Immunology of Liver

  • Zhigang Tian
  • Yongyan Chen


Liver is the largest solid organ in the body, which carries on the digestive and metabolic functions including secreting bile, synthesizing vital proteins and detoxification. With specific dual inputs for its blood supply, the liver receives 80% of its blood supply from the gut through portal vein, which contains the products of digestion, along with antigens and microbial products from intestine; and the remaining 20% is from the hepatic artery. The liver stands at a hemodynamic confluence, continuously exposed to a large load of foreign antigens, which making the liver act as an organ barrier or a filter between the digestive tract and the rest of the body. Liver harbours lymphoid cells with innate and adaptive immune responses, a unique local immune system properly ensuring its functions. In 2002, Mackay I R et al. proposed a new concept “hepatoimmunology” which provides new insights in the immunology of liver. In the recent years, the research in the hepatoimmunology has been developed rapidly. In this chapter, we will discuss these progresses in detail.


Major Histocompatibility Complex Class Primary Biliary Cirrhosis Patient Liver Sinusoidal Endothelial Cell Intrahepatic Lymphocyte Liver Natural Killer Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. [1]
    Mackay I R. Hepatoimmunology: a perspective. Immunol Cell Biol, 2002, 80: 36–44.PubMedCrossRefGoogle Scholar
  2. [2]
    Klugewitz K, Adams D H, Emoto M, et al. The composition of intrahepatic lymphocytes: shaped by selective recruitment? Trends Immunol, 2004, 25: 590–594PubMedCrossRefGoogle Scholar
  3. [3]
    Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology, 2006, 43: S54–S62.PubMedCrossRefGoogle Scholar
  4. [4]
    Crispe I N. The liver as a lymphoid organ. Annu Rev Immunol, 2009, 27: 147–163.PubMedCrossRefGoogle Scholar
  5. [5]
    Lalor P F, Shields P, Grant A, et al. Recruitment of lymphocytes to the human liver. Immunol Cell Biol, 2002, 80: 52–64.PubMedCrossRefGoogle Scholar
  6. [6]
    Gorham J D. Adaptive immunity in the liver. In: Eric G M (ed). Liver Immunology: Principles and Practice. 2nd edn. New Jersey, Humana Press, 2006.Google Scholar
  7. [7]
    Bertolino P, Bowen D G, McCaughan G W, et al. Antigen-specific primary activation of CD8+ T cells within the liver. J Immunol, 2001, 166: 5430–5438.PubMedGoogle Scholar
  8. [8]
    Wuensch S A, Pierce R H, Crispe I N. Local intrahepatic CD8+ T cell activation by a non-self-antigen results in full functional differentiation. J Immunol, 2006, 177: 1689–1697.PubMedGoogle Scholar
  9. [9]
    Klein Icrispe I N. Complete differentiation of CD8+ T cells activated locally within the transplanted liver. J Exp Med, 2006, 203: 437–447.CrossRefGoogle Scholar
  10. [10]
    Crispe I N, Dao T, Klugewitz K, et al. The liver as a site of T-cell apoptosis: graveyard, or killing field? Immunol Rev, 2000, 174: 47–62.PubMedCrossRefGoogle Scholar
  11. [11]
    Norris S, Collins C, Doherty D G, et al. Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J Hepatol, 1998, 28: 84–90.PubMedCrossRefGoogle Scholar
  12. [12]
    Biron C A, Nguyen K B, Pien G C, et al. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol, 1999, 17: 189–220.PubMedCrossRefGoogle Scholar
  13. [13]
    Cooper M A, Fehniger T A, Fuchs A, et al. NK cell and DC interactions. Trends Immunol, 2004, 25: 47–52.PubMedCrossRefGoogle Scholar
  14. [14]
    Crispe I N. Hepatic T cells and liver tolerance. Nat Rev Immunol, 2003, 3: 51–62.PubMedCrossRefGoogle Scholar
  15. [15]
    Zingoni A, Sornasse T, Cocks B G, et al. NK cell regulation of T cell-mediated responses. Mol Immunol, 2004, 42: 451–454.CrossRefGoogle Scholar
  16. [16]
