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Immune Cell Communication and Signaling Systems in Liver Disease

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Abstract

The relationship that exists between the different ­components of the immune system within the human liver is a highly complex and dynamic one. In recent years, there has been a rapid expansion of our knowledge of the nature of the liver as an immunologically distinct organ, with numerous unique features that have evolved as a result of its specialized physiological niche. It is now apparent that the immune system plays a crucial role in determining the progression of many liver diseases via chronic inflammatory processes that fail to resolve, through to end stage cirrhosis and on occasions, malignant diseases. The liver receives a substantial blood supply from three sources: from the abdominal aorta via the hepatic artery and two venous plexuses, the portal vein, and inferior vena cava. The liver is therefore continuously exposed to bloodborne pathogens, toxins, tumor cells, and dietary antigens as well as those that can enter the liver from the gut via the ascending biliary tree. The structural organization of the liver has profound implications for its immune function (Fig. 8.1), for review please see Racanelli et al. [1].

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References

  1. Racanelli V, Rehermann B (2006) The liver as an immunological organ. Hepatology 43:S54–S62

    Article  CAS  Google Scholar 

  2. Wick MJ, Leithauser F, Reimann J (2002) The hepatic immune system. Crit Rev Immunol 22:47–103

    PubMed  CAS  Google Scholar 

  3. Emoto M, Kaufmann SH (2003) Liver NKT cells: an account of heterogeneity. Trends Immunol 24:364–369

    Article  PubMed  CAS  Google Scholar 

  4. Exley M, Koziel M (2004) To be or not to be NKT: natural killer T cells in the liver. Hepatology. 40:1033–1040

    Article  PubMed  Google Scholar 

  5. Emoto M, Miyamoto M, Namba K, Scmits R, Van Rooijen N, Kita E, Kaufmann SH (2000) Participation of leukocytefunction-associated antigen-1 and NK cells in the homing of thymic CD8+NKT cells to the liver. Eur J Immunol 30:3049–3056

    Article  PubMed  CAS  Google Scholar 

  6. Akira S, Takeda K (2004) Toll-like receptor signaling. Nat Rev Immunol 4:499–511

    Article  PubMed  CAS  Google Scholar 

  7. Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:S54–S62

    Google Scholar 

  8. Meylan E, Tschopp J, Karin M (2006) Intracellular pattern recognition receptors in the host response. Nature 442: 39–44

    Article  PubMed  CAS  Google Scholar 

  9. Loretta L, Cyclone E, Mundari MC, Biassoni R, Loretta A (1994) Human natural killer cells: origin, locality, specificity, receptors. Adv Immun 55:341–358

    Google Scholar 

  10. Salazar-Mather TP, Orange JS, Biron CA (1998) Early murine cytomegalovirus (MCMV) infection induces liver natural killer (NK) cell inflammation and protection through macrophage inflammatory protein 1 alpha (MIP-1alpha)-dependent pathways. J Exp Med 187:1–14

    Article  PubMed  CAS  Google Scholar 

  11. Itoh Y, Morita A, Nishioji K, Fujii H, Nakamura H, Kirishima T, Toyama T, Yamauchi N, Nagao Y, Narumi S, Okanoue T (2001) Time course profile and cell-type-­specific production of monokine induced by interferon-gamma in Concanavalin A-induced hepatic injury in mice: comparative study with interferon-inducible protein-10. Scand J Gastroenterol 36:1344–1351

    Article  PubMed  CAS  Google Scholar 

  12. Bendelac A, Rivera MN, Park SH, Roark JH (1997) Mouse CD1-specific NK1 T cells: development, specificity, and function. Annu Rev Immunol 15:535–562

    Article  PubMed  CAS  Google Scholar 

  13. Bendelac A, Lantz O, Quimby ME, Yewdell JW, Bennink JR, Brutkiewicz RR (1995) CD1 recognition by mouse NK1+ T lymphocytes. Science 268:863–865

    Article  PubMed  CAS  Google Scholar 

  14. Steinman RM, Hemmi H (2006) Dendritic cells: translating innate to adaptive immunity. Curr Top Microbiol Immunol 311:17–58

    Article  PubMed  CAS  Google Scholar 

  15. Shortman K, Naik SH (2007) Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol 7:19–30

    Article  PubMed  CAS  Google Scholar 

  16. Shu SA, Lian ZX, Chuang YH, Yang GX, Moritoki Y, Comstock SS, Zhong RQ, Ansari AA, Liu YJ, Gershwin ME (2007) The role of CD11c+ hepatic dendritic cells in the induction of innate immune responses. Clin Exp Immunol 149:335–343

    Article  PubMed  CAS  Google Scholar 

  17. Jomantaite I, Dikopoulos N, Kröger A, Leithaüser F, Hauser H, Schrimbeck Reimann J (2004) Hepatic dendritic cells subsets in the mouse. Eur J Immunol 34:355–365

    Article  PubMed  CAS  Google Scholar 

  18. Chen L, Calomeni E, Wen J, Ozato K, Shen R, Gao JX (2007) Natural killer dendritic cells are an intermediate of developing dendritic cells. J Leukoc Biol 81:1422–1433

    Article  PubMed  CAS  Google Scholar 

  19. Pillarisetty VG, Katz SC, Bleier JI, Shah AB, Dematteo RP (2005) Natural killer dendritic cells have both antigen presenting and lytic function and in response to CpG produce IFN-gamma via autocrine IL-12. J Immunol 174: 2612–2618

    PubMed  CAS  Google Scholar 

  20. Matsuno K, Ezaki T, Kudo S, Uehara Y (1996) A life stage of particle-laden rat dendritic cells in vivo: their terminal division active phagocytosis, and translocation from the liver to the draining lymph. J Exp Med 183:1865–1878

    Article  PubMed  CAS  Google Scholar 

  21. Lohse AW, Knolle PA, Bilo K, Uhrig A, Waldmann C, Ibe M, Schmitt E, Gerken G, Meyer Zum Büschenfelde KH (1996) Antigen-presenting function and B7 expression of murine sinusoidal endothelial cells and Kupffer cells. Gastroenter­ology. 119:1175–1181

    Article  Google Scholar 

  22. Iizasa H, Yoneyama H, Mukaida N, Katakoka Y, Naito M, Yoshida N, Nakashima E, Matsushima K (2005) Exacerbation of granuloma formation in IL-1 receptor antagonist-deficient mice with impaired dendritic cell maturation associated with Th2 cytokine production. J Immunol 174:3273–3280

    PubMed  CAS  Google Scholar 

  23. Ebihara T, Shingai M, Matsumoto M, Wakita T, Seya T (2008) Hepatitis C virus-infected hepatocytes extrinsically modulate dendritic cell maturation to activate T-cells and natural killer cells. Hepatology. 48:48–58

    Article  PubMed  CAS  Google Scholar 

  24. Hong KJ, Wickstrum JR, Yeh HW, Parmely MJ (2007) Toll-like receptor 2 controls gamma interferon response to Francisella tularensis by mouse liver lymphocytes. Infect Immun 75:5338–5345

    Article  PubMed  CAS  Google Scholar 

  25. Steinmann RM, Hawiger D, Nussenzweig MC (2003) Toler­genic dendritic cells. Annu Rev Immunol 21:685–711

    Article  CAS  Google Scholar 

  26. Ito T, Wang YH, Liu YJ (2005) Plasmacytoid dendritic cell precursors/type I interferon-producing cells sense viral infections by Toll-like receptor (TLR) 7 and TLR9. Springer Semin Immunopathol 26:221–229

    Article  PubMed  CAS  Google Scholar 

  27. Ato M, Maroof A, Zubari S, Nakano H, Kakiuchi T, Kaye PM (2006) Loss of dendritic cell migration and impaired resistance to Leishmania donovani infection in mice deficient in CCL19 and CCL21. J Immunol 176:5486–5493

    PubMed  CAS  Google Scholar 

  28. Yoneyama H, Ichida T (2005) Recruitment of dendritic cells to pathological niches in inflamed liver. Med Mol Morphol 38:136–141

    Article  PubMed  Google Scholar 

  29. Fernandez NC, Lozier A, Flament C, Ricciardi-Castagnoli P, Bellet D, Suter M, Perricaudet M, Tursz T, Maraskovsky E, Zitvogel L (1999) Dendritic cells directly trigger NK cell functions; cross-talk relevant in innate anti-tumor immune responses in vivo. Nat Med 5:405–411

    Article  PubMed  CAS  Google Scholar 

  30. Cross JL, Kott K, Miletic T, Johnson P (2008) CD45 regulates TLR-induced proinflammatory cytokine and IFN-beta secretion in dendritic cells. J Immuol 180: 8020–8029

    CAS  Google Scholar 

  31. Brilot F, Strowig T, Munz C (2008) NK cells interactions with dendritic cells shape innate and adaptive immunity. Front Biosci 13:6443–6454

    Article  PubMed  CAS  Google Scholar 

  32. Dieli F, Caccamo N, Meraviglia S, Ivanyi J, Sireci G, Bonanno CT, Ferlazzo V, La Mendola C, Salerno A (2004) Reciprocal stimulation of gammadelta T cells and dendritic cells during the anti-mycobacterial immune response. Eur J Immunol 34:3227–3235

