期刊
JOURNAL OF IMMUNOLOGY
卷 166, 期 9, 页码 5619-5628出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.166.9.5619
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- NIDDK NIH HHS [DK 49745, DK 29961] Funding Source: Medline
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 (H2(k)) recipients of liver grafts from Flt3 ligand-treated BIO donors were given neutralizing anti-IL-12 mAb (200 or 500 mug) 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-T gene transcripts within the graft-infiltrating cell population and with reductions in circulating IFN-gamma 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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