Effector Mechanisms of Nonsuppurative Destructive Cholangitis in Graft-Versus-Host Disease and Allograft Rejection

ABSTRACT

The biliary epithelium provides a physical barrier to ascending infection from the gastrointestinal tract and is also involved in actively regulating the immune response to invading pathogens. Cholangiocytes secrete chemokines and express adhesion molecules that attract effector leukocytes and promote the clearance of infected cells. However in the context of transplantation these properties make cholangiocytes targets for allogeneic cytotoxic T cells, and both graft-versus-host disease and liver allograft rejection are characterized by destruction of intrahepatic bile ducts by infiltrating lymphocytes. The mechanisms of cholangiocyte killing are complex but involve activation of apoptosis by the granzyme/perforin pathway and by activation of death receptors belonging to the tumor necrosis factor (TNF) receptor superfamily, most notably Fas. Fas-dependent apoptosis is carefully regulated by cooperative interactions with other TNF receptors, particularly CD40, that act to amplify autocrine and paracrine expression of Fas ligand and Fas-mediated killing. A better understanding of the molecular control of these processes may explain why bile duct loss continues despite conventional immunosuppression in the vanishing bile duct syndromes, and lead to novel therapies aimed at switching off the chronic inflammatory response and protecting cholangiocytes from apoptosis.

KEYWORDS

Liver allograft rejection - GVHD - apoptosis - vanishing bile duct syndrome - Fas - CD40

REFERENCES

• 1 Burt A D. Primary biliary cirrhosis and other ductopenic diseases.  Clin Liver Dis. 2002;  6 363-380
• 2 Hubscher S G. Histological findings in liver allograft rejection-new insights into the pathogenesis of hepatocellular damage in liver allografts.  Histopathology. 1991;  18 377-383
• 3 Hubscher S G. Pathology of liver allograft rejection.  Transpl Immunol. 1994;  2 118-123
• 4 Scheuer P J. Ludwig Symposium on biliary disorders-part II. Pathologic features and evolution of primary biliary cirrhosis and primary sclerosing cholangitis.  Mayo Clin Proc. 1998;  73 179-183
• 5 Kim W R, Ludwig J, Lindor K D. Variant forms of cholestatic diseases involving small bile ducts in adults.  Am J Gastroenterol. 2000;  95 1130-1138
• 6 Celli A, Que F G. Dysregulation of apoptosis in the cholangiopathies and cholangiocarcinoma.  Semin Liver Dis. 1998;  18 177-185
• 7 Chen X M, Gores G J, Paya C V, LaRusso N F. Cryptosporidium parvum induces apoptosis in biliary epithelia by a Fas/Fas ligand-dependent mechanism.  Am J Physiol. 1999;  277 G599-G608
• 8 Patel T, Gores G J. Apoptosis in liver transplantation: a mechanism contributing to immune modulation, preservation injury, neoplasia, and viral disease.  Liver Transpl Surg. 1998;  4 42-50
• 9 Vierling J M. Animal models for primary sclerosing cholangitis.  Best Pract Res Clin Gastroenterol. 2001;  15 591-610
• 10 Vierling J M. Autoimmune cholangiopathy.  Clin Liver Dis. 1999;  3 571-584
• 11 Vierling J M. Immunology of acute and chronic hepatic allograft rejection.  Liver Transpl Surg. 1999;  5(4 suppl 1) S1-S20
• 12 Reddy P. Pathophysiology of acute graft-versus-host disease.  Hematol Oncol. 2003;  21 149-161
• 13 Reddy P, Ferrara J L. Immunobiology of acute graft-versus-host disease.  Blood Rev. 2003;  17 187-194
• 14 Jamieson N V, Joysey V, Friend P J et al.. Graft-versus-host disease in solid organ transplantation.  Transpl Int. 1991;  4 67-71
• 15 McDonald G B, Shulman H M, Sullivan K M, Spencer G D. Intestinal and hepatic complications of human bone marrow transplantation. Part I.  Gastroenterology. 1986;  90 460-477
• 16 Soiffer R J, Dear K, Rabinowe S N et al.. Hepatic dysfunction following T-cell-depleted allogeneic bone marrow transplantation.  Transplantation. 1991;  52 1014-1019
