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Hepatic antigen-presenting cells and regulation of liver transplant outcome

  • UNIVERSITY OF PITTSBURGH IMMUNOLOGY 2011
  • Published:
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Abstract

In the steady state, hepatic antigen (Ag)-presenting cells (APC) generally dampen systemic inflammatory responses to gut-derived Ags. Our studies focus on the role of specific liver APC populations, both non-parenchymal cells (dendritic cells [DC], Kupffer cells, and hepatic stellate cells [HSC]) and parenchymal cells, in the molecular regulation of tissue damage (ischemia and reperfusion [I/R] injury) and immunity following liver transplantation. We focus on factors that either promote or overwhelm the natural tendency of the liver to suppress inflammatory/immune responses. We are also examining molecular mechanisms that regulate liver DC maturation and function and that determine their role in the control of allogeneic T-cell function and the fate of the transplanted liver. Our studies are also aimed at elucidating mechanisms by which HSC regulate DC and T-cell function. These investigations may provide new targets for therapeutic intervention in liver inflammation.

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References

  1. Thomson AW, Knolle PA. Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol. 2010;10:753–66.

    Article  PubMed  CAS  Google Scholar 

  2. Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol. 2009;27:147–63.

    Article  PubMed  CAS  Google Scholar 

  3. De Creus A, Abe M, Lau AH, Hackstein H, Raimondi G, Thomson AW. Low TLR4 expression by liver dendritic cells correlates with reduced capacity to activate allogeneic T cells in response to endotoxin. J Immunol. 2005;174:2037–45.

    PubMed  Google Scholar 

  4. Abe M, Tokita D, Raimondi G, Thomson AW. Endotoxin modulates the capacity of CpG-activated liver myeloid DC to direct Th1-type responses. Eur J Immunol. 2006;36:2483–93.

    Article  PubMed  CAS  Google Scholar 

  5. Lunz JG 3rd, Specht SM, Murase N, Isse K, Demetris AJ. Gut-derived commensal bacterial products inhibit liver dendritic cell maturation by stimulating hepatic interleukin-6/signal transducer and activator of transcription 3 activity. Hepatology. 2007;46:1946–59.

    Article  PubMed  CAS  Google Scholar 

  6. Geller DA, Lowenstein CJ, Shapiro RA, Nussler AK, Di Silvio M, Wang SC, Nakayama DK, Simmons RL, Snyder SH, Billiar TR. Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci USA. 1993;90:3491–5.

    Article  PubMed  CAS  Google Scholar 

  7. Geller DA, Nussler AK, Di Silvio M, Lowenstein CJ, Shapiro RA, Wang SC, Simmons RL, Billiar TR. Cytokines, endotoxin, and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes. Proc Natl Acad Sci USA. 1993;90:522–6.

    Article  PubMed  CAS  Google Scholar 

  8. Uemura T, Gandhi CR. Inhibition of DNA synthesis in cultured hepatocytes by endotoxin-conditioned medium of activated stellate cells is transforming growth factor-beta and nitric oxide-independent. Br J Pharmacol. 2001;133:1125–33.

    Article  PubMed  CAS  Google Scholar 

  9. Gandhi CR. Hepatic Stellate Cells. In:Monga SP, editor. Molecular pathology of liver disease. Springer, New York. 53–80.

  10. Crispe IN. Hepatic T cells and liver tolerance. Nat Rev Immunol. 2003;3:51–62.

    Article  PubMed  CAS  Google Scholar 

  11. Kono H, Rock KL. How dying cells alert the immune system to danger. Nat Rev Immunol. 2008;8:279–89.

    Article  PubMed  CAS  Google Scholar 

  12. Tsung A, Sahai R, Tanaka H, Nakao A, Fink MP, Lotze MT, Yang H, Li J, Tracey KJ, Geller DA, Billiar TR. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med. 2005;201:1135–43.

    Article  PubMed  CAS  Google Scholar 

  13. Tsung A, Hoffman RA, Izuishi K, Critchlow ND, Nakao A, Chan MH, Lotze MT, Geller DA, Billiar TR. Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. J Immunol. 2005;175:7661–8.

    PubMed  CAS  Google Scholar 

  14. Steptoe RJ, Fu F, Li W, Drakes ML, Lu L, Demetris AJ, Qian S, McKenna HJ, Thomson AW. Augmentation of dendritic cells in murine organ donors by Flt3 ligand alters the balance between transplant tolerance and immunity. J Immunol. 1997;159:5483–91.

    PubMed  CAS  Google Scholar 

  15. Tsung A, Zheng N, Jeyabalan G, Izuishi K, Klune JR, Geller DA, Lotze MT, Lu L, Billiar TR. Increasing numbers of hepatic dendritic cells promote HMGB1-mediated ischemia-reperfusion injury. J Leukoc Biol. 2007;81:119–28.