    Yamagiwa S, Kamimura H, Ichida T. Natural killer cell receptors and their ligands in liver diseases. Med Mol Morphol, 2009, 42: 1–8.PubMedCrossRefGoogle Scholar
  17. [17]
    Cooper M A, Fehniger T A, Caligiuri M A. The biology of human natural killer-cell subsets. Trends Immunol, 2001, 22: 633–640.PubMedCrossRefGoogle Scholar
  18. [18]
    Cooper M A, Fehniger T A, Turner S C, et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56bright subset. Blood, 2001, 97: 3146–3151.PubMedCrossRefGoogle Scholar
  19. [19]
    Jacobs R, Hintzen G, Kemper A, et al. CD56bright cells differ in their KIR repertoire and cytotoxic features from CD56dim NK cells. Eur J Immunol, 2001, 31: 3121–3127.PubMedCrossRefGoogle Scholar
  20. [20]
    Fehniger T A, Cooper M A, Nuovo G J, et al. CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood, 2003, 101: 3052–3057.PubMedCrossRefGoogle Scholar
  21. [21]
    Hayakawa Y, Huntington N D, Nutt S L, et al. Functional subsets of mouse natural killer cells. Immunol Rev, 2006, 214: 47–55.PubMedCrossRefGoogle Scholar
  22. [22]
    Peritt D, Robertson S, Gri G, et al. Differentiation of human NK cells into NK1 and NK2 subsets. J Immunol, 1998, 161: 5821–5824.PubMedGoogle Scholar
  23. [23]
    Loza M J, Perussia B. Final steps of natural killer cell maturation: a model for type 1-type 2 differentiation? Nat Immunol, 2001, 2: 917–924.PubMedCrossRefGoogle Scholar
  24. [24]
    Loza M J, Zamai L, Azzoni L, et al. Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells. Blood, 2002, 99: 1273–1281.PubMedCrossRefGoogle Scholar
  25. [25]
    Chakir H, Camilucci A A, Filion L G, et al. Differentiation of murine NK cells into distinct subsets based on variable expression of the IL-12R beta 2 subunit. J Immunol, 2000, 165: 4985–4993.PubMedGoogle Scholar
  26. [26]
    Takeda K, Cretney E, Hayakawa Y, et al. TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver. Blood, 2005, 105: 2082–2089.PubMedCrossRefGoogle Scholar
  27. [27]
    Huntington N D, Vosshenrich C A, Di Santo J P. Developmental pathways that generate natural-killer-cell diversity in mice and humans. Nat Rev Immunol, 2007, 7: 703–714.PubMedCrossRefGoogle Scholar
  28. [28]
    Chen Y, Tian Z. Natural killer cell and itsimmunity in the liver. In: Xiang J (ed). Recent Development in Immunology. Kerala, Transworld Research Network, 2008.Google Scholar
  29. [29]
    Tian Z G. Innate immune recognition and regulation in liver injury: A brief report from a series of studies. Chinese Sci Bull, 2009, 54: 1817–1827.CrossRefGoogle Scholar
  30. [30]
    Emoto M, Kaufmann S H. Liver NKT cells: an account of heterogeneity. Trends Immunol, 2003, 24: 364–369.PubMedCrossRefGoogle Scholar
  31. [31]
    Long X, Deng S, Mattner J, et al. Synthesis and evaluation of stimulatory properties of Sphingomonadaceae glycolipids. Nat Chem Biol, 2007, 3: 559–564.PubMedCrossRefGoogle Scholar
  32. [32]
    Kinjo Y, Tupin E, Wu D, et al. Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nat Immunol, 2006, 7: 978–986.PubMedCrossRefGoogle Scholar
  33. [33]
    Tu Z, Bozorgzadeh A, Crispe I N, et al. The activation state of human intrahepatic lymphocytes. Clin Exp Immunol, 2007, 149: 186–193.PubMedCrossRefGoogle Scholar
  34. [34]
    Wilson S B, Delovitch T L. Janus-like role of regulatory iNKT cells in autoimmune disease and tumor immunity. Nat Rev Immunol, 2003, 3: 211–222.PubMedCrossRefGoogle Scholar
  35. [35]
    Swain M G. Hepatic NKT cells: friend or foe? Clin Sci (Lond), 2008, 114: 457–466.CrossRefGoogle Scholar
  36. [36]
    Kitamura H, Iwakabe K, Yahata T, et al. The natural killer T (NKT) cell ligand alpha-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J Exp Med, 1999, 189: 1121–1128.PubMedCrossRefGoogle Scholar
  37. [37]