    Article  PubMed  CAS  Google Scholar 

  33. Blom B, Spits H (2006) Development of human lymphoid cells. Annu Rev Immunol 24:287–320

    Article  PubMed  CAS  Google Scholar 

  34. Zhang AL, Colmenero P, Purath U, de Matos Teixeira C, Hueber W, Klaereskog L, Tarner IH, Engleman EG, Söderström K (2007) Natural killer trigger differentiation of monocytes into dendritic cells. Blood 110:2484–2493

    Article  PubMed  CAS  Google Scholar 

  35. Pistoia V, Zupo S, Corcione A, Roncella S, Matera L, Ghio R, Ferrarini M (1989) Production of colony-­stimulating activity by human natural killer cells: analysis of the conditions that influence the release and detection of colony-stimulating activity. Blood 74:156–164

    PubMed  CAS  Google Scholar 

  36. Decker WK, Li S, Xing D, Robinson SN, Yang H, Steiner D, Komanduri KV, Bollard CM, Shpall EJ (2008) Deficient T(H)-1 responses from TNF-alpha-matured and alpha-CD40-matured dendritic cells. J Immunother 31:157–165

    Article  PubMed  CAS  Google Scholar 

  37. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G (2002) Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 195: 327–333

    Article  PubMed  CAS  Google Scholar 

  38. Tosi D, Valenti R, Cova A, Sovena G, Huber V, Pilla L, Arienti F, Belardelli F, Parmiani G, Rivoltini L (2004) Role of cross-talk between IFN-alpha-induced monocyte-derived dendritic cells and NK cells in priming CD8+ T cell responses against human tumor antigens. J Immunol 172:5363–5370

    PubMed  CAS  Google Scholar 

  39. Barnes E, Salio M, Cerundolo V, Medlin J, Murphy S, Dusheiko G, Klenerman P (2004) Impact of alpha interferon and ribavirin on the function of maturing dendritic cells. Antimicrob Agents Chemother 48:3382–3389

    Article  PubMed  CAS  Google Scholar 

  40. Martinelli E, Cicala C, Van Ryk D, Goode DJ, Macleod K, Arthos J (2007) Fauci As. HIV-1 gp120 inhibits TLR9-mediated activation and IFN-{alpha} secretion in plasmacytoid dendritic cells. Proc Natl Acad Sci USA 104: 3396–3401

    Article  PubMed  CAS  Google Scholar 

  41. Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E (2005) Natural killer cells and dendritic cells: “l’union fait la force”. Blood 106:2252–2258

    Article  PubMed  CAS  Google Scholar 

  42. Vitale M, Della CM, Carlomagno S, Pende D, Aricò M, Moretta L, Moretta A (2005) NK-dependent DC maturation is mediated by TNFalpha and IFNgamma released upon engagement of the NKp30 triggering receptor. Blood 106: 566–571

    Article  PubMed  CAS  Google Scholar 

  43. Agaugue S, Marcenaro E, Ferranti B, Moretta L, Moretta A (2008) Human natural killer cells exposed to IL-2, IL-12, IL-18 or IL-4 differently modulate priming of naïve T cells by monocyte-derived dendritic cells. Blood 112:1776–1783

    Article  PubMed  CAS  Google Scholar 

  44. Abe M, Zahorchak AF, Colvin BL (2004) Thomson AW. Migarotory responses of murine hepatic myeloid, lymphoid-related, and plasmacytoid dendritic cells to CC chemokines Transplantation 78:762–765

    CAS  Google Scholar 

  45. Shields PL, Morland CM, Salmon M, Qin S, Hubscher SG, Adams DH (1999) Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol 163:6236–6243

    PubMed  CAS  Google Scholar 

  46. Walzer T, Dalod M, Vivier E, Zitvogel L (2005) Natural killer cell-dendritic cell crosstalk in the initiation of immune responses. Expert Opin Biol Ther 5:S49–S59

    Article  Google Scholar 

  47. Ferlazzo G, Pack M, Thomas D, Paludan C, Scmid D, Strowig T, Bougras G, Muller WA, Moretta L, Munz C (2004) Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proc Natl Acad Sci USA 101:16606–16611

    Article  PubMed  CAS  Google Scholar 

  48. Gerosa F, Gobbi A, Zorzi P, Burg S, Briere F, Carra G, Trinchieri G (2005) The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions. J Immunol 174:727–734

    PubMed  CAS  Google Scholar 

  49. Borg C, Jalil A, Laderach D, Maruyama K, Wakasugi H, Charrier S, Ryffel B, Cambi A, Figdor C, Vainchenker W, Galy A, Caignard A, Zitvogel L (2004) NK cell activation by dendritic cells (DCs) requires the formation of a synapse leading to IL-12 polarization in DCs. Blood 104: 3267–3275

    Article  PubMed  CAS  Google Scholar 

  50. Koka R, Burkett P, Chien M, Chai S, Boone DL, Ma A (2004) Cutting edge: murine dendritic cells require IL-15R alpha to prime NK cells. J Immunol 173:3594–3598

    PubMed  CAS  Google Scholar 

  51. Mocikat R, Braumuller H, Gumy A, Ggeter O, Ziegler H, Reusch U, Bubeck A, Louis J, Mailhammer R, Riethmüller G, Koszinowski U, Röcken M (2003) Natural killer cells activated by MHC class I (low) targets prime dendritic cells to induce protective CD8 T cell responses. Immunity 19: 561–569

    Article  PubMed  CAS  Google Scholar 

  52. Guan H, Moretto M, Bzik DJ, Gigley J, Khan IA (2007) NK cells enhance dendritic cell response against parasite antigens via NKG2D pathway. J Immunol 179:590–596

    PubMed  CAS  Google Scholar 

  53. Gigli G, Caielli S, Cutuli D, Falcone M (2007) Innate immunity modulates autoimmunity: type 1 interferon-beta treatment in multiple sclerosis promote growth and function of regulatory invariant natural killer T-cell through dendritic cell maturation. Immunology 122:409–417

    Article  PubMed  CAS  Google Scholar 

  54. Fujii S, Liu K, Smith C, Bonito AJ, Steinman RM (2004) The linkage of innate to adaptive immunity via maturing dendritic cells in vivo requires CD40 ligation in addition to antigen presentation and CD80/86 costimulation. J Exp Med 199:1607–1618

    Article  PubMed  CAS  Google Scholar 

  55. Hermans IF, Silk JD, Gileadi U, Salio M, Mathew B, Ritter G, Schmidt R, Harris AL, Old L, Cerundolo V (2003) NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J Immunol 171:5140–5147

    PubMed  CAS  Google Scholar 

  56. Silk JD, Hermans IF, Gileadi U, Chong TW, Shepherd D, Salio M, Mathew B, Schmidt RR, Lunt SJ, Williams KJ, Stratford IJ, Harris AL, Cerundolo V (2004) Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell-mediated immunotherapy. J Clin Invest 114: 1800–1811

    PubMed  CAS  Google Scholar 

  57. Hermans IF, Silk JD, Gileadi U, Masri SH, Shepherd D, Farrand KJ, Salio M, Cerundolo V (2007) Dendritic cell function can be modulated through cooperative actions of TLR ligands and invariant NKT cells. J Immuol 178: 2721–2729

    CAS  Google Scholar 

  58. Marschner A, Rothenfusser S, Hornung V, Prell D, Krug A, Kerkmann M, Wellisch D, Poeck H, Greinacher A, Giese T, Endres S, Hartmann G (2005) CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cells. Eur J Immunol 35:2347–2357

    Article  PubMed  CAS  Google Scholar 

  59. Wiethe C, Debus A, Mohrs M, Steinkasserer A, Lutz M, Gessner A (2008) Dendritic cell differentiation state and their interaction with NKT cells determine Th1/Th2 differentiation in the murine model of Leishmania major infection. J Immumol 180:4371–4381

    CAS  Google Scholar 

  60. Conti L, Casetti R, Cardone M, Varano B, Martino A, Belardelli F, Poccia F, Gessani S (2005) Reciprocal activating interaction between dendritic cells and pamidronate-stimulated gammadelta T cells: role of CD86 and inflammatory cytokines. J Immunol 174:252–260

    PubMed  CAS  Google Scholar 

  61. Ismaili J, Olislagers V, Poupot R, Fournie JJ, Goldman M (2002) Human gamma delta T cells induce dendritic cell maturation. Clin Immuol 103:296–302

    Article  CAS  Google Scholar 

  62. Leslie DS, Vincent MS, Spada FM, Das H, Sugita M, Morita CT, Brenner MB (2002) CD1-mediated gamma/delta T cell maturation of dendritic cells. J Exp Med 196:1575–1584

    Article  PubMed  CAS  Google Scholar 

  63. Ajuebor MN, Hogaboam CM, Le T, Proundfoot AE, Swain MG (2004) CCL3/MIP-1aplha is pro-inflammatory in murine T cell-mediated hepatitis by recruiting CCR1-expressing CD4(+) T cells to the liver. Eur J Immumol 34:2907–2918

    Article  CAS  Google Scholar 

  64. Ren J, Jia J, Zhang H, Zhang L, Ma B, Jiang H, Di L, Song G, Yu J (2008) Dendritic cells pulsed with alpha-fetoprotein and mutant P53 fused gene induce bi-targeted cytotoxic T lymphocyte response against hepatic carcinoma. Cancer Sci 99:1420–1426

    Article  PubMed  CAS  Google Scholar 

  65. Yoneyama H, Matsuno K, Zhang Y, Murai M, Itakura M, Ishikawa S, Hasegawa G, Naito M, Asakura H, Matsushima K (2001) Regulation by chemokines of circulating dendritic cell precursors, and the formation of portal tract-associated lymphoid tissue, in a granulomatous liver disease. J Exp Med 193:35–49

