitro during allogeneic stimulation.
  
  
  METHODS
  CD154 expression was determined by immunohistochemistry and flow cytometry in human lymph nodes and spleen sections from rhesus monkeys with or without CI treatment. The effect of CI on induction of CD154 expression was studied by stimulating lymphocytes with phorbol 12-myristate 13-acetate (PMA) and ionomycin or with allogeneic monocyte-derived mature dendritic cells.
  
  
  RESULTS
  Lymph nodes from patients with or without CI cyclosporine (CsA) or FK506 (FK) treatment showed comparable CD154 expression, which was present on the cell surface of T cells. CD154-expressing cells were also present in spleens from monkeys treated with CsA in comparable numbers to those in the nontreated group. Moreover, in several liver transplant rejection biopsies taken during CI therapy CD154-expressing cells were observed. In vitro, CsA and FK strongly inhibited induction of CD154 expression on peripheral blood mononuclear cells by pharmacologic stimuli. Maximum inhibition was found at 50 ng/ml CsA and 20 ng/ml FK. CD154 expression induced by dendritic cells in peripheral blood mononuclear cells or spleen cells was also almost completely inhibited by CsA.
  
  
  CONCLUSIONS
  Although CI strongly suppressed pharmacologic and allogeneic induction of CD154 expression on T cells in vitro at concentrations at approximately clinical trough levels, CD154 is prominently expressed during CI therapy in lymphoid tissue and (sporadically) in liver allografts. This suggests that the CD154-CD40 pathway remains functional during CI therapy, which may contribute to allograft rejections in the clinical setting.
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital Rotterdam, Rotterdam, The Netherlands.
authors.forename: Miranda M L
authors.initials: MM
authors.lastname: van Rijen
authors.forename: Mark L
authors.initials: ML
authors.lastname: Kuijf
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.forename: Hugo W
authors.initials: HW
authors.lastname: Tilanus
authors.forename: Gerda J
authors.initials: GJ
authors.lastname: Bouma
authors.forename: Roel A
authors.initials: RA
authors.lastname: de Weger
authors.forename: Margreet
authors.initials: M
authors.lastname: Jonker
authors.forename: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D023201:CD40 Ligand / Q000235:genetics*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000627:therapeutic use; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology; D016031:Liver Transplantation / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D013154:Spleen / Q000276:immunology; D016559:Tacrolimus / Q000627:therapeutic use; D014184:Transplantation, Homologous / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D016572:Cyclosporine; D016559:Tacrolimus