• 17 McDonald G B, Shulman H M, Sullivan K M, Spencer G D. Intestinal and hepatic complications of human bone marrow transplantation. Part II.  Gastroenterology. 1986;  90 770-784
• 18 Diamond D J, Chang K L, Jenkins K A, Forman S J. Immunohistochemical analysis of T cell phenotypes in patients with graft-versus-host disease following allogeneic bone marrow transplantation.  Transplantation. 1995;  59 1436-1444
• 19 Tanaka M, Umihara J, Shimmoto K et al.. The pathogenesis of graft-versus-host reaction in the intrahepatic bile duct. An immunohistochemical study.  Acta Pathol Jpn. 1989;  39 648-655
• 20 Hubscher S G, Adams D H, Buckels J A, McMaster P, Neuberger J, Elias E. Massive haemorrhagic necrosis of the liver after liver transplantation.  J Clin Pathol. 1989;  42 360-370
• 21 Neuberger J, Adams D H. What is the significance of acute liver allograft rejection?.  J Hepatol. 1998;  29 143-150
• 22 Vierling J M, Fennell Jr R H. Histopathology of early and late human hepatic allograft rejection: evidence of progressive destruction of interlobular bile ducts.  Hepatology. 1985;  5 1076-1082
• 23 Dousset B, Hubscher S G, Padbury R T et al.. Acute liver allograft rejection-is treatment always necessary?.  Transplantation. 1993;  55 529-534
• 24 Goddard S, Adams D H. New approaches to immunosuppression in liver transplantation.  J Gastroenterol Hepatol. 2002;  17 116-126
• 25 Neil D A, Adams D H, Gunson B, Hubscher S G. Is chronic rejection of liver transplants different from graft arteriosclerosis of kidney and heart transplants?.  Transplant Proc. 1997;  29 2539-2540
• 26 Freese D K, Snover D C, Sharp H L, Gross C R, Savick S K, Payne W D. Chronic rejection after liver transplantation: a study of clinical, histopathological and immunological features.  Hepatology. 1991;  13 882-891
• 27 Snover D C, Freese D K, Bloomer J R, Sharp H L, Ascher N L. An analysis of histological prognostic features of liver allograft rejection based on 270 serial biopsies.  Transplant Proc. 1987;  19(1 pt 3) 2457-2458
• 28 Lunz III J G, Contrucci S, Ruppert K et al.. Replicative senescence of biliary epithelial cells precedes bile duct loss in chronic liver allograft rejection: increased expression of p21(WAF1/Cip1) as a disease marker and the influence of immunosuppressive drugs.  Am J Pathol. 2001;  158 1379-1390
• 29 Matsumoto Y, McCaughan G W, Painter D M, Bishop G A. Evidence that portal tract microvascular destruction precedes bile- duct loss in human liver allograft-rejection.  Transplantation. 1993;  56 69-75
• 30 Patel T, Steer C J, Gores G J. Apoptosis and the liver: a mechanism of disease, growth regulation, and carcinogenesis.  Hepatology. 1999;  30 811-815
• 31 Fausto N. Liver regeneration.  J Hepatol. 2000;  32(suppl 1) 19-31
• 32 Palmer J M, Kirby J A, Jones D E. The immunology of primary biliary cirrhosis: the end of the beginning?.  Clin Exp Immunol. 2002;  129 191-197
• 33 Kita H, Mackay I R, Van de Water J, Gershwin M E. The lymphoid liver: considerations on pathways to autoimmune injury.  Gastroenterology. 2001;  120 1485-1501
• 34 Gershwin M E, Ansari A A, Mackay I R et al.. Primary biliary cirrhosis: an orchestrated immune response against epithelial cells.  Immunol Rev. 2000;  174 210-225
• 35 Adams D H, Afford S C. The role of cholangiocytes in the development of chronic inflammatory liver disease.  Front Biosci. 2002;  7 e276-e285
• 36 Vierling J M. Immunological mechanisms of hepatic allograft rejection.  Semin Liver Dis. 1992;  12 16-27
• 37 Message S D, Johnston S L. Host defense function of the airway epithelium in health and disease: clinical background.  J Leukoc Biol. 2004;  75 5-17
• 38 Mahida Y R, Cunliffe R N. Defensins and mucosal protection.  Novartis Found Symp. 2004;  263 71-77
• 39 Nozaki I, Lunz III J G, Specht S et al.. Regulation and function of trefoil factor family 3 expression in the biliary tree.  Am J Pathol. 2004;  165 1907-1920
• 40 Reynoso-Paz S, Coppel R L, Mackay I R, Bass N M, Ansari A A, Gershwin M E. The immunobiology of bile and biliary epithelium.  Hepatology. 1999;  30 351-357