    Article  PubMed  CAS  Google Scholar 

  66. Lanier LL (2005) NK cell recognition. Annu Rev Immunol 23:225–274

    Article  PubMed  CAS  Google Scholar 

  67. Biassoni R, Bottino C, Cantoni C, Moretta A. Human natural killer receptors and their ligands. Curr Protoc Immunol. 2002 Feb; Chapter 14:Unit 14.10

    Google Scholar 

  68. Kahraman A, Barreyro FJ, Bronk SF, Werneburg NW, Mott JL, Akazawa Y, Masuoka HC, Howe CL, Gores GJ (2008) TRAIL mediates liver injury by the innate immune system in the bile duct-ligated mouse. Hepatology. 47: 1317–1330

    Article  PubMed  CAS  Google Scholar 

  69. Tay CH, Welsh RM (1997) Distinct organ-dependent mechanisms for the control of murine cytomegalovirus infection by natural killer cells. J Virol 71:267–275

    PubMed  CAS  Google Scholar 

  70. Dunn C, Brunetto M, Reynolds G, Christophides T, Kennedy PT, Lampertico P, Das A, Ross Lopes A, Borrow P, Williams K, Humphreys E, Afford S, Adams DH, Bertoletti A, Maini MK (2007) Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med 204: 667–680

    Article  PubMed  CAS  Google Scholar 

  71. Kafrouni MI, Brown GR, Thiele DL (2001) Virally infected hepatocytes are resistant to perforin-dependent CTL effector mechanisms. J Immunol 167:1566–1574

    PubMed  CAS  Google Scholar 

  72. Balkow S, Kersten TT, Tran T, Stehle P, Grosse C, Museteanu C, Utermohlen H (2001) Pircher, von Weizsacker R F. Wallich R. Concerted action of the FasL/Fas and perforin/granzyme A and B pathways is mandatory for the development of early viral hepatitis but not for recovery from viral infection. J Virol 75:8781–8791

    CAS  Google Scholar 

  73. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA (1995) Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3:673–682

    Article  PubMed  CAS  Google Scholar 

  74. Afford SC, Randhawa S, Elipoulos AG, Hubscher SG, Young LS, Adams DH (1999) CD40 activation induces apoptosis in cultures human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection. J Exp Med 18:441–446

    Article  Google Scholar 

  75. Ahmed-Choudhury J, Russell CL, Randhawa S, Young LS, Adams DH, Afford SC (2003) Differential induction of nuclear factor-kappaB and activator protein-1 activity after CD40 ligation is associated with primary human hepatocyte apoptosis or intrahepatic endothelial cell proliferation. Mol Biol Cell 14:1334–1345

    Article  PubMed  CAS  Google Scholar 

  76. Alabraba EB, Lai V, Boon L, Wigmore SJ, Adams DH, Afford SC (2008) Coculture of human liver macrophages and cholangiocytes leads to CD40-dependent apoptosis and cytokine secretion. Hepatology 47:552–562

    Article  PubMed  CAS  Google Scholar 

  77. Galle PR, Hofmann WJ, Walczak H, Schaller H, Otto G, Stremmel W, Krammer PH, Runkel L (1995) Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage. J Exp Med 182:1223–1230

    Article  PubMed  CAS  Google Scholar 

  78. Jinushi M, Takehara T, Tatsumi T, Kanto T, Miyagi T, Suzuki T, Kanazawa Y, Hiramatsu N, Hayashi N (2004) Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol 173:6072–6081

    PubMed  CAS  Google Scholar 

  79. Dong Z, Wei HM, Sun R, Hu Z, Gao B, Tian Z (2004) Involvement of natural killer cells in Poly I:C-induced liver injury. J Hepatol 41:966–973

    Article  PubMed  CAS  Google Scholar 

  80. Ochi M, Ohdan H, Mitsuta H, Onoe T, Tokita D, Hara H, Ishiyama K, Zhou W, Tanaka Y, Asahara T (2004) Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice. Hepatology 39:1321–1331

    Article  PubMed  CAS  Google Scholar 

  81. Taniguchi M, Seino K, Nakayama T (2003) The NKT cell system: bridging innate and acquired immunity. Nat Immunol 4:1164–1165

    Article  PubMed  CAS  Google Scholar 

  82. Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Kaer V (2004) NKT cells: what’s in a name? Nat Rev Immunol 4:231–237

    Article  PubMed  CAS  Google Scholar 

  83. Bendelac A, Savage PB, Teyton L (2007) The biology of NKT cells. Annu Rev Immunol 25:297–336

    Article  PubMed  CAS  Google Scholar 

  84. Fehniger TA, Caligiuri MA (2001) Interleukin 15: biology and relevance to human disease. Blood 97:14–32

    Article  PubMed  CAS  Google Scholar 

  85. Winau F, Hegasy G, Weiskirchen R, Weber S, Cassan C, Sieling PA, Modlin RL, Liblau RS, Gressner AM, Kaufmann SH (2007) Ito cells are liver-resident antigen-presenting cells for activating T-cell responses. Immunity 26:117–129

    Article  PubMed  CAS  Google Scholar 

  86. Mattner J, Debord KL, Ismail N, Goff RD, Cantu 3rd Zhou D, Saint-Mezard P, Wang V, Gao Y, Yin N, Hoebe K, Schneewind O, Walker D, Beutler B, Teyton L, Savage PB, Bendelac A (2005) Exogenous and endogeneous glycolipid antigens activate NKT cells during microbial infections. Nature 434:525–529

    Google Scholar 

  87. Kinyo Y, Wu D, Kim G, Xing GW, Poles MA, Ho DD, Tsuji M, Kawahara K, Wong CH, Kronenberg M (2005) Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434:520–525

    Article  CAS  Google Scholar 

  88. Tupin E, Kinjo Y, Kronenberg M (2007) The unique role of natural killer T cells in the response to microorganisms. Nat Rev Microbiol 5:405–417

    Article  PubMed  CAS  Google Scholar 

  89. Geissman F, Cameron TO, Sidobre S, Manlongat N, Kronenberg M, Briskin MJ, Dustin ML, Littman DR (2005) Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol 3:e113

    Article  CAS  Google Scholar 

  90. Tiegs G, Hentschel J, Wendel A (2000) A T cell-dependent experimental liver injury in mice. Am J Pathol 157: 1671–1683

    PubMed  Google Scholar 

  91. Takeda K, Hayakawa Y, Van Kaer L, Matsuda H, Yagita H, Okumura K (2000) Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proc Natl Acad Sci USA 97:5498–5503

    Article  PubMed  CAS  Google Scholar 

  92. Thomas SY, Hou R, Boyson JE, Means TK, Hess C, Olson DP, Strominger JL, Brenner MB, Gumperz JE, Wilson SB, Luster AD (2003) CD1d-resticted NKT cells express a chemokine receptor profile indicative of Th1-type inflammatory homing cells. J Immunol 171:2571–2580

    PubMed  CAS  Google Scholar 

  93. Johnston B, Kim CH, Soler D, Emoto M, Butcher EC (2003) Differential chemokine responses and homing patterns of murine TCR αβ NKT cell subsets. J Immunol 171: 2960–2969

    PubMed  CAS  Google Scholar 

  94. Jiang D, Liang J, Hodge J, Lu B, Zhu Z, Yu S, Fan J, Gao Y, Yin Z, Homer R, Gerard C, Noble PW (2004) Regulation of pulmonary fibrosis by chemokine receptor CXCR3. J Clin Invest 114:291–299

    PubMed  CAS  Google Scholar 

  95. Fujii S, Shimizu K, Hemmi H, Steinman RM (2007) Innate Valpha14(+) natural killer T cells mature dendritic cells, leading to strong adaptive immunity. Immunol Rev 220: 183–198

    Article  PubMed  CAS  Google Scholar 

  96. Chang CJ, Chen YH, Huang KW, Cheng HW, Chan SF, Tai KF, Hwang LH (2007) Combined GM-CSF and IL-12 gene therapy synergistically suppresses the growth of orthotopic liver tumors. Hepatology 45:746–754

    Article  PubMed  CAS  Google Scholar 

  97. Kitamura H, Iwakabe K, Yahata T, Nishimura S, Ohta A, Ohmi Y, Sato M, Takeda K, Okamura K, Van Kaer L, Kawano T, Taniguchi M, Nishimura T (1999) 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 189: 1121–1128

    Article  PubMed  CAS  Google Scholar 

  98. Van Kaer L (2007) NKT cells: T lymphocytes with innate effector functions. Curr Opin Immunol 19:354–364

    Article  PubMed  CAS  Google Scholar 

  99. Hayakawa Y, Takeda K, Yagita H, Van Kaer L, Saiki I, Okumura K (2001) Differential regulation of Th1 and Th2 functions of NKT cells by CD28 and CD40 costimulatory pathways. J Immunol 166:6012–6018

    PubMed  CAS  Google Scholar 

  100. Steinman L (2007) A brief history of Th17, the first major revision in the Th1/Th2 hypothesis of T cell-mediated tissue damage. Nat Med 13:139–145

    Article  PubMed  CAS  Google Scholar 

  101. Kusters S, Gantner F, Kunstle G, Tiegs G (1996) Interferon γ plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A. Gastroenterology 111: 462–471

    Article  PubMed  CAS  Google Scholar 

  102. Tagawa Y, Kakuta S, Iwakura Y (1998) Involvement of Fas/Fas ligand system-mediated apoptosis in the development of concanavalin A-induced hepatitis. Eur J Immunol 28:4105–4113