    Fujii S, Shimizu K, Smith C, et al. Activation of natural killer T cells by alpha-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein. J Exp Med, 2003, 198: 267–279.PubMedCrossRefGoogle Scholar
  38. [38]
    Matsuda J L, Gapin L, Sidobre S, et al. Homeostasis of V alpha 14i NKT cells. Nat Immunol, 2002, 3: 966–974.PubMedCrossRefGoogle Scholar
  39. [39]
    Steptoe R J, Patel R K, Subbotin V M, et al. Comparative analysis of dendritic cell density and total number in commonly transplanted organs: morphometric estimation in normal mice. Transpl Immunol, 2000, 8: 49–56.PubMedCrossRefGoogle Scholar
  40. [40]
    Hsu W, Shu S A, Gershwin E, et al. The current immune function of hepatic dendritic cells. Cell Mol Immunol, 2007, 4: 321–328.PubMedGoogle Scholar
  41. [41]
    Sumpter T L, Abe M, Tokita D, et al. Dendritic cells, the liver, and transplantation. Hepatology, 2007, 46: 2021–2031.PubMedCrossRefGoogle Scholar
  42. [42]
    Bouwens L, Baekeland M, De Zanger R, et al. Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology, 1986, 6: 718–722.PubMedCrossRefGoogle Scholar
  43. [43]
    MacPhee P J, Schmidt E E, Groom A C. Evidence for Kupffer cell migration along liver sinusoids, from high-resolution in vivo microscopy. Am J Physiol, 1992, 263: G17–G23.PubMedGoogle Scholar
  44. [44]
    Smith F, Golden-Mason L, Deignan T, et al. Localization of T and B lymphocytes in histologically normal adult human donor liver. Hepatogastroenterology, 2003, 50: 1311–1315.PubMedGoogle Scholar
  45. [45]
    Velardi A, Cooper M D. An immunofluorescence analysis of the ontogeny of myeloid, T, and B lineage cells in mouse hemopoietic tissues. J Immunol, 1984, 133: 672–677.PubMedGoogle Scholar
  46. [46]
    Herzenberg L A. B-1 cells: the lineage question revisited. Immunol Rev, 2000, 175: 9–22.PubMedCrossRefGoogle Scholar
  47. [47]
    Novobrantseva T I, Majeau G R, Amatucci A, et al. Attenuated liver fibrosis in the absence of B cells. J Clin Invest, 2005, 115: 3072–3082.PubMedCrossRefGoogle Scholar
  48. [48]
    Cong Y Z, Rabin E, Wortis H H. Treatment of murine CD5 B cells with anti-Ig, but not LPS, induces surface CD5: two B-cell activation pathways. Int Immunol, 1991, 3: 467–476.PubMedCrossRefGoogle Scholar
  49. [49]
    O'Farrelly C. Innate Immune Mechanisms in the Liver. In: Gershwin M E (ed). Liver Immunology: Principles and Practice. 2nd edn. New Jersey: Humana Press, 2006.Google Scholar
  50. [50]
    Tu Z, Bozorgzadeh A, Pierce R H, et al. TLR-dependent cross talk between human Kupffer cells and NK cells. J Exp Med, 2008, 205: 233–244.PubMedCrossRefGoogle Scholar
  51. [51]
    Chen Y, Wei H, Gao B, et al. Activation and function of hepatic NK cells in hepatitis B infection: an underinvestigated innate immune response. J Viral Hepat, 2005, 12: 38–45.PubMedCrossRefGoogle Scholar
  52. [52]
    Chen Y, Wei H, Sun R, et al. Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells. Hepatology, 2007, 46: 706–715.PubMedCrossRefGoogle Scholar
  53. [53]
    Chen Y, Wei H, Sun R, et al. Impaired function of hepatic natural killer cells from murine chronic HBsAg carriers. Int Immunopharmacol, 2005, 5: 1839–1852.PubMedCrossRefGoogle Scholar
  54. [54]
    Chen Y, Cheng M, Tian Z. Hepatitis B virus down-regulates expressions of MHC class I molecules on hepatoplastoma cell line. Cell Mol Immunol, 2006, 3: 373–378.PubMedGoogle Scholar
  55. [55]
    Kakimi K, Guidotti L G, Koezuka Y, et al. Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med, 2000, 192: 921–930.PubMedCrossRefGoogle Scholar
  56. [56]
    Baron J L, Gardiner L, Nishimura S, et al. Activation of a nonclassical NKT cell subset in a transgenic mouse model of hepatitis B virus infection. Immunity, 2002, 16: 583–594.PubMedCrossRefGoogle Scholar
  57. [57]