• 41 Kaetzel C S, Robinson J K, Chintalacharuvu K R, Vaerman J P, Lamm M E. The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: a local defense function for IgA.  Proc Natl Acad Sci USA. 1991;  88 8796-8800
• 42 Lamm M E. Current concepts in mucosal immunity. IV. How epithelial transport of IgA antibodies relates to host defense.  Am J Physiol. 1998;  274(4 pt 1) G614-G617
• 43 Coulomb-L’Hermin A, Amara A, Schiff C et al.. Stromal cell-derived factor 1 (SDF-1) and antenatal human B cell lymphopoiesis: expression of SDF-1 by mesothelial cells and biliary ductal plate epithelial cells.  Proc Natl Acad Sci USA. 1999;  96 8585-8590
• 44 Terada R, Yamamoto K, Hakoda T et al.. Stromal cell-derived factor-1 from biliary epithelial cells recruits CXCR4-positive cells: implications for inflammatory liver diseases.  Lab Invest. 2003;  83 665-672
• 45 Morland C M, Fear J, McNab G, Joplin R, Adams D H. Promotion of leukocyte transendothelial cell migration by chemokines derived from human biliary epithelial cells in vitro.  Proc Assoc Am Physicians. 1997;  109 372-382
• 46 Loffreda S, Rai R, Yang S Q, Lin H Z, Diehl A M. Bile ducts and portal and central veins are major producers of tumor necrosis factor alpha in regenerating rat liver.  Gastroenterology. 1997;  112 2089-2098
• 47 Dienes H P, Lohse A W, Gerken G et al.. Bile duct epithelia as target cells in primary biliary cirrhosis and primary sclerosing cholangitis.  Virchows Arch. 1997;  431 119-124
• 48 Leon M P, Bassendine M F, Gibbs P, Thick M, Kirby J A. Immunogenicity of biliary epithelium: study of the adhesive interaction with lymphocytes.  Gastroenterology. 1997;  112 968-977
• 49 Saxena R, Hytiroglou P, Thung S N, Theise N D. Destruction of canals of Hering in primary biliary cirrhosis.  Hum Pathol. 2002;  33 983-988
• 50 Woolf G M, Vierling J M. Disappearing intrahepatic bile ducts: the syndromes and their mechanisms.  Semin Liver Dis. 1993;  3 261-275
• 51 Banchereau J, Steinman R M. Dendritic cells and the control of immunity.  Nature. 1998;  392 245-252
• 52 Reis e Sousa C. Dendritic cells as sensors of infection.  Immunity. 2001;  14 495-498
• 53 Muller W A, Randolph G J. Migration of leukocytes across endothelium and beyond: molecules involved in the transmigration and fate of monocytes.  J Leukoc Biol. 1999;  66 698-704
• 54 Kudo S, Matsuno K, Ezaki T, Ogawa M. A novel migration pathway for rat dendritic cells from the blood: hepatic sinusoids-lymph translocation.  J Exp Med. 1997;  185 777-784
• 55 Matsuno K, Kudo S, Ezaki T. The liver sinusoids as a specialized site for blood-lymph translocation of rat dendritic cells.  Adv Exp Med Biol. 1997;  417 77-81
• 56 Uwatoku R, Suematsu M, Ezaki T et al.. Kupffer cell-mediated recruitment of rat dendritic cells to the liver: roles of N-acetylgalactosamine-specific sugar receptors.  Gastroenterology. 2001;  121 1460-1472
• 57 Mempel T R, Henrickson S E, von Andrian U H. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases.  Nature. 2004;  427 154-159
• 58 Cremer I, Dieu-Nosjean M C, Marechal S et al.. Long-lived immature dendritic cells mediated by TRANCE-RANK interaction.  Blood. 2002;  100 3646-3655
• 59 Goddard S, Youster J, Morgan E, Adams D H. Interleukin-10 secretion differentiates dendritic cells from human liver and skin.  Am J Pathol. 2004;  164 511-519
• 60 Csencsits K, Wood S C, Lu G et al.. Graft rejection mediated by CD4(+) T cells via indirect recognition of alloantigen is associated with a dominant Th2 response.  Eur J Immunol. 2005;  35 843-851
• 61 Stanford R E, Ahmed S, Hodson M, Banner N R, Rose M L. A role for indirect allorecognition in lung transplant recipients with obliterative bronchiolitis.  Am J Transplant. 2003;  3 736-742
• 62 Thomson A W, Lu L. Dendritic cells as regulators of immune reactivity: implications for transplantation.  Transplantation. 1999;  68 1-8
