Inhibition of NF-kappaB-dependent T cell activation abrogates acute allograft rejection.
Using a heterotopic model of transplantation, we investigated the role of T cell activation in vivo during allograft rejection in I-kappaB(DeltaN)-transgenic mice that express a transdominant inhibitor of NF-kappaB in T cells. Our results show indefinite prolongation of graft survival in the I-kappaB(DeltaN)-transgenic recipients. Interestingly, at the time of rejection of grafts in wild-type recipients, histology of grafts in the I-kappaB(DeltaN)-transgenic recipients showed moderate rejection; nevertheless, grafts in the I-kappaB(DeltaN) recipients survived >100 days. Analysis of acute phase cytokines, chemokine, chemokine receptors, and immune responses shows that the blockade of NF-kappaB activation in T cells inhibits up-regulation of many of these parameters. Interestingly, our data also suggest that the T cell component of the immune response exerted positive feedback regulation on the expression of multiple chemokines that are produced predominantly by non-T cells. In conclusion, our studies indicate NF-kappaB activation in T cells is necessary for acute allograft rejection.
Finn
P W
PW
Laboratory of Molecular Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Stone
J R
JR
Boothby
M R
MR
Perkins
D L
DL
D000210:Acute-Phase Reaction / Q000276:immunology; D000818:Animals; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D006082:Graft Enhancement, Immunologic; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival; D020672:I-kappa B Proteins / Q000235:genetics; D007519:Isoantigens / Q000276:immunology; D007700:Kinetics; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
D018925:Chemokines; D016207:Cytokines; D020672:I-kappa B Proteins; D007519:Isoantigens; D016328:NF-kappa B; D012333:RNA, Messenger; D019707:Receptors, Chemokine