HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, W. Articles by Qian, S. Search for Related Content PubMed PubMed Citation Articles by Li, W. Articles by Qian, S. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Liver Transplantation

IL-12 Antagonism Enhances Apoptotic Death of T Cells Within Hepatic Allografts from Flt3 Ligand-Treated Donors and Promotes Graft Acceptance¹

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 (H2^k) 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.

This article has been cited by other articles:

				C. C. Caldwell, J. Tschoep, and A. B. Lentsch Lymphocyte function during hepatic ischemia/reperfusion injury J. Leukoc. Biol., September 1, 2007; 82(3): 457 - 464. [Abstract] [Full Text] [PDF]

				P.-H. Chiang, L. Wang, C. A. Bonham, X. Liang, J. J. Fung, L. Lu, and S. Qian Mechanistic Insights into Impaired Dendritic Cell Function by Rapamycin: Inhibition of Jak2/Stat4 Signaling Pathway J. Immunol., February 1, 2004; 172(3): 1355 - 1363. [Abstract] [Full Text] [PDF]

				S. W. Lee, Y. Park, J. K. Yoo, S. Y. Choi, and Y. C. Sung Inhibition of TCR-Induced CD8 T Cell Death by IL-12: Regulation of Fas Ligand and Cellular FLIP Expression and Caspase Activation by IL-12 J. Immunol., March 1, 2003; 170(5): 2456 - 2460. [Abstract] [Full Text] [PDF]

				A H Lau and A W Thomson Dendritic cells and immune regulation in the liver Gut, February 1, 2003; 52(2): 307 - 314. [Abstract] [Full Text] [PDF]

				H. Kitaura, N. Nagata, Y. Fujimura, H. Hotokezaka, N. Yoshida, and K. Nakayama Effect of IL-12 on TNF-{alpha}-Mediated Osteoclast Formation in Bone Marrow Cells: Apoptosis Mediated by Fas/Fas Ligand Interaction J. Immunol., November 1, 2002; 169(9): 4732 - 4738. [Abstract] [Full Text] [PDF]

				C. A. Bonham, L. Peng, X. Liang, Z. Chen, L. Wang, L. Ma, H. Hackstein, P. D. Robbins, A. W. Thomson, J. J. Fung, et al. Marked Prolongation of Cardiac Allograft Survival by Dendritic Cells Genetically Engineered with NF-{kappa}B Oligodeoxyribonucleotide Decoys and Adenoviral Vectors Encoding CTLA4-Ig J. Immunol., September 15, 2002; 169(6): 3382 - 3391. [Abstract] [Full Text] [PDF]

				T. Teshima, P. Reddy, K. P. Lowler, M. A. KuKuruga, C. Liu, K. R. Cooke, and J. L. M. Ferrara Flt3 ligand therapy for recipients of allogeneic bone marrow transplants expands host CD8alpha + dendritic cells and reduces experimental acute graft-versus-host disease Blood, March 1, 2002; 99(5): 1825 - 1832. [Abstract] [Full Text] [PDF]