• 63 Howell C D, Yoder T, Claman H N, Vierling J M. Hepatic homing of mononuclear inflammatory cells isolated during murine chronic graft-vs-host disease.  J Immunol. 1989;  143 476-483
• 64 Vierling J M, Howell C D. Disappearing bile ducts: immunologic mechanisms.  Hosp Pract (Off Ed). 1990;  25 141-150
• 65 McCaughan G W, Davies J W, Waugh J A. A quantitative analysis of T-lymphocyte populations in human liver allografts undergoing rejection.  Hepatology. 1990;  12 1305-1313
• 66 McCaughan G W, Bishop G A. Atherosclerosis of the liver allograft.  J Hepatol. 1997;  27 592-598
• 67 Kim Y M, Sachs T, Asavaroengchai W, Bronson R, Sykes M. Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720.  J Clin Invest. 2003;  111 659-669
• 68 Masubuchi Y, Kawaguchi T, Ohtsuki M et al.. FTY720, a novel immunosuppressant, possessing unique mechanisms. IV. Prevention of graft versus host reactions in rats.  Transplant Proc. 1996;  28 1064-1065
• 69 Azhipa O, Kimizuka K, Nakao A et al.. Comparative analysis of the fate of donor dendritic cells and B cells and their influence on alloreactive T cell responses under tacrolimus immunosuppression.  Clin Immunol. 2005;  114 199-209
• 70 Morelli A E, Thomson A W. Dendritic cells: regulators of alloimmunity and opportunities for tolerance induction.  Immunol Rev. 2003;  196 125-146
• 71 McCaughan G W, Gorrell M D, Bishop G A et al.. Molecular pathogenesis of liver disease: an approach to hepatic inflammation, cirrhosis and liver transplant tolerance.  Immunol Rev. 2000;  174 172-191
• 72 Lalor P F, Shields P, Grant A, Adams D H. Recruitment of lymphocytes to the human liver.  Immunol Cell Biol. 2002;  80 52-64
• 73 Campbell J J, Butcher E C. Chemokines in tissue-specific and microenvironment-specific lymphocyte homing.  Curr Opin Immunol. 2000;  12 336-341
• 74 von Andrian U H, Mackay C R. T-cell function and migration. Two sides of the same coin.  N Engl J Med. 2000;  343 1020-1034
• 75 Rot A, von Andrian U H. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells.  Annu Rev Immunol. 2004;  22 891-928
• 76 Gretz J E, Kaldjian E P, Anderson A O, Shaw S. Commentary-sophisticated strategies for information encounter in the lymph-node - the reticular network as a conduit of soluble information and a highway for cell traffic.  J Immunol. 1996;  157 495-499
• 77 Tanaka Y, Adams D H, Hubscher S, Hirano H, Siebenlist U, Shaw S. T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1β.  Nature. 1993;  361 79-82
• 78 Middleton J, Patterson A M, Gardner L, Schmutz C, Ashton B A. Leukocyte extravasation: chemokine transport and presentation by the endothelium.  Blood. 2002;  100 3853-3860
• 79 Klugewitz K, Adams D H, Emoto M, Eulenburg K, Hamann A. The composition of intrahepatic lymphocytes: shaped by selective recruitment?.  Trends Immunol. 2004;  25 590-594
• 80 Crispe I N. Hepatic T cells and liver tolerance.  Nat Rev Immunol. 2003;  3 51-62
• 81 Adams D H, Hubscher S, Fear J, Johnston J, Shaw S, Afford S. Hepatic expression of macrophage inflammatory protein-1 alpha and macrophage inflammatory protein-1 beta after liver transplantation.  Transplantation. 1996;  61 817-825
• 82 Goddard S, Williams A, Morland C et al.. Differential expression of chemokines and chemokine receptors shapes the inflammatory response in rejecting human liver transplants.  Transplantation. 2001;  72 1957-1967
• 83 Steinhoff G, Behrend M, Wonigeit K. Expression of adhesion molecules on lymphocytes/monocytes and hepatocytes in human liver grafts.  Hum Immunol. 1990;  28 123-127
• 84 Steinhoff G, Behrend M, Schrader B, Pichlmayr R. Intercellular immune adhesion molecules in human liver transplants: overview on expression patterns of leukocyte receptor and ligand molecules.  Hepatology. 1993;  18 440-453
• 85 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
• 86 Hamann A, Klugewitz K, Austrup F, Jablonski-Westrich D. Activation induces rapid and profound alterations in the trafficking of T cells.  Eur J Immunol. 2000;  30 3207-3218