    Vilarinho S, Ogasawara K, Nishimura S, et al. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus. Proc Natl Acad Sci USA, 2007, 104: 18187–18192.PubMedCrossRefGoogle Scholar
  58. [58]
    Dong Z, Zhang J, Sun R, et al. Impairment of liver regeneration correlates with activated hepatic NKT cells in HBV transgenic mice. Hepatology, 2007, 45: 1400–1412.PubMedCrossRefGoogle Scholar
  59. [59]
    Nuti S, Rosa D, Valiante N M, et al. Dynamics of intra-hepatic lymphocytes in chronic hepatitis C: enrichment for Valpha24+ T cells and rapid elimination of effector cells by apoptosis. Eur J Immunol, 1998, 28: 3448–3455.PubMedCrossRefGoogle Scholar
  60. [60]
    Lucas M, Gadola S, Meier U, et al. Frequency and phenotype of circulating Valpha24/Vbeta11 double-positive natural killer T cells during hepatitis C virus infection. J Virol, 2003, 77: 2251–2257.PubMedCrossRefGoogle Scholar
  61. [61]
    Morishima C, Paschal D M, Wang C C, et al. Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. Hepatology, 2006, 43: 573–580.PubMedCrossRefGoogle Scholar
  62. [62]
    Kanto T. Virus associated innate immunity in liver. Front Biosci, 2008, 13: 6183–6192.PubMedCrossRefGoogle Scholar
  63. [63]
    Golden-Mason L Rosen H R. Natural killer cells: primary target for hepatitis C virus immune evasion strategies? Liver Transpl, 2006, 12: 363–372.PubMedCrossRefGoogle Scholar
  64. [64]
    Jinushi M, Takehara T, Tatsumi T, et al. Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid. Int J Cancer, 2003, 104: 354–361.PubMedCrossRefGoogle Scholar
  65. [65]
    Jinushi M, Takehara T, Tatsumi T, et al. Impairment of natural killer cell and dendritic cell functions by the soluble form of MHC class I-related chain A in advanced human hepatocellular carcinomas. J Hepatol, 2005, 43: 1013–1020.PubMedCrossRefGoogle Scholar
  66. [66]
    Miyagi T, Takehara T, Tatsumi T, et al. Concanavalin a injection activates intrahepatic innate immune cells to provoke an antitumor effect in murine liver. Hepatology, 2004, 40: 1190–1196.PubMedCrossRefGoogle Scholar
  67. [67]
    Exley M A, Koziel M J. To be or not to be NKT: natural killer T cells in the liver. Hepatology, 2004, 40: 1033–1040.PubMedCrossRefGoogle Scholar
  68. [68]
    Kan Z, Ivancev K, Lunderquist A, et al. In vivo microscopy of hepatic metastases: dynamic observation of tumor cell invasion and interaction with Kupffer cells. Hepatology, 1995, 21: 487–494.PubMedCrossRefGoogle Scholar
  69. [69]
    Aono K, Isobe K, Nakashima I, et al. Kupffer cells cytotoxicity against hepatoma cells is related to nitric oxide. Biochem Biophys Res Commun, 1994, 201: 1175–1181.PubMedCrossRefGoogle Scholar
  70. [70]
    Rushfeldt C, Sveinbjornsson B, Seljelid R, et al. Early events of hepatic metastasis formation in mice: role of Kupffer and NK-cells in natural and interferon-gamma-stimulated defense. J Surg Res, 1999, 82: 209–215.PubMedCrossRefGoogle Scholar
  71. [71]
    Pearson H J, Anderson J, Chamberlain J, et al. The effect of Kupffer cell stimulation or depression on the development of liver metastases in the rat. Cancer Immunol Immunother, 1986, 23: 214–216.PubMedCrossRefGoogle Scholar
  72. [72]
    Kolios G, Valatas V, Kouroumalis E. Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol, 2006, 12: 7413–7420.PubMedGoogle Scholar
  73. [73]
    Huang L, Soldevila G, Leeker M, et al. The liver eliminates T cells undergoing antigen-triggered apoptosis in vivo. Immunity, 1994, 1: 741–749.PubMedCrossRefGoogle Scholar
  74. [74]
    Mehal W Z, Juedes A E, Crispe I N. Selective retention of activated CD8+ T cells by the normal liver. J Immunol, 1999, 163: 3202–3210.PubMedGoogle Scholar
  75. [75]