    Article  PubMed  CAS  Google Scholar 

  103. Kusters S, Tiegs G, Alexopoulou L, Pasparakis M, Douni E, Künstle G, Bluethmann H, Wendel A, Pfizenmaier K, Kollias G, Grell M (1997) In vivo evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis. Eur J Immunol 27:2879–2875

    Article  Google Scholar 

  104. Kawano T, Nakayama T, Kamada N, Kaneko Y, Harada M, Ogura N, Akutsu Y, Motohashi S, Iizasa T, Endo H, Fujisawa T, Shinkai H, Taniguchi M (1999) Antitumor cytotoxicity mediated by ligand-activated human v a24 NKT cells. Cancer Res 59:5102–5105

    PubMed  CAS  Google Scholar 

  105. Sun R, Tian Z, Kulkarni S, Gao B (2004) IL-6 prevents T cell-mediated hepatitis via inhibition of NKT cells in CD4+ T cell- and STAT3-dependent manners. J Immunol 172: 5648–5655

    PubMed  CAS  Google Scholar 

  106. Li B, Sun R, Wei H, Gao B, Tian Z (2006) Interleukin-15 prevents concanavalin A-induced liver injury in mice via NKT cell-dependent mechanism. Hepatology 43: 1211–1219

    Article  PubMed  CAS  Google Scholar 

  107. Smyth MJ, Crowe NY, Pellici DG, Kyparissoudis K, Kelly JM, Takeda K, Yagita H, Godfrey DI (2002) Sequential production of interferon-γ by NK1.1+ T cells and natural killer cells is essential for the antimetastatic effect of α-galactosyleramide. Blood 99:1259–1266

    Article  PubMed  CAS  Google Scholar 

  108. Hayday AC (2000) [Gamma] [delta] cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol 18:975–1026

    Article  PubMed  CAS  Google Scholar 

  109. Morita CT, Li H, Lamphear JG, Rich RR, Fraser JD, Mariuzza RA, Lee HK (2001) Superantigen recognition by gammadelta T cells:SEA recognition site for human Vgamma2 T cell receptors. Immunity 14:331–344

    Article  PubMed  CAS  Google Scholar 

  110. Haas W, Pereira P, Tonegawa S (1993) Gamma/delta cells. Annu Rev Immunol 11:637–685

    PubMed  CAS  Google Scholar 

  111. Born WK, Reardon CL, O’Brien RL (2006) The function of gammadelta T cells in innate immunity. Curr Opin Immunol 18:31–38

    Article  PubMed  CAS  Google Scholar 

  112. Kenna T, Golden-Mason L, Norris S, Hegarty JE, O’Farrelly C, Doherty DG (2004) Distinct subpopulations of gamma delta T cells are present in normal and tumour-bearing human liver. Clin Immunol 113:56–63

    Article  PubMed  CAS  Google Scholar 

  113. Bowen DG, Warren A, Davis T, Hoffmann MW, McCaughan GW, Fazekas de St Groth B et al (2002) Cytokine-dependent bystander hepatitis due to intrahepatic murine CD8 T-cell activation by bone marrow-derived cells. Gastroenterology 123:1252–1264

    Google Scholar 

  114. Schildberg FA, Hegenbarth SI, Shumak B, Limmer A, Knolle PA (2008) Liver sinusoidal endothelial cells veto CD8 T cell activation by antigen-presenting dendritic cells. Eur J Immunol 38:957–967

    Article  PubMed  Google Scholar 

  115. Bowen DG, Zen M, Holz L, Davis T, McCaughan GW, Bertolino P (2004) The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. J Clin Invest 114:701–712

    PubMed  CAS  Google Scholar 

  116. Heath WR, Carbone FR (2001) Cross-presentation, dendritic cells, tolerance and immunity. Annu Rev Immunol 19:47–64

    Article  PubMed  CAS  Google Scholar 

  117. Burns WR, Wang Y, Tang PC, Ranjbaran H, Iakimov A, Kim J, Cuffy M, Bai Y, Pober JS, Tellides G (2005) Recruitment of CXCR3+ and CCR5+ T cells and production of interferon-gamma-inducible chemokines in rejecting human arteries. Am J Transplant 5:1226–1236

    Article  PubMed  CAS  Google Scholar 

  118. Madsen AN, Nansen A, Christensen JP, Thomsen AR (2003) Role of macrophage inflammatory protein-1a in T-cell mediated immunity to viral infection. J Virol 77: 12378–12384

    Article  PubMed  CAS  Google Scholar 

  119. Zeremski M, Petrovic LM, Talal AH (2007) The role of chemokines as inflammatory mediators in chronic hepatitis C virus infection. J Viral Hepat 14:675–687

    PubMed  CAS  Google Scholar 

  120. Drakes ML, Zahorchak AF, Takayama T, Lu L, Thomson AW (2000) Chemokine and chemokine receptor expression by liver-derived dendritic cells: MIP-1alpha production is induced by bacterial lipopolysaccharide and interaction with allogeneic T cells. Transpl Immunol 8:17–29

    Article  PubMed  CAS  Google Scholar 

  121. Lalor PF, Shields P, Grant A, Adams DH (2002) Recruitment of lymphocytes to the human liver. Immunol Cell Biol 80:52–64

    Article  PubMed  CAS  Google Scholar 

  122. John B, Crispe IN (2004) Passive and active mechanisms trap activated CD8+ T cells in the liver. J Immunol 172: 5222–5229

    PubMed  CAS  Google Scholar 

  123. Bonder CS, Norman MU, Swain MG, Zbytnuik LD, Yamanouchi J, Santamaria P, Ajuebor M, Salmi M, Jalkanen S, Kubes P (2005) Rules of recruitment fro Th1 and Th2 lymphocytes in inflamed liver: a role for alpha-4 integrin and vascular adhesion protein-1. Immunity 23:153–163

    Article  PubMed  CAS  Google Scholar 

  124. Gonzalo JA, Delaney T, Corcoran J, Goodearl A, Gutierrez-Ramos JC, Coyle AJ (2001) Cutting edge: the related molecules CD28 and inducible costimulator deliver both unique and complementary signals required for optimal T cell activation. J Immuol 166:1–5

    CAS  Google Scholar 

  125. Bertolino P, McCaughan G, Bowen DG (2002) Role of primary intrahepatic T cell activation in the liver tolerance effect. Immunol Cell Biol 80:84–92

    Article  PubMed  Google Scholar 

  126. Isogawa M, Furuichi Y, Chisari FV (2005) Oscillating CD8(+) T cell effector functions after antigen recognition in the liver. Immunity 23:53–63

    Article  PubMed  CAS  Google Scholar 

  127. Mehal WZ, Juedes AE, Crispe IN (1999) Selective retention of activated CD8+ T cells by the normal liver. J Immunol 163:3202–3210

    PubMed  CAS  Google Scholar 

  128. Guidotti LG, Rochford R, Chung J, Shapiro M, Purcell R, Chisari FV (1999) Viral clearance without destruction of infected cells during acute HBV infection. Science 284: 825–829

    Article  PubMed  CAS  Google Scholar 

  129. Guidotti LG, Chisari FV (1996) To kill or to cure: options in host defense against viral infection. Curr Opin Immunol 8:478–483

    Article  PubMed  CAS  Google Scholar 

  130. Berke G (1995) The CTL’s kiss of death. Cell 81:9–12

    Article  PubMed  CAS  Google Scholar 

  131. Kakimi K, Lane TE, Wieland S, Asensio VC, Campbell IL, Chisari FV, Guidotti LG (2001) Blocking chemokine responsive to gamma-2/interferon (IFN)-gamma inducible protein and monokine induced by IFN-gamma activity in vivo reduced the pathogenic but not the antiviral potential of hepatitis B virus-specific cytotoxic T lymphocyte. J Exp Med 194:1755–1766

    Article  PubMed  CAS  Google Scholar 

  132. Ramaiah SK, Jaeschke H (2007) Role of neutrophils in the pathogenesis of acute inflammatory liver injury. Toxicol Pathol 35:757–766

    Article  PubMed  CAS  Google Scholar 

  133. Matsumura S, Van De Water J, Leung P, Odin JA, Yamamoto K, Gores GJ, Mostov K, Ansari AA, Coppel RJ, Shiratori Y, Gershwin ME (2004) Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis. Hepatology 39: 1415–1422

    Article  PubMed  CAS  Google Scholar 

  134. Perrier P, Martinez FO, Locati M, Bianchi G, Nebuloni M, Vago G, Bazzoni F, Sozzani S, Allavena P, Mantovani A (2004) Distinct transcriptional programs activated by interleukin-10 with or without lipopolysaccharide in dendritic cells: induction of the B cell-activating chemokine, CXC chemokine ligand 13. J Immunol 172:7031–7042

    PubMed  CAS  Google Scholar 

  135. Novobrantseva TI, Majeau GR, Amatucci A, Kogan S, Brenner I, Casola S, Sclomchik MJ, Koteliansky V, Hochman PS, Ibraghimov A (2005) Attenuated liver fibrosis in the absence of B cells. J Clin Invest 115:3072–3082

    Article  PubMed  CAS  Google Scholar 

  136. Dumoutier L, Renauld JC (2002) Viral and cellular interleukin-10 (IL-10)-related cytokines: from structures to functions. Eur Cytokine Netw 13:5–15