• 87 Klugewitz K, Blumenthal-Barby F, Schrage A, Knolle P A, Hamann A, Crispe I N. Immunomodulatory effects of the liver: deletion of activated CD4+ effector cells and suppression of IFN-gamma-producing cells after intravenous protein immunization.  J Immunol. 2002;  169 2407-2413
• 88 Itoh Y, Morita A, Nishioji K et al.. Clinical significance of elevated serum interferon- inducible protein-10 levels in hepatitis C virus carriers with persistently normal serum transaminase levels.  J Viral Hepat. 2001;  8 341-348
• 89 Narumi S, Tominaga Y, Tamaru M et al.. Expression of IFN-inducible protein-10 in chronic hepatitis.  J Immunol. 1997;  158 5536-5544
• 90 Yoong K F, Afford S C, Jones R et al.. Expression and function of CXC and CC chemokines in human malignant liver tumors: a role for human monokine induced by gamma-interferon in lymphocyte recruitment to hepatocellular carcinoma.  Hepatology. 1999;  30 100-111
• 91 Tamaru M, Nishioji K, Kobayashi Y et al.. Liver-infiltrating T lymphocytes are attracted selectively by IFN-inducible protein-10.  Cytokine. 2000;  12 299-308
• 92 Kim C H, Kunkel E J, Boisvert J et al.. Bonzo/CXCR6 expression defines type 1-polarized T-cell subsets with extralymphoid tissue homing potential.  J Clin Invest. 2001;  107 595-601
• 93 Heydtmann M, Lalor P F, Eksteen J A, Hubscher S G, Briskin M, Adams D H. CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed human liver.  J Immunol. 2005;  174 1055-1062
• 94 Shields P L, Morland C M, Salmon M, Qin S, Hubscher S G, Adams D H. Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver.  J Immunol. 1999;  163 6236-6243
• 95 Wysocki C A, Panoskaltsis-Mortari A, Blazar B R, Serody J S. Leukocyte migration and graft-versus-host disease.  Blood. 2005;  105 4191-4199
• 96a Ichiba T, Teshima T, Kuick R et al.. Early changes in gene expression profiles of hepatic GVHD uncovered by oligonucleotide microarrays.  Blood. 2003;  102 763-771
• 96b Curbishley S M, Eksteen B, Lalor P F, Adam D H. CXCR3 activation promotes lymphocyte transendothelial migration across hepatic endothelium under conditions of flow.  Am J Pathol. 2005;  , (in press)
• 97 Duffner U, Lu B, Hildebrandt G C et al.. Role of CXCR3-induced donor T-cell migration in acute GVHD.  Exp Hematol. 2003;  31 897-902
• 98 Murai M, Yoneyama H, Harada A et al.. Active participation of CCR5(+)CD8(+) T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease.  J Clin Invest. 1999;  104 49-57
• 99 New J Y, Li B, Koh W P et al.. T cell infiltration and chemokine expression: relevance to the disease localization in murine graft-versus-host disease.  Bone Marrow Transplant. 2002;  29 979-986
• 100 Serody J S, Cook D N, Kirby S L, Reap E, Shea T C, Frelinger J A. Murine T lymphocytes incapable of producing macrophage inhibitory protein-1 are impaired in causing graft-versus-host disease across a class I but not class II major histocompatibility complex barrier.  Blood. 1999;  93 43-50
• 101 Adams D H, Hubscher S G, Fisher N C, Williams A, Robinson M. Expression of E-selectin and E-selectin ligands in human liver inflammation.  Hepatology. 1996;  24 533-538
• 102 Wong J, Johnston B, Lee S S et al.. A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature.  J Clin Invest. 1997;  99 2782-2790
• 103 Lalor P F, Edwards S, McNab G, Salmi M, Jalkanen S, Adams D H. Vascular adhesion protein-1 mediates adhesion and transmigration of lymphocytes on human hepatic endothelial cells.  J Immunol. 2002;  169 983-992
• 104 Adams D H, Hubscher S G, Shaw J, Rothlein R, Neuberger J M. Intercellular adhesion molecule 1 on liver allografts during rejection.  Lancet. 1989;  2 1122-1125
• 105 Harning R, Koo G C, Szalay J. Regulation of the metastasis of murine ocular melanoma by natural killer cells.  Invest Ophthalmol Vis Sci. 1989;  30 1909-1915
• 106 Wong J, Kubes P, Zhang Y et al.. Role of ICAM-1 in chronic hepatic allograft rejection in the rat.  Am J Physiol Gastrointest Liver Physiol. 2002;  283 G196-G203