    Isogawa M, Furuichi Y, Chisari F V. Oscillating CD8+T cell effector functions after antigen recognition in the liver. Immunity, 2005, 23: 53–63.PubMedCrossRefGoogle Scholar
  76. [76]
    Latchman Y, Wood C R, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol, 2001, 2: 261–268.PubMedCrossRefGoogle Scholar
  77. [77]
    Racanelli V, Sansonno D, Piccoli C, et al. Molecular characterization of B cell clonal expansions in the liver of chronically hepatitis C virus-infected patients. J Immunol, 2001, 167: 21–29.PubMedGoogle Scholar
  78. [78]
    Murakami J, Shimizu Y, Kashii Y, et al. Functional B-cell response in intrahepatic lymphoid follicles in chronic hepatitis C. Hepatology, 1999, 30: 143–150.PubMedCrossRefGoogle Scholar
  79. [79]
    Bowlus L C. Tumor immunology. In: Eric G M (ed). Liver Immunology: Principles and Practice. 2nd edn. New Jersey: Humana Press, 2006.Google Scholar
  80. [80]
    Gonzalez-Carmona M A, Marten A, Hoffmann P, et al. Patient-derived dendritic cells transduced with an a-fetoprotein-encoding adenovirus and co-cultured with autologous cytokine-induced lymphocytes induce a specific and strong immune response against hepatocellular carcinoma cells. Liver Int, 2006, 26: 369–379.PubMedCrossRefGoogle Scholar
  81. [81]
    Lee W C, Wang H C, Hung C F, et al. Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: a clinical trial. J Immunother, 2005, 28: 496–504.PubMedCrossRefGoogle Scholar
  82. [82]
    Gonzalez-Carmona M A, Lukacs-Kornek V, Timmerman A, et al. CD40ligandexpressing dendritic cells induce regression of hepatocellular carcinoma by activating innate and acquired immunity in vivo. Hepatology, 2008, 48: 157–168.PubMedCrossRefGoogle Scholar
  83. [83]
    Gao Z, McAlister V C, Williams G M. Repopulation of liver endothelium by bone-marrow-derived cells. Lancet, 2001, 357: 932–933.PubMedCrossRefGoogle Scholar
  84. [84]
    Smedsrod B, Pertoft H, Gustafson S, et al. Scavenger functions of the liver endothelial cell. Biochem J, 1990, 266: 313–327.PubMedGoogle Scholar
  85. [85]
    Magnusson S, Berg T. Extremely rapid endocytosis mediated by the mannose receptor of sinusoidal endothelial rat liver cells. Biochem J, 1989, 257: 651–656.PubMedGoogle Scholar
  86. [86]
    Knolle P A. Role and function of liver sinusoidal endothelial cells. In: Eric G M (ed). Liver Immunology: Principles and Practice. 2nd edn. New Jersey: Humana Press, 2006.Google Scholar
  87. [87]
    Uhrig A, Banafsche R, Kremer M, et al. Development and functional consequences of LPS tolerance in sinusoidal endothelial cells of the liver. J Leukoc Biol, 2005, 77: 626–633.PubMedCrossRefGoogle Scholar
  88. [88]
    Martin-Armas M, Simon-Santamaria J, Pettersen I, et al. Toll-like receptor 9 (TLR9) is present in murine liver sinusoidal endothelial cells (LSECs) and mediates the effect of CpG-oligonucleotides. J Hepatol, 2006, 44: 939–946.PubMedCrossRefGoogle Scholar
  89. [89]
    Breiner K M, Schaller H, Knolle P A. Endothelial cell-mediated uptake of a hepatitis B virus: a new concept of liver targeting of hepatotropic microorganisms. Hepatology, 2001, 34: 803–808.PubMedCrossRefGoogle Scholar
  90. [90]
    Gardner J P, Durso R J, Arrigale R R, et al. L-SIGN (CD209L) is a liver-specific capture receptor for hepatitis C virus. Proc Natl Acad Sci USA, 2003, 100: 4498–4503.PubMedCrossRefGoogle Scholar
  91. [91]
    Cormier E G, Durso R J, Tsamis F, et al. L-SIGN (CD209L) and DC-SIGN (CD209) mediate transinfection of liver cells by hepatitis C virus. Proc Natl Acad Sci USA, 2004, 101: 14067–14072.PubMedCrossRefGoogle Scholar
  92. [92]
    Knolle P A, Gerken G. Local control of the immune response in the liver. Immunol Rev, 2000, 174: 21–34.PubMedCrossRefGoogle Scholar
  93. [93]
    Katz S C, Pillarisetty V G, Bleier J I, et al. Liver sinusoidal endothelial cells are insufficient to activate T cells. J Immunol, 2004, 173: 230–235.PubMedGoogle Scholar
