Differential NF-kappa B and I kappa B gene expression during development of cardiac allograft rejection versus CD154 monoclonal antibody-induced tolerance

Background The Rel/NF-kappaB transcription factor pathway, regulated by I k appaB proteins, is considered central to immune responses, although there a re surprisingly few in vivo data concerning alloresponses. Methods, We undertook analysis of NF-kappaB and I kappaB mRNA intracardiac allograft expression, and NF-kappaB nuclear translocation, during acute rej ection versus CD154 monoclonal antibody (mAb)-induced tolerance induction i n fully MHC-disparate mice. Results. Intragraft expression of all nine NF-kappaB and I kappaB genes inc reased during development of rejection, and nuclear translocation of p50, p 52, and p65 was detected. CD154 mAb therapy decreased mRNA levels of all ni ne NF-kappaB and I kappaB 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, indicat ing an absolute requirement for expression of these genes in CD154 mAb-indu ced tolerance. Conclusions, We conclude that, whereas blanket approaches to NF-kappaB supp ression are unlikely to be effective strategies for tolerance induction, a better understanding of the roles of individual NF-kappaB and I kappaB gene s may allow development of more precise and effective therapies.