• 107 Gassel H J, Otto C, Gassel A M et al.. Tolerance of rat liver allografts induced by short-term selective immunosuppression combining monoclonal antibodies directed against CD25 and CD54 with subtherapeutic cyclosporine.  Transplantation. 2000;  69 1058-1067
• 108 Panoskaltsis-Mortari A, Hermanson J R, Haddad I Y, Wangensteen O D, Blazar B R. Intercellular adhesion molecule-I (ICAM-I, CD54) deficiency segregates the unique pathophysiological requirements for generating idiopathic pneumonia syndrome (IPS) versus graft-versus-host disease following allogeneic murine bone marrow transplantation.  Biol Blood Marrow Transplant. 2001;  7 368-377
• 109 Martelius T, Salaspuro V, Salmi M et al.. Blockade of vascular adhesion protein-1 inhibits lymphocyte infiltration in rat liver allograft rejection.  Am J Pathol. 2004;  165 1993-2001
• 110 Ayres R C, Neuberger J M, Shaw J, Joplin R, Adams D H. Intercellular adhesion molecule-1 and MHC antigens on human intrahepatic bile duct cells: effect of pro-inflammatory cytokines.  Gut. 1993;  34 1245-1249
• 111 Grakoui A, Bromley S K, Sumen C et al.. The immunological synapse: a molecular machine controlling T cell activation.  Science. 1999;  285 221-227
• 112 Yasoshima M, Nakanuma Y, Tsuneyama K, Van de Water J, Gershwin M E. 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. 1995;  175 319-325
• 113 Liang Y, Sasaki K. Expression of adhesion molecules relevant to leukocyte migration on the microvilli of liver peritoneal mesothelial cells.  Anat Rec. 2000;  258 39-46
• 114 Bloom S, Fleming K, Chapman R, Neuberger J, Hubscher S. Inappropriate expression of blood-group antigens in hepatic allografts.  Hepatology. 1994;  19 876-881
• 115 Isse K, Harada K, Zen Y et al.. Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts.  Hepatology. 2005;  41 506-516
• 116 Efsen E, Grappone C, Defranco R M et al.. Up-regulated expression of fractalkine and its receptor CX3CR1 during liver injury in humans.  J Hepatol. 2002;  37 39-47
• 117 Matloubian M, David A, Engel S, Ryan J E, Cyster J G. A transmembrane CXC chemokine is a ligand for HIV-coreceptor Bonzo.  Nat Immunol. 2000;  1 298-304
• 118 Wilbanks A, Zondlo S C, Murphy K et al.. Expression cloning of the strl33/bonzo/tymstr ligand reveals elements of cc, cxc, and cx3c chemokines.  J Immunol. 2001;  166 5145-5154
• 119 Sharron M, Pohlmann S, Price K et al.. Expression and coreceptor activity of STRL33/Bonzo on primary peripheral blood lymphocytes.  Blood. 2000;  96 41-49
• 120 Campbell J J, Qin S, Unutmaz D et al.. Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire.  J Immunol. 2001;  166 6477-6482
• 121 Boisvert J, Kunkel E J, Campbell J J, Keeffe E B, Butcher E C, Greenberg H B. Liver-infiltrating lymphocytes in end-stage hepatitis C virus: subsets, activation status, and chemokine receptor phenotypes.  J Hepatol. 2003;  38 67-75
• 122 Sato T, Thorlacius H, Johnston B et al.. Role for CXCR6 in recruitment of activated CD8+ lymphocytes to inflamed liver.  J Immunol. 2005;  174 277-283
• 123 Leon M P, Bassendine M F, Wilson J L, Ali S, Thick M, Kirby J A. Immunogenicity of biliary epithelium: investigation of antigen presentation to CD4+ T cells.  Hepatology. 1996;  24 561-567
• 124 Leon M P, Bassendine M F, Gibbs P, Thick M, Kirby J A. Immunogenicity of biliary epithelium: study of the adhesive interaction with lymphocytes.  Gastroenterology. 1997;  112(3) 968-977
• 125 Dollinger M M, Howie S E, Plevris J N, Graham A M, Hayes P C, Harrison D J. Intrahepatic proliferation of ‘naïve’ and ‘memory’ T cells during liver allograft rejection: primary immune response within the allograft.  FASEB J. 1998;  12 939-947
• 126 Yang Z F, Ho D W, Chu A C, Wang Y Q, Fan S T. Linking inflammation to acute rejection in small-for-size liver allografts: the potential role of early macrophage activation.  Am J Transplant. 2004;  4 196-209
• 127 Henkart P A. Mechanism of lymphocyte-mediated cytotoxicity.  Annu Rev Immunol. 1985;  3 31-58