  94. [94]
    Knolle P A, Uhrig A, Hegenbarth S, et al. IL-10 down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells through decreased antigen uptake via the mannose receptor and lowered surface expression of accessory molecules. Clin Exp Immunol, 1998, 114: 427–433.PubMedCrossRefGoogle Scholar
  95. [95]
    Limmer A, Ohl J, Kurts C, et al. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat Med, 2000, 6: 1348–1354.PubMedCrossRefGoogle Scholar
  96. [96]
    Scoazec J Y, Feldmann G. The cell adhesion molecules of hepatic sinusoidal endothelial cells. J Hepatol, 1994, 20: 296–300.PubMedCrossRefGoogle Scholar
  97. [97]
    Essani N A, McGuire G M, Manning A M, et al. Endotoxin-induced activation of the nuclear transcription factor kappa B and expression of E-selectin messenger RNA in hepatocytes, Kupffer cells, and endothelial cells in vivo. J Immunol, 1996, 156: 2956–2963.PubMedGoogle Scholar
  98. [98]
    Jaeschke H. Cellular adhesion molecules: regulation and functional significance in the pathogenesis of liver diseases. Am J Physiol, 1997, 273: G602–G611.PubMedGoogle Scholar
  99. [99]
    Eksteen B, Grant A J, Miles A, et al. Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J Exp Med, 2004, 200: 1511–1517.PubMedCrossRefGoogle Scholar
  100. [100]
    Knolle P A, Schmitt E, Jin S, et al. Induction of cytokine production in naive CD4+ T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells. Gastroenterology, 1999, 116: 1428–1440.PubMedCrossRefGoogle Scholar
  101. [101]
    Preiss S, Thompson A, Chen X, et al. Characterization of the innate immune signalling pathways in hepatocyte cell lines. J Viral Hepat, 2008, 15: 888–900.PubMedCrossRefGoogle Scholar
  102. [102]
    Gao B, Jeong W I, Tian Z. Liver: an organ with predominant innate immunity. Hepatology, 2008, 47: 729–736.PubMedCrossRefGoogle Scholar
  103. [103]
    Malhi H, Gores G J. Cellular and molecular mechanisms of liver injury. Gastroenterology, 2008, 134: 1641–1654.PubMedCrossRefGoogle Scholar
  104. [104]
    Dong Z, Wei H, Sun R, et al. Involvement of natural killer cells in PolyI:C-induced liver injury. J Hepatol, 2004, 41: 966–973.PubMedCrossRefGoogle Scholar
  105. [105]
    Chen Y, Sun R, Jiang W, et al. Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell-and IFNgamma-dependent manner. J Hepatol, 2007, 47: 183–190.PubMedCrossRefGoogle Scholar
  106. [106]
    Radaeva S, Sun R, Jaruga B, et al. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology, 2006, 130: 435–452.PubMedCrossRefGoogle Scholar
  107. [107]
    Ochi M, Ohdan H, Mitsuta H, et al. Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice. Hepatology, 2004, 39: 1321–1331.PubMedCrossRefGoogle Scholar
  108. [108]
    Hou X, Zhou R, Wei H, et al. NKG2D-retinoic acid early inducible-1 recognition between natural killer cells and Kupffer cells in a novel murine natural killer cell-dependent fulminant hepatitis. Hepatology, 2009, 49: 940–949.PubMedCrossRefGoogle Scholar
  109. [109]
    Jiang J X, Mikami K, Venugopal S, et al. Apoptotic body engulfment by hepatic stellate cells promotes their survival by the JAK/STAT and Akt/NF-kappaB-dependent pathways. J Hepatol, 2009, 51: 139–148.PubMedCrossRefGoogle Scholar
  110. [110]
    Purohit V, Brenner D A. Mechanisms of alcohol-induced hepatic fibrosis: a summary of the Ron Thurman Symposium. Hepatology, 2006, 43: 872–878.PubMedCrossRefGoogle Scholar
  111. [111]
    Bowen D G, McCaughan G W, Bertolino P. Intrahepatic immunity: a tale of two sites? Trends Immunol, 2005, 26: 512–517.PubMedCrossRefGoogle Scholar
  112. [112]
