title: Pimecrolimus and tacrolimus differ in their inhibition of lymphocyte activation during the sensitization phase of contact hypersensitivity.
abstract: BACKGROUND
  As reported previously, oral administration of the calcineurin inhibitors (CNI) pimecrolimus and tacrolimus resulted in equipotent inhibition of the elicitation phase of contact hypersensitivity (CHS) in mice. The sensitization phase was inhibited by tacrolimus but was unaffected by pimecrolimus, even at higher doses.
  
  
  OBJECTIVE
  The kinetics of lymph node hyperplasia and up-regulation of T and B cell activation antigens were analyzed to obtain a better understanding of the divergent CNI profile in CHS.
  
  
  METHODS
  Lymph node (LN) cells of CNI-untreated and treated mice were examined with flow cytometry at various time points after sensitization with oxazolone. LN hyperplasia and drug levels were also determined.
  
  
  RESULTS
  Sensitization induced a higher portion of LN cells expressing the activation antigens CD25, CD69 and CD134 and an increase in activated B cells (B220(+)/CD40(+)) compared to naïve mice. Up-regulation of these markers was completely or profoundly blocked with tacrolimus, whereas pimecrolimus at the three-fold higher dose caused significantly less inhibition. Tacrolimus also completely blocked the sensitization-associated increase of CD11c(+) antigen presenting cells (APC) in LN, whereas pimecrolimus showed significantly less inhibition. In contrast to tacrolimus, LN weight and cellularity were not affected by pimecrolimus at any time point after sensitization. Concentration of tacrolimus in blood and in the draining LN substantially exceeded that of pimecrolimus by factors 6.7-14 and 5.6-5.8, respectively, at the same dose levels.
  
  
  CONCLUSIONS
  In contrast to tacrolimus, systemic treatment of mice with pimecrolimus only weakly interferes with lymphocyte activation and does not affect hyperplasia of the draining lymph nodes during sensitization.
authors.affiliation: Novartis Institutes for BioMedical Research, Brunnerstrasse 59, A 1235 Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Bavandi
authors.forename: H
authors.initials: H
authors.lastname: Fahrngruber
authors.forename: H
authors.initials: H
authors.lastname: Aschauer
authors.forename: B
authors.initials: B
authors.lastname: Hartmann
authors.forename: J G
authors.initials: JG
authors.lastname: Meingassner
authors.forename: F S
authors.initials: FS
authors.lastname: Kalthoff
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000032:analysis; D003877:Dermatitis, Contact / Q000276:immunology* / Q000503:physiopathology; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D039521:CD11c Antigen; D007166:Immunosuppressive Agents; C117268:pimecrolimus; D016559:Tacrolimus