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Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213
Mouse livers are accepted across MHC barriers and induce
donor-specific tolerance without immunosuppressive therapy. By
contrast, livers from donors treated with Flt3 ligand, which
dramatically increases hepatic interstitial dendritic cells, are
rejected acutely (median survival time 5 days). This switch from
tolerance to rejection is associated with a marked reduction in
apoptotic activity of graft-infiltrating cells. We hypothesized that
IL-12 production by enhanced numbers of donor APC might inhibit
apoptosis, promote expansion of Th1 cells, and play a key role in liver
rejection. Therefore, C3H (H2k) recipients of liver grafts
from Flt3 ligand-treated B10 donors were given neutralizing
anti-IL-12 mAb (200 or 500 µg) on days 0 and 2 after transplant.
Graft survival was markedly prolonged at the higher mAb dose, with 50%
of grafts surviving >100 days. This effect was associated with
reductions in IFN-
gene transcripts within the graft-infiltrating
cell population and with reductions in circulating IFN- and IL-10
levels, donor-specific CTL and NK cell activities, and circulating
alloantibody levels. At the same time, there were marked increases in
apoptotic (TUNEL+) CD4+ and especially
CD8+ cells, both within the grafts and in spleens of
anti-IL-12 mAb-treated mice. In vitro, exogenous IL-12 inhibited
apoptotic death induced in naive allogeneic T cells by liver
nonparenchymal cells. These findings suggest that suppression of
rejection by IL-12 antagonism, linked to restoration of apoptotic
activity within the peripheral alloreactive T cell population, is
important for liver allograft survival and tolerance
induction.
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