    Gorczynski R M, Chan Z, Chung S, et al. Prolongation of rat small bowel or renal allograft survival by pretransplant transfusion and/or by varying the route of allograft venous drainage. Transplantation, 1994, 58: 816–820.PubMedGoogle Scholar
  113. [113]
    Rao V K, Burris D E, Gruel S M, et al. Evidence that donor spleen cells administered through the portal vein prolong the survival of cardiac allografts in rats. Transplantation, 1988, 45: 1145–1146.PubMedCrossRefGoogle Scholar
  114. [114]
    Cantor H M, Dumont A E. Hepatic suppression of sensitization to antigen absorbed into the portal system. Nature, 1967, 215: 744–745.PubMedCrossRefGoogle Scholar
  115. [115]
    Chen Y, Ong C R, McKenna G J, et al. Induction of immune hyporesponsiveness after portal vein immunization with ovalbumin. Surgery, 2001, 129: 66–75.PubMedCrossRefGoogle Scholar
  116. [116]
    You Q, Cheng L, Kedl R M, et al. Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology, 2008, 48: 978–990.PubMedCrossRefGoogle Scholar
  117. [117]
    Bowen D G, Zen M, Holz L, et al. The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. J Clin Invest, 2004, 114: 701–712.PubMedGoogle Scholar
  118. [118]
    Teague R M, Sather B D, Sacks J A, et al. Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat Med, 2006, 12: 335–341.PubMedCrossRefGoogle Scholar
  119. [119]
    Roland C R, Walp L, Stack R M, et al. Outcome of Kupffer cell antigen presentation to a cloned murine Th1 lymphocyte depends on the inducibility of nitric oxide synthase by IFN-gamma. J Immunol, 1994, 153: 5453–5464.PubMedGoogle Scholar
  120. [120]
    Miyagawa-Hayashino A, Tsuruyama T, Egawa H, et al. FasL expression in hepatic antigen-presenting cells and phagocytosis of apoptotic T cells by FasL+ Kupffer cells are indicators of rejection activity in human liver allografts. Am J Pathol, 2007, 171: 1499–1508.PubMedCrossRefGoogle Scholar
  121. [121]
    Luth S, Huber S, Schramm C, et al. Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. J Clin Invest, 2008, 118: 3403–3410.PubMedGoogle Scholar
  122. [122]
    Abe M, Akbar S M, Horiike N, et al. Induction of cytokine production and proliferation of memory lymphocytes by murine liver dendritic cell progenitors: role of these progenitors as immunogenic resident antigenpresenting cells in the liver. J Hepatol, 2001, 34: 61–67.PubMedCrossRefGoogle Scholar
  123. [123]
    Ilkovitch D, Lopez D M. The liver is a site for tumor-induced myeloid-derived suppressor cell accumulation and immunosuppression. Cancer Res, 2009, 69: 5514–5521.PubMedCrossRefGoogle Scholar
  124. [124]
    Hoechst B, Voigtlaender T, Ormandy L, et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology, 2009, 50: 799–807.PubMedCrossRefGoogle Scholar
  125. [125]
    Liu C. Clinical use of immunopathology techniques in liver diseases. In: Gershwin M E (ed). Liver Immunology: principles and practice. 2nd edn. New Jersey: Humana Press, 2006.Google Scholar
  126. [126]
    Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest, 1992, 90: 196–203.PubMedCrossRefGoogle Scholar
  127. [127]
    Galanos C, Freudenberg M A, Reutter W. Galactosamine-induced sensitization to the lethal effects of endotoxin. Proc Natl Acad Sci USA, 1979, 76: 5939–5943.PubMedCrossRefGoogle Scholar
  128. [128]
    Dong Z, Wei H, Sun R, et al. The roles of innate immune cells in liver injury and regeneration. Cell Mol Immunol, 2007, 4: 241–252.PubMedGoogle Scholar
  129. [129]
    Wang J, Sun R, Wei H, et al. Pre-activation of T lymphocytes by low dose of concanavalin A aggravates toll-like receptor-3 ligand-induced NK cell-mediated liver injury. Int Immunopharmacol, 2006, 6: 800–807.PubMedCrossRefGoogle Scholar
  130. [130]
    Jiang W, Sun R, Zhou R, et al. TLR-9 activation aggravates concanavalin A-induced hepatitis via promoting accumulation and activation of liver CD4+ NKT cells. J Immunol, 2009, 182: 3768–3774.PubMedCrossRefGoogle Scholar