• 128 Atkinson E A, Bleackley R C. Mechanisms of lysis by cytotoxic T cells.  Crit Rev Immunol. 1995;  15 359-384
• 129 Simon M M, Waring P, Lobigs M et al.. Cytotoxic T cells specifically induce Fas on target cells, thereby facilitating exocytosis-independent induction of apoptosis.  J Immunol. 2000;  165 3663-3672
• 130 Smyth M J, Kelly J M, Sutton V R et al.. Unlocking the secrets of cytotoxic granule proteins.  J Leukoc Biol. 2001;  70 18-29
• 131 Lieberman J, Fan Z. Nuclear war: the granzyme A-bomb.  Curr Opin Immunol. 2003;  15 553-559
• 132 Bossi G, Griffiths G M. CTL secretory lysosomes: biogenesis and secretion of a harmful organelle.  Semin Immunol. 2005;  17 87-94
• 133 Bossi G, Trambas C, Booth S, Clark R, Stinchcombe J, Griffiths G M. The secretory synapse: the secrets of a serial killer.  Immunol Rev. 2002;  189 152-160
• 134 Ryo R, Saigo K, Hashimoto M et al.. Treatment of post-transfusion graft-versus-host disease with nafamostat mesylate, a serine protease inhibitor.  Vox Sang. 1999;  76 241-246
• 135 Graubert T A, Dipersio J F, Russell J H, Ley T J. Perforin/granzyme-dependent and independent mechanisms are both important for the development of graft-versus-host disease after murine bone marrow transplantation.  J Clin Invest. 1997;  100 904-911
• 136 Pham C T, Ley T J. The role of granzyme B cluster proteases in cell-mediated cytotoxicity.  Semin Immunol. 1997;  9 127-133
• 137 Kuijf M L, Kwekkeboom J, Kuijpers M A et al.. Granzyme expression in fine-needle aspirates from liver allografts is increased during acute rejection.  Liver Transpl. 2002;  8 952-956
• 138 Harada K, Ozaki S, Gershwin M E, Nakanuma Y. Enhanced apoptosis relates to bile duct loss in primary biliary cirrhosis.  Hepatology. 1997;  26 1399-1405
• 139 Jaiswal M, LaRusso N F, Shapiro R A, Billiar T R, Gores G J. Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage in cholangiocytes.  Gastroenterology. 2001;  120 190-199
• 140 Nathan C, Muller W A. Putting the brakes on innate immunity: a regulatory role for CD200?.  Nat Immunol. 2001;  2 17-19
• 141 Afford S C, Randhawa S, Eliopoulos A G, Hubscher S G, Young L S, Adams D H. CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection.  J Exp Med. 1999;  189 441-446
• 142 Afford S C, Ahmed-Choudhury J, Randhawa S et al.. CD40 activation-induced, Fas-dependent apoptosis and NF-kappaB/AP-1 signaling in human intrahepatic biliary epithelial cells.  FASEB J. 2001;  15 2345-2354
• 143 Duffield J S, Forbes S J, Constandinou C M et al.. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair.  J Clin Invest. 2005;  115 56-65
• 144 Ogasawara J, Watanabe-Fukunaga R, Adachi M et al.. Lethal effect of the anti-Fas antibody in mice.  Nature. 1993;  364 806-809 , [published erratum: Nature 1993;365:568]
• 145 Lacronique V, Mignon A, Fabre M et al.. Bcl-2 protects from lethal hepatic apoptosis induced by an anti-Fas antibody in mice.  Nat Med. 1996;  2 80-86
• 146 Galle P R, Hofmann W J, Walczak H et al.. Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage.  J Exp Med. 1995;  182 1223-1230
• 147 Bradham C A, Plumpe J, Manns M P, Brenner D A, Trautwein C. Mechanisms of hepatic toxicity. I. TNF-induced liver injury.  Am J Physiol. 1998;  275(3 pt 1) G387-G392
• 148 Ahmed-Choudhury J, Russell C L, Randhawa S et al.. 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. 2003;  14 1334-1345
• 149 Nagata S, Golstein P. The Fas death factor.  Science. 1995;  267 1449-1456
• 150 Beyaert R, Van L G, Heyninck K, Vandenabeele P. Signaling to gene activation and cell death by tumor necrosis factor receptors and Fas.  Int Rev Cytol. 2002;  214 225-272
• 151 Dempsey P W, Doyle S E, He J Q, Cheng G. The signaling adaptors and pathways activated by TNF superfamily.  Cytokine Growth Factor Rev. 2003;  14 193-209
• 152 Jiang X, Wang X. Cytochrome C-mediated apoptosis.  Annu Rev Biochem. 2004;  73 87-106