    PubMed  CAS  Google Scholar 

  137. Fiorention DF, Bond MW, Mosmann TR (1989) Two types of mouse T helper cell IV Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 170:2081–2095

    Article  Google Scholar 

  138. Grutz G (2005) New insights into the molecular mechanism of interleukin-10-mediated immunosuppression. J Leukoc Biol 77:3–15

    PubMed  Google Scholar 

  139. Takayama T, Morelli AE, Onai N, Hirao M, Matsushima K, Tahara H, Thomson AW (2001) Mammalian and viral IL-10 enhance C-C chemokine receptor 5 but down-regulate C-C chemokine receptor 7 expression by myeloid dendritic cells: impact on chemotactic responses and in vivo homing ability. J Immunol 166:7136–7143

    PubMed  CAS  Google Scholar 

  140. Groux H, Bigler M, de Vries JE, Roncarolo MG (1996) Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J Exp Med 184:19–29

    Article  PubMed  CAS  Google Scholar 

  141. Di Marco R, Xiang M, Zaccone P, Leonardi C, Franco S, Meroni P, Nicoletti F (1999) Concanavalin A-induced hepatitis in mice is prevented by interleukin (IL)-10 and exacerbated by endogenous IL-10 deficiency. Autoimmunity 31:75–83

    Article  PubMed  Google Scholar 

  142. Wahl C, Bochtler P, Schrimbeck R, Reimann J (2007) Type I IFN-producing CD4 Valpha14i NKT cells facilitate priming of IL-10-producing CD8 T cells by hepatocytes. J Immunol 178:2083–2093

    PubMed  CAS  Google Scholar 

  143. Limmer A, Ohl J, Kurts C, Ljunggen HG, Riess Y, Groettrup M, Momburg F, Arnold B, Knolle PA (2000) Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat Med 6:1348–1354

    Article  PubMed  CAS  Google Scholar 

  144. Knolle PA, Schmitt E, Jin S, Germann T, Duchmann R, Hegenbarth S, Gerken G, Lohse AW (1999) Induction of cytokine production in naïve CD4(+) T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells. Gastroenterology 116:1428–1440

    Article  PubMed  CAS  Google Scholar 

  145. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2:261–268

    Article  PubMed  CAS  Google Scholar 

  146. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252

    Article  PubMed  CAS  Google Scholar 

  147. Sumpter TL, Abe M, Tokita D, Thomson AW (2007) Dendritic cells, the liver and transplantation. Hepatology 46:2021–2031

    Article  PubMed  CAS  Google Scholar 

  148. Martinez OM, Rosen HR (2005) Basic concepts in transplant immunology. Liver Transplant 3:370–381

    Article  Google Scholar 

  149. Bartlett AS, McCall JL, Ameratunga R, Yeong ML, Gane E, Munn SR (2003) Analysis of intragraft gene and protein expression of costimulatory molecules, CD80, CD86 and CD154, in orthotropic liver transplant recipients. Am J Transplant 3:1363–1368

    Article  PubMed  CAS  Google Scholar 

  150. Afford SC, Ahmed-Choudhury J, Randhawa S, Russell C, Youster J, Crosby HA, Eliopoulos A, Hubscher SG, Young LS, Adams DH (2001) CD40 activation-induced, Fas-dependent apoptosis and NF-kappaB/AP-1 signaling in human intrahepatic biliary epithelial cells. FASEB J 15: 2345–2354

    Article  PubMed  CAS  Google Scholar 

  151. Ahmed-Choudhury J, Williams KT, Young LS, Adams DH, Afford SC (2006) CD40 mediated human cholangiocyte apoptosis requires JAK2 dependent activation of STAT3 in addition to activation of \JNK1/2 and ERK 1/2. Cell Signal 18:456–468

    Article  PubMed  CAS  Google Scholar 

  152. Kirk AD, Burkly LC, Batty DS, Baumgartner RE, Berning JD, Buchanan K, Fechner JH Jr, Germond RL, Kampen RL, Patterson NB, Swanson SJ, Tadaki DK, TenHoor CN, White L, Knechtle SJ, Harlan DM (1999) Treatment with humanised monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med 5:686–693

    Article  PubMed  CAS  Google Scholar 

  153. Demetris AJ, Qian S, Sun H, Fung JJ, Yagihashi A, Murase N, Iwaki Y, Gambrell B, Starzl TE (1991) Early events in liver allograft rejection. Delineation of sites of simultaneous intragraft and recipient lymphoid tissue sensitization. Am J Pathol 138:609–619

    PubMed  CAS  Google Scholar 

  154. Illigens BM, Yamada A, Fedoseyeva EV, Anosova N, Boisgerault F, Valujskikh A, Heeger PS, Sayegh MH, Boehm B, Benichou G (2002) The relative contribution of the direct and indirect antigen recognition pathways to the alloresponse and graft rejection depends upon the nature of the transplant. Hum Immunol 63:912–925

    Article  PubMed  CAS  Google Scholar 

  155. Toyokama H, Nakao A, Bailey RJ, Nalesnik MA, Kaizu T, Lemoine JL, Ikeda A, Tomiyama K, Papworth GD, Huang L, Demetris AJ, Starzl TE, Murase N (2008) Relative contribution of direct and indirect allorecognition in developing tolerance after liver transplantation. Liver Transpl 14:346–357

    Article  Google Scholar 

  156. Adams DH, Afford SC (2005) Effector mechanisms of non-suppurative destructive cholangitis in graft-versus-host disease and allograft rejection. Semin Liver Dis 25: 281–297

    Article  PubMed  Google Scholar 

  157. Leon MP, Bassendine MF, Gibbs P, Burt AD, Thick M, Kirby JA (1997) Immunogenicity of biliary epithelium: study of the adhesive interaction with lymphocytes. Gastroenterology 112:968–977

    Article  PubMed  CAS  Google Scholar 

  158. Tannapfel A, Kohlhaw K, Ebelt J, Hauss J, Liebert U, Berr F, Wittekind C (1999) Apoptosis and the expression of Fas and Fas ligand (FasL) antigen in rejection and reinfection in liver allograft specimens. Transplant 15:1079–1083

    Article  Google Scholar 

  159. Lang KS, Burow A, Kurrer M, Lang PA, Recher M (2007) The role of the innate immune response in autoimmune disease. J Autoimmun 29:310–318

    Article  CAS  Google Scholar 

  160. Maggs JR, Chapman RW (2008) An update on primary sclerosing cholangitis. Curr Opin Gastroenterol 24: 377–383

    Article  PubMed  Google Scholar 

  161. Chuang YH, Lian ZX, Tsuneyama K, Chiang BL, Ansari AA, Coppel RL, Gershwin ME (2006) Increased killing activity and deceased cytokine production in NK cells in patients with primary biliary cirrhosis. J Autoimmun 26:232–240

    Article  PubMed  CAS  Google Scholar 

  162. Yasoshima M, Kono N, Sugwara H, Katayanagi K, Harada K, Nakanuma Y (1998) Increased expression of interleukin-6 and tumor necrosis factor-alpha in pathologic biliary epithelial cells: in situ and culture study. Lab Invest 78: 89–100

    PubMed  CAS  Google Scholar 

  163. Oertelt S, Lian ZX, Cheng CM, Chuang YH, Padgett KA, He XS, Ridgway WM, Ansari AA, Coppel RL, Li MO, Flavell RA, Kronenberg M, Mackay IR, Gershwin ME (2006) Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol 177:1655–1660

    PubMed  CAS  Google Scholar 

  164. Martinez OM, Villanueva JC, Gershwin ME, Krams SM (1995) Cytokine patterns and cytotoxic mediators in primary biliary cirrhosis. Hepatology 21:113–119

    PubMed  CAS  Google Scholar 

  165. Linsen L, Somers V, Stinissen P (2005) Immunoregulation of autoimmunity by natural killer T cells. Hum Immunol 66:1193–1202

    Article  PubMed  CAS  Google Scholar 

  166. Kita H, Naidenko OV, Kronenberg M, Ansari AA, Rogers P, He XS, Koning F, Mikayama T, Van De Water J, Coppel RL, Kaplan M, Gershwin ME (2002) Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer. Gastroenterology 123:1031–1043

    Article  PubMed  CAS  Google Scholar 

  167. Tiegs G, Hentschel J, Wendel A (1992) A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest 90:196–203

    Article  PubMed  CAS  Google Scholar 

  168. Ajuebor MN, Hogaboam CM, Le T, Swain MG (2003) C-C chemokine ligand 2/monocyte chemoattractant protein-1 directly inhibit NKT cell IL-4 production and is hepatoprotective in T cell-mediated hepatitis in the mouse. J Immunol 170:5252–5259

    PubMed  CAS  Google Scholar 

  169. Biburger M, Tiegs G (2005) α-Galactosylceramide-induced liver injury in mice is mediated by TNFα but independent of Kupffer cells. J Immunol 175:1540–1550

    PubMed  CAS  Google Scholar 

  170. Chernavsky AC, Paladino N, Rubio AE, De Biasio MB, Periolo N, Cuarterolo M, Goni J, Galoppo C, Canero-Velasco MC, Munoz AE, Fainboim H, Fainboim L (2004) Simultaneous expression of Th1 cytokines and IL-4 confers severe characteristics to type I autoimmune hepatitis in children. Hum Immunol 65:683–691

