title: Differential NF-kappaB and IkappaB gene expression during development of cardiac allograft rejection versus CD154 monoclonal antibody-induced tolerance.
abstract: BACKGROUND
  The Rel/NF-kappaB transcription factor pathway, regulated by IkappaB proteins, is considered central to immune responses, although there are surprisingly few in vivo data concerning alloresponses.
  
  
  METHODS
  We undertook analysis of NF-kappaB and IkappaB mRNA intracardiac allograft expression, and NF-kappaB nuclear translocation, during acute rejection versus CD154 monoclonal antibody (mAb)-induced tolerance induction in fully MHC-disparate mice.
  
  
  RESULTS
  Intragraft expression of all nine NF-kappaB and IkappaB genes increased during development of rejection, and nuclear translocation of p50, p52, and p65 was detected. CD154 mAb therapy decreased mRNA levels of all nine NF-kappaB and IkappaB genes, and impaired nuclear translocation of p50, p52, and p65 NF-kappaB proteins. However, prolonged survival could not be induced by CD154 mAb in p50- or p52-deficient allograft recipients, indicating an absolute requirement for expression of these genes in CD154 mAb-induced tolerance.
  
  
  CONCLUSIONS
  We conclude that, whereas blanket approaches to NF-kappaB suppression are unlikely to be effective strategies for tolerance induction, a better understanding of the roles of individual NF-kappaB and IkappaB genes may allow development of more precise and effective therapies.
authors.affiliation: Transplantation, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
authors.forename: V
authors.initials: V
authors.lastname: Csizmadia
authors.forename: W
authors.initials: W
authors.lastname: Gao
authors.forename: S A
authors.initials: SA
authors.lastname: Hancock
authors.forename: J B
authors.initials: JB
authors.lastname: Rottman
authors.forename: Z
authors.initials: Z
authors.lastname: Wu
authors.forename: L A
authors.initials: LA
authors.lastname: Turka
authors.forename: U
authors.initials: U
authors.lastname: Siebenlist
authors.forename: W W
authors.initials: WW
authors.lastname: Hancock
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D004586:Electrophoresis; D015870:Gene Expression; D006084:Graft Rejection; D016027:Heart Transplantation / Q000276:immunology*; D020672:I-kappa B Proteins / Q000235:genetics*; D007108:Immune Tolerance; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics*; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
chemical_list: D000911:Antibodies, Monoclonal; D020672:I-kappa B Proteins; D016328:NF-kappa B; D023201:CD40 Ligand