  131. [131]
    Wang J, Sun R, Wei H, et al. Poly I:C prevents T cell-mediated hepatitis via an NK-dependent mechanism. J Hepatol, 2006, 44: 446–454.PubMedCrossRefGoogle Scholar
  132. [132]
    Wei H X, Chuang Y H, Li B, et al. CD4+ CD25+ FOXP3+ regulatory T cells protect against T cell-mediated fulminant hepatitis in a TGF-beta-dependent manner in mice. J Immunol, 2008, 181: 7221–7229.PubMedGoogle Scholar
  133. [133]
    Jiang W, Sun R, Wei H, et al. Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages. Proc Natl Acad Sci USA, 2005, 102: 17077–17082.PubMedCrossRefGoogle Scholar
  134. [134]
    Guidotti L G, Chisari F V. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol, 2006, 1: 23–61.PubMedCrossRefGoogle Scholar
  135. [135]
    He X S, Ansari A A, Ridgway W M, et al. New insights to the immunopathology and autoimmune responses in primary biliary cirrhosis. Cell Immunol, 2006, 239: 1–13.PubMedCrossRefGoogle Scholar
  136. [136]
    Israel Y, Orrego H, Niemela O. Immune responses to alcohol metabolites: pathogenic and diagnostic implications. Semin Liver Dis, 1988, 8: 81–90.PubMedCrossRefGoogle Scholar
  137. [137]
    Tilg H, Diehl A M. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med, 2000, 343: 1467–1476.PubMedCrossRefGoogle Scholar
  138. [138]
    Chedid A, Mendenhall C L, Moritz T E, et al. Cell-mediated hepatic injury in alcoholic liver disease. Veterans Affairs Cooperative Study Group 275. Gastroenterology, 2003, 105: 254–266.Google Scholar
  139. [139]
    Kremer M, Hines I N. Natural killer T cells and non-alcoholic fatty liver disease: fat chews on the immune system. World J Gastroenterol, 2008, 14: 487–488.PubMedCrossRefGoogle Scholar
  140. [140]
    Xu C F, Yu C H, Li Y M, et al. Association of the frequency of peripheral natural killer T cells with nonalcoholic fatty liver disease. World J Gastroenterol, 2007, 13: 4504–4508.PubMedGoogle Scholar
  141. [141]
    Chen Q, Wei H, Sun R, et al. Therapeutic RNA silencing of Cys-X3-Cys chemokine ligand 1 gene prevents mice from adenovirus vector-induced acute liver injury. Hepatology, 2008, 47: 648–658.PubMedCrossRefGoogle Scholar
  142. [142]
    Sun Z, Klein A S, Radaeva S, et al. In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats. Gastroenterology, 2003, 125: 202–215.PubMedCrossRefGoogle Scholar
  143. [143]
    Hong F, Jaruga B, Kim W H, et al. Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS. J Clin Invest, 2002, 110: 1503–1513.PubMedGoogle Scholar
  144. [144]
    Hong F, Radaeva S, Pan H N, et al. Interleukin 6 alleviates hepatic steatosis and ischemia/reperfusion injury in mice with fatty liver disease. Hepatology, 2004, 40: 933–941.PubMedGoogle Scholar
  145. [145]
    Sun R, Tian Z, Kulkarni S, et al. IL-6 prevents T cell-mediated hepatitis via inhibition of NKT cells in CD4+ T cell-and STAT3-dependent manners. J Immunol, 2004, 172: 5648–5655.PubMedGoogle Scholar
  146. [146]
    Li B, Sun R, Wei H, et al. Interleukin-15 prevents concanavalin A-induced liver injury in mice via NKT cell-dependent mechanism. Hepatology, 2006, 43: 1211–1219.PubMedCrossRefGoogle Scholar
  147. [147]
    Tian Z, Shen X, Feng H, et al. IL-1 beta attenuates IFN-alpha beta-induced antiviral activity and STAT1 activation in the liver: involvement of proteasome-dependent pathway. J Immunol, 2000, 165: 3959–3965.PubMedGoogle Scholar

Copyright information

© Zhejiang University Press, Hangzhou and Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Zhigang Tian
    • 1
  • Yongyan Chen
    • 1
  1. 1.Institute of Immunology, School of Life SciencesUniversity of Science & Technology of ChinaHefeiChina

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