IL-12 antagonism enhances apoptotic death of T cells within hepatic allografts from Flt3 ligand-treated donors and promotes graft acceptance

Mouse livers are accepted across MHC barriers and induce donor-specific tol erance without immunosuppressive therapy. By contrast, livers from donors t reated with Flt3 ligand, which dramatically increases hepatic interstitial dendritic cells, are rejected acutely (median survival time 5 days). This s witch 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, promot e expansion of Th1 cells, and play a key role in liver rejection. Therefore , C3H (H2(k)) recipients of liver grafts from Flt3 ligand-treated BIO donor s were given neutralizing anti-IL-12 mAb (200 or 500 mug) on days 0 and 2 a fter transplant. Graft survival was markedly prolonged at the higher mAb do se, with 50% of grafts surviving > 100 days. This effect was associated wit h reductions in IFN-T gene transcripts within the graft-infiltrating cell p opulation and with reductions in circulating IFN-gamma and IL-10 levels, do nor-specific CTL and NK cell activities, and circulating alloantibody level s. At the same time, there were marked increases in apoptotic (TUNEL+) CD4( +) and especially CD8(+) cells, both within the grafts and in spleens of an ti-IL-12 mAb-treated mice. In vitro, exogenous IL-12 inhibited apoptotic de ath induced in naive allogeneic T cells by liver nonparenchymal cells. Thes e findings suggest that suppression of rejection by IL-12 antagonism, linke d to restoration of apoptotic activity within the peripheral alloreactive T cell population, is important for liver allograft survival and tolerance i nduction.