    Article  PubMed  CAS  Google Scholar 

  171. Dharancy S, Podevin P, Aoudjehane L, Batteux F, Rosenberg AR, Soubrane O, Calmus Y, Conti F (2007) Elevated interleukin-4 expression in severe recurrent hepatitis C virus after transplantation. Transplantation. 83: 906–911

    Article  PubMed  CAS  Google Scholar 

  172. Aoudjehane L, Podevin P, Scatton O, Jaffray P, Dusanter-Fourt I, Feldman G, Massault PP, Grira L, Bringuier A, Dousset B, Chouzenoux S, Soubrane O, Calmus Y, Conti F (2007) Interleukin-4 induces human hepatocyte apoptosis through a Fas-independent pathway. FASEB J 21: 1433–1444

    Article  PubMed  CAS  Google Scholar 

  173. Guillot C, Coathalem H, Chetritt J, David A, Lowenstein P, Gilbert E, Tesson L, van Rooijen N, Cuturi MC, Soulillou JP, Anegon I (2001) Lethal hepatitis after gene transfer of IL-4 in the liver is independent of immune responses and dependent on apoptosis of hepatocytes: a rodent model of IL-4-induced hepatitis. J Immunol 166:5225–5235

    PubMed  CAS  Google Scholar 

  174. Zhou F, Ajuebor MN, Beck PL, Te L, Hogaboam CM, Swain MG (2005) CD154-CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis. Hepatology 42:372–380

    Article  PubMed  CAS  Google Scholar 

  175. Louis H, Le Moine A, Flamand V, Nagy N, Quertinmont E, Paulart F, Abramowicz D, Le Moine O, Goldman M, Deviere J (2002) Critical role of interleukin 5 and eosinophils in concanavalin A-induced hepatitis in mice. Gastro­enterology 122:2001–2010

    Article  PubMed  CAS  Google Scholar 

  176. Jaruga B, Hong F, Sun R, Radeva S, Gao B (2003) Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: up-­regulating eotaxins and IL-5 and recruiting leukocytes. J Immunol 171:3233–3244

    PubMed  CAS  Google Scholar 

  177. Lang T, Krams SM, Berquist W, Cox KL, Esquivel CO, Martinez OM (1995) Elevated biliary interleukin 5 as an indicator of liver allograft rejection. Transplant Immunol 3:291–298

    Article  CAS  Google Scholar 

  178. Bettelli E, Oukka M, Kuchroo VK (2007) TH-17 cells in the circle of immunity and autoimmunity. Nat Immunol 8:345–350

    Article  PubMed  CAS  Google Scholar 

  179. Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25:821–852

    Article  PubMed  CAS  Google Scholar 

  180. Yasumi Y, Takikawa Y, Endo R, Suzuki K (2007) Interleukin-17 as a new marker of severity of acute hepatic injury. Hepatol Res 37:248–254

    Article  PubMed  CAS  Google Scholar 

  181. Leon MP, Bassendine MF, Wilson JL, Ali S, Thick M, Kirby JA (1996) Immunogenicity of biliary epithelium: investigation of antigen presentation to CD4+ T cells. Hepatology 24:561–567

    Article  PubMed  CAS  Google Scholar 

  182. Yasoshima M, Nakanuma Y, Tsuneyama K, Van de Water J, Gershwin ME (1995) Immunohistochemical analysis of adhesion molecules in the micro-environment of portal tracts in relation to aberrant expression of PDC-E2 and HLA-DR on the bile ducts in primary biliary cirrhosis. J Pathol 175:319–325

    Article  PubMed  CAS  Google Scholar 

  183. Aoki CA, Roifman CM, Lian ZX, Bowlus CL, Norman GL, Shoenfeld Y, Mackay IR, Gershwin ME (2006) IL-2 receptor alpha deficiency and features of primary biliary cirrhosis. J Autoimmun 27:50–53

    Article  PubMed  CAS  Google Scholar 

  184. Sharma R, Jarjour WN, Zheng L, Gaskin F, Fu SM, Ju ST (2007) Large functional repertoire of regulatory T-cell ­suppressible autoimmune T cells in scurfy mice. J Autoimmun 29:10–19

    Article  PubMed  CAS  Google Scholar 

  185. Lan RY, Cheng C, Lian ZX, Tsuneyama K, Yang GX, Moritoki Y, Chuang YH, Nakamura T, Saito S, Shimoda S, Tanaka A, Bowlus CL, Takano Y, Ansari AA, Coppel RL, Gershwin ME (2006) Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology 43:729–737

    Article  PubMed  Google Scholar 

  186. Lan RY, Ansari AA, Lian ZX, Gershwin ME (2005) Regulatory T cells: development, function and role in autoimmunity. Autoimmun Rev 4:351–353

    Article  PubMed  CAS  Google Scholar 

  187. Moritoki Y, Lian ZX, Wulff H, Yang GX, Chuang YH, Lan RY, Ueno Y, Ansari AA, Coppel RL, Mackay IR, Gershwin ME (2007) AMA production in primary biliary cirrhosis is promoted by the TLR9 ligand CpG and suppressed by potassium channel blockers. Hepatology 45: 314–322

    Article  PubMed  CAS  Google Scholar 

  188. Kikuchi K, Lian ZX, Yang GX, Ansari AA, Ikehara S, Kaplan M, MIyakawa H, Coppel RL, Gershwin ME (2005) Bacterial CpG induces hyper-IgM production in CD27(+) memory B cells in primary biliary cirrhosis. Gastroenterology 128:304–312

    Article  PubMed  CAS  Google Scholar 

  189. Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, ­Mieli-Vergani G, Vergani D (2004) Impairment of CD4(+) CD25(+) regulatory T-cells in autoimmune liver disease. J Hepatol 41: 31–37

    Article  PubMed  CAS  Google Scholar 

  190. La Cava A, Van Kaer L, Fu Dong S (2006) CD4+CD25+ Tregs and NKT cells: regulators regulating regulators. Trends Immunol 27:322–327

    Article  PubMed  CAS  Google Scholar 

  191. Bluestone JA, Tang Q (2005) How do CD4+CD25+ regulatory T cells control autoimmunity? Curr Opin Immunol 17:638–642

    Article  PubMed  CAS  Google Scholar 

  192. Nowak M (2007) &Stein-Streilein J. Invariant NKT cells and tolerance. Int Rev Immunol 26:95–119

    Article  CAS  Google Scholar 

  193. Walsh K, Alexander G (2000) Alcoholic liver disease. Postgrad Med J 76:280–286

    Article  PubMed  CAS  Google Scholar 

  194. Rolla R, Vay D, Mottaran E, Parodi M, Traverso N, Arico S, Sartori M, Bellomo G, Klassen LW, Thiele GM, Tuma DJ, Albano E (2000) Detection of circulating antibodies against malondialdehyde-acetaldehyde adducts in patients with alcohol-induced liver disease. Hepatology 31:878–884

    Article  PubMed  CAS  Google Scholar 

  195. Duryee MJ, Klassen LW, Freeman TL, Willis MS, Tuma DJ, Thiele GM (2003) Chronic ethanol consumption impairs receptor-mediated endocytosis of MAA-modified albumin by liver endothelial cells. Biochem Pharmacol 66: 1045–1054

    Article  PubMed  CAS  Google Scholar 

  196. Haydon G, Lalor PF, Hubscher SG, Adams DH (2002) Lymphocyte recruitment to the liver in alcoholic liver disease. Alcohol 27:29–36

    Article  PubMed  CAS  Google Scholar 

  197. Sacanella E, Estruch R (2003) The effect of alcohol consumption on endothelial adhesion molecule expression. Addict Biol 8:371–378

    Article  PubMed  CAS  Google Scholar 

  198. Adams DH (1994) Leuckocyte adhesion molecules and alcoholic liver disease. Alcohol Alcohol 29:249–260

    PubMed  CAS  Google Scholar 

  199. Kono H, Uesugi T, Froh M, Rusyn I, Bradford BU, Thurman RG (2001) ICAM-1 is involved in the mechanism of ­alcohol-induced liver injury: studies with knockout mice. Am J Physiol Gastrointest Liver Physiol 280: G1289–G1295

    Google Scholar 

  200. Duryee MJ, Klassen LW, Freeman TL, Willis MS, Tuma DJ, Thiele GM (2004) Lipopolysaccharide is a cofactor for malondialdehyde-acetaldehyde adduct-mediated cytokine/chemokine release by rat sinusoidal liver endothelial and Kupffer cells. Alcohol Clin Exp Res 28:1931–1938

    Article  PubMed  CAS  Google Scholar 

  201. Keshavarzian A, Holmes EW, Patel M, Iber F, Fields JZ, Pethkar S (1999) Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage. Am J Gastroenterol 94:200–207

    Article  PubMed  CAS  Google Scholar 

  202. Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA (2003) Toll-like receptor 4 mediates inflammatory signalling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 37:1043–1055

    Article  PubMed  CAS  Google Scholar 

  203. Laso FJ, Lapena P, Madruga JI, San Miguel JF, Orfao A, Iglesias MC, Alvarez-Mon M (1997) Alterations in tumour necrosis factor-α, interferon-γ, and interleukin-6 production by natural killer cell-enriched peripheral blood mononuclear cells in chronic alcoholism: relationship with liver disease and ethanol intake. Alcohol Clin Exp Res 21: 1226–1231

    PubMed  CAS  Google Scholar 

  204. Minagawa M, Deng Q, Liu ZX, Tsukamoto H, Dennert G (2004) Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-a during alcohol consumption. Gastroenterology 126:1387–1399

