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 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 B10 donors were given neutralizing anti-IL-12 mAb (200 or 500 microg) 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-gamma 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.
Li
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Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
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Wang
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Z
Wang
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Fung
J J
JJ
Thomson
A W
AW
Qian
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S
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D016466:CHO Cells; D002478:Cells, Cultured; D018920:Coculture Techniques; D006224:Cricetinae; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology; D008024:Ligands; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016031:Liver Transplantation / Q000276:immunology* / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D000276:Adjuvants, Immunologic; D016207:Cytokines; D007106:Immune Sera; D008024:Ligands; D008565:Membrane Proteins; C084881:flt3 ligand protein; D018664:Interleukin-12; D007371:Interferon-gamma