    Article  PubMed  CAS  Google Scholar 

  16. Shen XD, Ke B, Zhai Y, Gao F, Tsuchihashi S, Lassman CR, Busuttil RW, Kupiec-Weglinski JW. Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model. Liver Transpl. 2007;13:1435–43.

    Article  PubMed  Google Scholar 

  17. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N. IRF family of transcription factors as regulators of host defense. Annu Rev Immunol. 2001;19:623–55.

    Article  PubMed  CAS  Google Scholar 

  18. Geller DA, Nguyen D, Shapiro RA, Nussler A, Di Silvio M, Freeswick P, Wang SC, Tweardy DJ, Simmons RL, Billiar TR. Cytokine induction of interferon regulatory factor-1 in hepatocytes. Surgery. 1993;114:235–42.

    PubMed  CAS  Google Scholar 

  19. Starzl TE, Demetris AJ, Murase N, Ildstad S, Ricordi C, Trucco M. Cell migration, chimerism, and graft acceptance [see comments]. Lancet. 1992;339:1579–82.

    Article  PubMed  CAS  Google Scholar 

  20. Thomson AW, Lu L, Murase N, Demetris AJ, Rao AS, Starzl TE. Microchimerism, dendritic cell progenitors and transplantation tolerance. Stem Cells (Dayt). 1995;13:622–39.

    Article  CAS  Google Scholar 

  21. Demetris AJ, Murase N, Starzl TE. Donor dendritic cells after liver and heart allotransplantation under short-term immunosuppression. Lancet. 1992;339:1610.

    Article  CAS  Google Scholar 

  22. Woo J, Lu L, Rao AS, Li Y, Subbotin V, Starzl TE, Thomson AW. Isolation, phenotype, and allostimulatory activity of mouse liver dendritic cells. Transplantation. 1994;58:484–91.

    Article  PubMed  CAS  Google Scholar 

  23. Lu L, Rudert WA, Qian S, McCaslin D, Fu F, Rao AS, Trucco M, Fung JJ, Starzl TE, Thomson AW. Growth of donor-derived dendritic cells from the bone marrow of murine liver allograft recipients in response to granulocyte/macrophage colony stimulating factor. J Exp Med. 1995;182:379–87.

    Article  PubMed  CAS  Google Scholar 

  24. Drakes ML, Lu L, Subbotin VM, Thomson AW. In vivo administration of flt3 ligand markedly stimulates generation of dendritic cell progenitors from mouse liver. J Immunol. 1997;159:4268–78.

    PubMed  CAS  Google Scholar 

  25. Sumpter TL, Abe M, Tokita D, Thomson AW. Dendritic cells, the liver, and transplantation. Hepatology. 2007;46:2021–31.

    Article  PubMed  CAS  Google Scholar 

  26. Rastellini C, Lu L, Ricordi C, Starzl TE, Rao AS, Thomson AW. Granulocyte/macrophage colony-stimulating factor-stimulated hepatic dendritic cell progenitors prolong pancreatic islet allograft survival. Transplantation. 1995;60:1366–70.

    PubMed  CAS  Google Scholar 

  27. Morelli AE, Thomson AW. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol. 2007;7:610–21.

    Article  PubMed  CAS  Google Scholar 

  28. Bamboat ZM, Stableford JA, Plitas G, Burt BM, Nguyen HM, Welles AP, Gonen M, Young JW, DeMatteo RP. Human liver dendritic cells promote T cell hyporesponsiveness. J Immunol. 2009;182:1901–11.

    Article  PubMed  CAS  Google Scholar 

  29. Castellaneta A, Sumpter TL, Chen L, Tokita D, Thomson AW. NOD2 ligation subverts IFN-alpha production by liver plasmacytoid dendritic cells and inhibits their T cell allostimulatory activity via B7–H1 up-regulation. J Immunol. 2009;183:6922–32.

    Article  PubMed  CAS  Google Scholar 

  30. Sumpter TL, Packiam V, Turnquist HR, Castellaneta A, Yoshida O, Thomson AW. DAP12 promotes IRAK-M expression and IL-10 production by liver myeloid dendritic cells and restrains their T cell allostimulatory ability. J Immunol. 2011;186:1970–80.

    Article  PubMed  CAS  Google Scholar 

  31. Sumpter TL, Lunz JG 3rd, Demetris AJ, Thomson AW. Molecular regulation of hepatic dendritic cell function and its relation to liver transplant outcome. Transplantation. 2009;88:S40–4.

    Article  PubMed  CAS  Google Scholar 

  32. Geerts A. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis. 2001;21:311–35.

    Article  PubMed  CAS  Google Scholar 

  33. Enzan H, Hara H, Yamashita Y, Ohkita T, Yamane T. Fine structure of hepatic sinusoids and their development in human embryos and fetuses. Acta Pathol Jpn. 1983;33:447–66.