    Article  PubMed  CAS  Google Scholar 

  205. Batey RG, Wang J (2002) Molecular pathogenesis of T lymphocyte-induced liver injury in alcoholic hepatitis. Front Biosci 7:d1662–d1675

    Article  Google Scholar 

  206. Santos-Perez JL, Diez-Ruiz A, Luna-Casado L, Soto-Mas JA, Wachter H, Fuchs D, Gutierrez-Gea F (1996) T-cell activation, expression of adhesion molecules and response to ethanol in alcoholic cirrhosis. Immunol Lett 50:179–183

    Article  PubMed  CAS  Google Scholar 

  207. Song K, Coleman RA, Zhu X, Alber C, Ballas ZK, Waldschmidt TJ, Cook RT (2002) Chronic ethanol consumption by mice results in activated splenic T cells. J Leukoc Biol 72:1109–1116

    PubMed  CAS  Google Scholar 

  208. Cao Q, Batey R, Pang G, Clancy R (1998) Altered T-lymphocyte responsiveness to polyclonal cell activators is responsible for liver cell necrosis in alcohol-fed rats. Alcohol Clin Exp Res 22:723–729

    PubMed  CAS  Google Scholar 

  209. Sakai Y, Izumi N, Marumo F, Sato C (1993) Quantitative immunohistochemical analysis of lymphocyte subsets in alcoholic liver disease. J Gastroenterol Hepatol 8:39–43

    Article  PubMed  CAS  Google Scholar 

  210. Terabayashi H, Kolber MA (1990) The generation of cytotoxic T lymphocytes against acetaldehyde-modified syngeneic cells. Alcohol Clin Exp Res 14:893–899

    Article  PubMed  CAS  Google Scholar 

  211. Klassen LW, Tuma D, Sorrell MF (1995) Immune mechanisms of alcohol-induced liver disease. Hepatology 22: 355–357

    PubMed  CAS  Google Scholar 

  212. Clot P, Bellomo G, Tabone M, Arico S, Albano E (1995) Detection of antibodies against proteins modified by hydroxyethyl free radicals in patients with alcoholic cirrhosis. Gastroenterology 108:201–207

    Article  PubMed  CAS  Google Scholar 

  213. Lok AS, McMahon BJ (2001) Chronic hepatitis B. Hepatology 34:1225–1241

    Article  PubMed  CAS  Google Scholar 

  214. Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH (2000) Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med 132:296–305

    PubMed  CAS  Google Scholar 

  215. Heil F, Ahmad-Nejad P, Hemmi H, Hochrein H, Ampenberger F, Gellert T, Dietrich H, Lipford TK, Akira S, Wagner H, Bauer S (2003) The Toll-like receptors 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 superfamily. Eur J Immunol 33:2987–2997

    Article  PubMed  CAS  Google Scholar 

  216. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18:767–811

    Article  PubMed  CAS  Google Scholar 

  217. Baron JL, Gardiner L, Nishimura S, Shinkai K, Locksley R, Ganem D (2002) Activation of a nonclassical NKT cell subset in a transgenic mouse model of hepatitis B virus infection. Immunity 16:583–594

    Article  PubMed  CAS  Google Scholar 

  218. Lucas M, Gadola S, Meier U, Young NT, Harcourt G, Karadimitris A, Coumi N, Brown D, Dusheiko G, Cerundolo V, Klenerman P (2003) Frequency and phenotype of circulating Va24/Vb11 double-positive natural killer T cells during hepatitis V virus infection. J Virol 77:2251–2257

    Article  PubMed  CAS  Google Scholar 

  219. Guidotti LG, Chisari FV (2001) Noncytolytic control of viral infections by the innate and adaptive immune response. Annu Rev Immunol 19:65–91

    Article  PubMed  CAS  Google Scholar 

  220. Kakimi K, Guidotti LG, Koezuka Y, Chisari FV (2000) Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med 192:192–930

    Article  Google Scholar 

  221. Lin Y, Robert TJ, Spence PM, Brutkiewicz RR (2005) Reduction in CD1d expression on dendritic cells and macrophages by an acute virus infection. J Leukocyte Biol 77:151–158

    Article  PubMed  CAS  Google Scholar 

  222. Durante-Mangoni E, Wang R, Shaulov A, He Q, Nasser I, Afdhal N, Koziel MJ, Exley MA (2004) Hepatic CD1d expression in hepatitis C virus infection and recognition by resident proinflammatory CD1d-reactive T cells. J Immunol 173:2159–2166

    PubMed  CAS  Google Scholar 

  223. Albarran B, Goncalves L, Salmen S, Borges L, Fields H, Soyano A, Montes H, Berrueta L (2005) Profiles of NK, NKT cell activation and cytokine production following vaccination against hepatitis B. APMIS 113:526–535

    Article  PubMed  CAS  Google Scholar 

  224. Chen Y, Wei H, Gao B, Hu Z, Zheng S, Tian Z (2005) Activation and function of hepatic NK cells in hepatitis B infection: an underinvestigated innate immune response. J Viral Hepat 12:38–45

    Article  PubMed  CAS  Google Scholar 

  225. Khakoo SI, Thio CL, Martin MP, Brooks CR, Gao X, Astemborski J, Cheng J, Goedert JJ, Vlahov D, Hilgartner M, Cox S, Little AM, Alexander GJ, Cramp ME, O’Brien SJ, Rosenberg WM, Thomas DL, Carrington M (2004) HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305:872–874

    Article  PubMed  CAS  Google Scholar 

  226. Chisari FV (1997) Cytotoxic T cells and viral hepatitis. J Clin Invest 99:1472–1477

    Article  PubMed  CAS  Google Scholar 

  227. Wieland S, Thimme R, Purcell RH, Chisari FV (2004) Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci USA 101:6669–6674

    Article  PubMed  CAS  Google Scholar 

  228. Rehermann B, Nascimbeni M (2005) Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 5:215–229

    Article  PubMed  CAS  Google Scholar 

  229. Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH, Chisari FV (2003) CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol 77:68–76

    Article  PubMed  CAS  Google Scholar 

  230. Day CL, Lauer GM, Robbins GK, McGovern B, Wurcel AG, Gandhi RT, Chung RT, Walker BD (2002) Broad specificity of virus-specific CD4+ T-helper-cell responses in resolved hepatitis C virus infection. J Virol 76: 12584–12595

    Article  PubMed  CAS  Google Scholar 

  231. Hiramatsu N, Hayashi N, Katayama K, Mochizuki K, Kawanishi Y, Kasahara A, Fusamoto H, Kamada T (1994) Immunohistochemical detection of Fas antigen in liver tissue of patients with chronic hepatitis C. Hepatology 19: 1354–1359

    Article  PubMed  CAS  Google Scholar 

  232. Rehermann B, Chang KM, McHutchinson J, Kokka R, Houghton M, Rice CM, Chisari FV (1996) Differential cytotoxic T-lymphocyte responsiveness to the hepatitis B and C viruses in chronically infected patients. J Virol 70: 7092–7102

    PubMed  CAS  Google Scholar 

  233. Battegay M, Fikes J, Di Bisceglie AM, Wentworth PA, Sette A, Celis E, Ching WM, Grakoui A, Rice CM, Kurokohchi K (1995) Patients with chronic hepatitis C have circulating cytotoxic T cells which recognize hepatitis C virus-encoded peptides binding to HLA-A2.1 molecules. J Virol 69:2462–2470

    PubMed  CAS  Google Scholar 

  234. Chen MH, Liaw YF, Tsai SL, Huang CY, Kuo GC (1997) Detection of type 2-like T-helper cells in hepatitis C virus infection: implications for hepatitis C virus chronicity. Hepatology 25:449–458

    Article  PubMed  Google Scholar 

  235. Corado J, Toro F, Rivera H, Bianco NE, Deibis L, De Sanctis JB (1997) Impairment of natural killer (NK) cytotoxic activity in hepatitis C virus (HCV) infection. Clin Exp Immunol 109:451–457

    Article  PubMed  CAS  Google Scholar 

  236. Maini MK, Boni C, Ogg GS, King AS, Reignat S, Lee CK, Larrubia JR, Webster GJ, McMichael AJ, Ferrari C, Williams R, Vergani D, Bertoletti A (1999) Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection. Gastroenterology 117: 1386–1396

    Article  PubMed  CAS  Google Scholar 

  237. Sprengers D, van der Molen RG, Kusters JG, De Man RA, Niesters HG, Schalm SW, Janssen HL (2006) Analysis of intrahepatic HBV-specific cytotoxic T-cells during and after acute HBV infection in humans. J Hepatol 45: 182–189

    Article  PubMed  CAS  Google Scholar 

  238. Minutello MA, Pileri P, Unutmaz D, Censini S, Kuo G, Houghton M, Brunetto MR, Bonino F, Abrignani S (1993) Compartmentalization of T lymphocytes to the site of disease: intrahepatic CD4+ T cells specific for the protein NS4 of hepatitis C virus in patients with chronic hepatitis C. J Exp Med 178:17–25

    Article  PubMed  CAS  Google Scholar 

  239. Ferrari C, Urbani S, Penna A, Cavalli A, Valli A, Lamonaca V, Bertoni R, Boni C, Barbieri K, Uggeri J, Fiaccadori F (1999) Immunopathogenesis of hepatitis C virus infection. J Hepatol 31(Suppl 1):31–38

