Differential NF-kappaB and IkappaB gene expression during development of cardiac allograft rejection versus CD154 monoclonal antibody-induced tolerance.
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.
Csizmadia
V
V
Transplantation, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Gao
W
W
Hancock
S A
SA
Rottman
J B
JB
Wu
Z
Z
Turka
L A
LA
Siebenlist
U
U
Hancock
W W
WW
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
D000911:Antibodies, Monoclonal; D020672:I-kappa B Proteins; D016328:NF-kappa B; D023201:CD40 Ligand