    PubMed  CAS  Google Scholar 

  34. Baba S, Fujii H, Hirose T, Yasuchika K, Azuma H, Hoppo T, Naito M, Machimoto T, Ikai I. Commitment of bone marrow cells to hepatic stellate cells in mouse. J Hepatol. 2004;40:255–60.

    Article  PubMed  Google Scholar 

  35. Winau F, Quack C, Darmoise A, Kaufmann SH. Starring stellate cells in liver immunology. Curr Opin Immunol. 2008;20:68–74.

    Article  PubMed  CAS  Google Scholar 

  36. Gandhi CR, Uemura T, Kuddus R. Endotoxin causes up-regulation of endothelin receptors in cultured hepatic stellate cells via nitric oxide-dependent and -independent mechanisms. Br J Pharmacol. 2000;131:319–27.

    Article  PubMed  CAS  Google Scholar 

  37. Thirunavukkarasu C, Uemura T, Wang LF, Watkins SC, Gandhi CR. Normal rat hepatic stellate cells respond to endotoxin in LBP-independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes. J Cell Physiol. 2005;204:654–65.

    Article  PubMed  CAS  Google Scholar 

  38. Thirunavukkarasu C, Watkins SC, Gandhi CR. Mechanisms of endotoxin-induced NO, IL-6, and TNF-alpha production in activated rat hepatic stellate cells: role of p38 MAPK. Hepatology. 2006;44:389–98.

    Article  PubMed  CAS  Google Scholar 

  39. Sumpter TL, Dangi A, Thomson AW, Gandhi C. Hepatic stellate cells affect the maturation of liver dendritic cells and undermine the induction of allogeneic CD8+ T cell responses: implications for allograft tolerance. Am J Transplant. 2011; 11 (Suppl 2; Abstract):217.

    Google Scholar 

  40. Winau F, Hegasy G, Weiskirchen R, Weber S, Cassan C, Sieling PA, Modlin RL, Liblau RS, Gressner AM, Kaufmann SH. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity. 2007;26:117–29.

    Article  PubMed  CAS  Google Scholar 

  41. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007;204:1757–64.

    Article  PubMed  CAS  Google Scholar 

  42. Yu MC, Chen CH, Liang X, Wang L, Gandhi CR, Fung JJ, Lu L, Qian S. Inhibition of T-cell responses by hepatic stellate cells via B7–H1-mediated T-cell apoptosis in mice. Hepatology. 2004;40:1312–21.

    Article  PubMed  CAS  Google Scholar 

  43. Chen CH, Kuo LM, Chang Y, Wu W, Goldbach C, Ross MA, Stolz DB, Chen L, Fung JJ, Lu L, Qian S. In vivo immune modulatory activity of hepatic stellate cells in mice. Hepatology. 2006;44:1171–81.

    Article  PubMed  CAS  Google Scholar 

  44. Dangi A, Sumpter TL, Raimondi G, Vodovotz Y, Thomson AW, Gandhi C. Selective expansion of allogenic regulatory T cells by endotoxin-challenged hepatic stellate cells: implication for allograft tolerance. Am J Transplant. 2011;11 (Suppl 2; Abstract):523.

    Google Scholar 

  45. Grasl-Kraupp B, Ruttkay-Nedecky B, Koudelka H, Bukowska K, Bursch W, Schulte-Hermann R. In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology. 1995;21:1465–8.

    PubMed  CAS  Google Scholar 

  46. Lu L, Bonham CA, Liang X, Chen Z, Li W, Wang L, Watkins SC, Nalesnik MA, Schlissel MS, Demestris AJ, Fung JJ, Qian S. Liver-derived DEC205+B220+CD19- dendritic cells regulate T cell responses. J Immunol. 2001;166:7042–52.

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors’ investigations are supported by National Institutes of Health grant P01 AI081678.

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Authors and Affiliations

  1. Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, 200 Lothrop Street, W1540 BST, Pittsburgh, PA, 15261, USA

    Angus W. Thomson, David A. Geller, Chandrashekhar Gandhi, Noriko Murase & A. Jake Demetris

  2. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA

    Angus W. Thomson

  3. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA

    A. Jake Demetris

  4. Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA

    Donna Beer-Stolz

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  1. Angus W. Thomson
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  2. David A. Geller
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  5. A. Jake Demetris
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Correspondence to Angus W. Thomson.

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Thomson, A.W., Geller, D.A., Gandhi, C. et al. Hepatic antigen-presenting cells and regulation of liver transplant outcome. Immunol Res 50, 221–227 (2011). https://doi.org/10.1007/s12026-011-8223-0

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