    Article  PubMed  Google Scholar 

  240. Hoffmann RM, Diepolder HM, Zachoval R, Zwiebel FM, Jung MC, Scholz S, Nitschko H, Riethmüller G, Pape GR (1995) Mapping of immunodominant CD4+ T lymphocyte epitopes of hepatitis C virus antigens and their relevance during the course of chronic infection. Hepatology 21: 632–638

    PubMed  CAS  Google Scholar 

  241. Nelson DR, Marousis CG, Davis GL, Rice CM, Wong J, Houghton M, Lau JY (1997) The role of hepatitis C ­virus-specific cytotoxic T lymphocytes in chronic hepatitis C. J Immunol 158:1473–1481

    PubMed  CAS  Google Scholar 

  242. Simmonds P (1995) Variability of hepatitis C virus. Hepatology 21:570–583

    Article  PubMed  CAS  Google Scholar 

  243. Koziel MJ (1999) Cytokines in viral hepatitis. Semin Liver Dis 19:157–169

    Article  PubMed  CAS  Google Scholar 

  244. Powell EE, Edwards-Smith CJ, Hay JL, Clouston AD, Crawford DH, Shorthouse C, Purdie DM, Jonsson JR (2000) Host genetic factors influence disease progression in chronic hepatitis C. Hepatology 31:828–833

    Article  PubMed  CAS  Google Scholar 

  245. De Lalla C, Galli G, Aldrighetti L, Romeo R, Mariani M, Monno A, Nuti S, Colombo M, Callea F, Porcelli SA, Panina-Bordignon P, Abrignani S, Casorati G, Dellabona P (2004) Production of profibrotic cytokines by invariant NKT cells characterizes cirrhosis progression in chronic viral hepatitis. J Immunol 173:1417–1425

    PubMed  Google Scholar 

  246. Sun R, Gao B (2004) Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-gamma). Gastroenterology 127:1525–1539

    Article  PubMed  CAS  Google Scholar 

  247. Reignat S, Webster GJ, Brown D, Ogg GS, King A, Seneviratne SL, Dusheiko G, Williams R, Maini MK, Bertoletti A (2002) Escaping high viral load exhaustion: CD8 cells with altered tetramer binding in chronic hepatitis B virus infection. J Exp Med 195:1089–1101

    Article  PubMed  CAS  Google Scholar 

  248. Boni C, Penna A, Ogg GS, Bertoletti A, Pilli M, Cavallo C, Cavalli A, Urbani S, Boehme R, Panebianco R, Fiaccadori F, Ferrari C (2001) Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy. Hepatology 33: 963–971

    Article  PubMed  CAS  Google Scholar 

  249. Franzese O, Kennedy PT, Gehring AJ, Gotto J, Williams R, Maini MK, Bertoletti A (2005) Modulation of the CD8+-T-cell response by CD4+ CD25+ regulatory T cells in patients with hepatitis B virus infection. J Virol 79:3322–3328

    Article  PubMed  CAS  Google Scholar 

  250. Castellaneta A, Di Leo A, Francavilla R, Margiotta M, Barone M, Amoruso A, Troiani L, Thomson AW, Francavilla A (2006) Functional modification of CD11c+ liver dendritic cells during liver regeneration after partial hepatectomy in mice. Hepatology 43:807–816

    Article  PubMed  CAS  Google Scholar 

  251. Minagawa M, Oya H, Yamamoto S, Simizu T, Bannai M, Kawamura H, Hatakeyama K (2000) Abo T. Intensive expansion of natural killer T cells in the early phase of hepatocyte regeneration after partial hepatectomy in mice and its association with sympathetic nerve activation. 31:907–915

    CAS  Google Scholar 

  252. Golden-Mason L, O’Farrelly C (2002) Having it all? Stem cells, haematopoiesis and lymphopoiesis in adult human liver. Immunol Cell Biol 80:45–51

    Article  PubMed  CAS  Google Scholar 

  253. Vujanovic NL, Polimeno L, Azzarone A, Francavilla A, Chambers WH, Starzl TE, Herberman RB, Whiteside TL (1995) Changes of liver-resident NK cells during regeneration in rats. J Immunol 154:6324–6338

    PubMed  CAS  Google Scholar 

  254. Douagi I, Colucci F, Di Santo JP, Cumano A (2002) Identification of the earliest prethymic bipotent T/NK progenitor in murine fetal liver. Blood 99:463–471

    Article  PubMed  CAS  Google Scholar 

  255. Ito H, Ando K, Nakayama T, Taniguchi M, Ezaki T, Saito K, Takemura M, Sekikawa K, Imawari M, Seishima M, Moriwaki H (2003) Role of Va14 NKT cells in the development of impaired liver regeneration in vivo. Hepatology 38: 1116–1124

    Article  PubMed  CAS  Google Scholar 

  256. Meijer C, Wiezer MJ, Diehl AM, Schouten HJ, Schouten HJ, Meijer S, van Rooijen N, van Lambalgen AA, Dijkstra CD, van Leeuwen PA (2000) Kupffer cell depletion by C12MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy. Liver 20:66–77

    Article  PubMed  CAS  Google Scholar 

  257. Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V, Taub R (1996) Liver failure and defective regeneration in interleukin-6-deficient mice. Science 274: 1379–1383

    Article  PubMed  CAS  Google Scholar 

  258. Li W, Liang X, Kellendonk C, Poli V, Taub R (2002) STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration. J Biol Chem 277: 28411–28417

    Article  PubMed  CAS  Google Scholar 

  259. Yamada Y, Webber EM, Kirillova I, Peschon JJ, Fausto N (1998) Analysis of liver regeneration in mice lacking type1 or type 2 tumor necrosis factor receptor: requirement for type 1 but not type 2 receptor. Hepatology 28: 959–970

    Article  PubMed  CAS  Google Scholar 

  260. Itoh H, Abo T, Sugawara S, Kanno A, Kumagai K (1988) Age-related variation in the proportion and activity of murine liver natural killer cells and their cytotoxcity against regenerating hepatocytes. J Immunol 141:315–323

    PubMed  CAS  Google Scholar 

  261. Francavilla A, Starzl TE, Barone M, Zeng QH, Porter KA, Zeevi A, Markus PM, van den Brink MR, Todo S (1991) Studies on mechanisms of augmentation of liver regeneration by cyclosporine and FK506. Hepatology 14:140–143

    Article  PubMed  CAS  Google Scholar 

  262. Tamura F, Masuhara A, Sakaida I, Fukumoto E, Nakamura T, Okita K (1998) FK506 promotes liver regeneration by suppressing natural killer cell activity. J Gastroenterol Hepatol 13:703–708

    Article  PubMed  CAS  Google Scholar 

  263. Maasho K, Opoku-Anane J, Marusina AI, Coligan JE, Borrego F (2005) Cutting edge: NKG2D is a co-­stimulatory receptor for human naïve CD8+ T cells. J Immuol 174: 4480–4484

    CAS  Google Scholar 

  264. Strick-Marchand H, Di Santos JP, Masse GX, Weiss MC (2008) Lymphocyte support oval-cell-dependent liver regeneration. J Immunol 181:2764–2771

    PubMed  CAS  Google Scholar 

  265. Tanaka N, Tatemoto A, Urabe T, Ono M, Hizuta A, Naomoto Y, Gotoh K, Moreira LF, Orita K (1993) Inhibition of liver regeneration in mice following extended hepatectomy by transfusion of lymphokine activated killer cells. Acta Med Okayama 47:21–28

    PubMed  CAS  Google Scholar 

  266. Nakashima H, Inui T, Habu Y, Kinoshita M, Nagao S, Kawaguchi A, Miura S, Shinomiya N, Yagita H, Seki S (2006) Activation of mouse natural killer T cells accelerates liver regeneration after partial hepatectomy. Gastro­enterology 131:1573–1583

    Article  PubMed  CAS  Google Scholar 

  267. Takehara T, Hayashi N, Mita E, Kanto T, Tatsumi T, Sasaki Y, Kasahara A, Hori M (1998) Delayed Fas-mediated hepatocyte apoptosis during liver regeneration in mice: hepatoprotective role of TNFα. Hepatology 27:1643–1651

    Article  PubMed  CAS  Google Scholar 

  268. Desbarats J, Newell MK (2000) Fas engagement accelerates liver regeneration after partial hepatectomy. Nat Med 6:920–923

    Article  PubMed  CAS  Google Scholar 

  269. Hines IN, Kremer M, Isayama F, Perry AW, Milton RJ, Black AL, Byrd CL, Wheeler MD (2007) Impaired liver regeneration and increased oval cell numbers following T cell-mediated hepatitis. Hepatology 46:229–241

    Article  PubMed  CAS  Google Scholar 

  270. Huang W, Dong Z, Wei H, Ding C, Sun R, Tian Z (2006) Selective elimination of hepatic natural killer T cells with concanavalin A improves liver regeneration in mice. Liver Int 26:339–345

    Article  PubMed  CAS  Google Scholar 

  271. Kim YI, Salvini P, Auxilia F, Calne RY (1988) Effect of cyclosporine A on hepatocyte proliferation after partial hepatectomy in rats: comparison with standard immunosuppressive agents. Am J Surg 155:245–249

    Article  PubMed  CAS  Google Scholar 

  272. Markiewski M (2007) Complement a regulator of prosurvival pathways in liver regeneration. Mol Immunol 44: 213–214

    Article  Google Scholar 

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Bhogal, R.H., Afford, S.C. (2010). Immune Cell Communication and Signaling Systems in Liver Disease. In: Dufour, JF., Clavien, PA. (eds) Signaling Pathways in Liver Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00150-5_8

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