• 153 Bossi G, Stinchcombe J C, Page L J, Griffiths G M. Sorting out the multiple roles of Fas ligand.  Eur J Cell Biol. 2000;  79 539-543
• 154 Bossi G, Griffiths G M. Degranulation plays an essential part in regulating cell surface expression of Fas ligand in T cells and natural killer cells.  Nat Med. 1999;  5 90-96
• 155 Kojima Y, Kawasaki-Koyanagi A, Sueyoshi N, Kanai A, Yagita H, Okumura K. Localization of Fas ligand in cytoplasmic granules of CD8+ cytotoxic T lymphocytes and natural killer cells: participation of Fas ligand in granule exocytosis model of cytotoxicity.  Biochem Biophys Res Commun. 2002;  296 328-336
• 156 Tanaka M, Itai T, Adachi M, Nagata S. Downregulation of Fas ligand by shedding.  Nat Med. 1998;  4 31-36
• 157 Eliopoulos A G, Davies C, Knox P G et al.. CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily.  Mol Cell Biol. 2000;  20 5503-5515
• 158 Grell M, Zimmermann G, Gottfried E et al.. Induction of cell death by tumour necrosis factor (TNF) receptor 2, CD40 and CD30: a role for TNF-R1 activation by endogenous membrane- anchored TNF.  EMBO J. 1999;  18 3034-3043
• 159 Van Kooten C, Bancherau J. Functions of CD40 on B cells, dendritic cells and other cells.  Curr Opin Immunol. 1997;  9 330-337
• 160 Young L S, Eliopoulos A G, Gallagher N J, Dawson C W. CD40 and epithelial cells: across the great divide.  Immunol Today. 1998;  19 502-506
• 161 Schmitz M L, Mattioli I, Buss H, Kracht M. NF-kappaB: a multifaceted transcription factor regulated at several levels.  ChemBioChem. 2004;  5 1348-1358
• 162 Hanissian S H, Geha R S. Jak3 is associated with CD40 and is critical for CD40 induction of gene expression in B cells.  Immunity. 1997;  6 379-387
• 163 Hirano T, Ishihara K, Hibi M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors.  Oncogene. 2000;  19 2548-2556
• 164 Levy D E, Lee C K. What does Stat3 do?.  J Clin Invest. 2002;  109 1143-1148
• 165 Kusters S, Tiegs G, Alexopoulou L et al.. In vivo evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis.  Eur J Immunol. 1997;  27 2870-2875
• 166 Stephens J, Cosyns M, Jones M, Hayward A. Liver and bile duct pathology following cryptosporidium parvum infection of immunodeficient mice.  Hepatology. 1999;  30 27-35
• 167 Hayward A R, Levy J, Facchetti F et al.. Cholangiopathy and tumors of the pancreas, liver and biliary tree in boys with X-linked immunodeficiency and hyper-IgM.  J Immunol. 1997;  158 977-983
• 168 Guillonneau C, Louvet C, Renaudin K et al.. The role of TNF-related activation-induced cytokine-receptor activating NF-kappa B interaction in acute allograft rejection and CD40L-independent chronic allograft rejection.  J Immunol. 2004;  172 1619-1629
• 169 Mehling A, Loser K, Varga G et al.. Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity.  J Exp Med. 2001;  194 615-628
• 170 Kiener P A, Moran-Davis P, Rankin B M, Wahl A F, Aruffo A, Hollenbaugh D. Stimulation of CD40 with purified soluble gp39 induces proinflammatory responses in human monocytes.  J Immunol. 1995;  155 4917-4925
• 171 Yellin M J, Winikoff S, Fortune S M et al.. Ligation of CD40 on fibroblasts induces CD54 (ICAM-1) and CD106 (VCAM-1) up-regulation and IL-6 production and proliferation.  J Leukoc Biol. 1995;  58 209-216
• 172 Malik N, Greenfield B W, Wahl A F, Kiener P A. Activation of human monocytes through CD40 induces matrix metalloproteinases.  J Immunol. 1996;  156 3952-3960
• 173 Grewal I S, Flavell R A. CD40 and CD154 in cell-mediated immunity.  Annu Rev Immunol. 1998;  16 111-135
• 174 Streetz K, Leifeld L, Grundmann D et al.. Tumor necrosis factor alpha in the pathogenesis of human and murine fulminant hepatic failure.  Gastroenterology. 2000;  119 446-460
• 175 Plumpe J, Malek N P, Bock C T, Rakemann T, Manns M P, Trautwein C. NF-kappaB determines between apoptosis and proliferation in hepatocytes during liver regeneration.  Am J Physiol Gastrointest Liver Physiol. 2000;  278 G173-G183
• 176 Liedtke C, Trautwein C. A protective role of Stat3 in Fas mediated apoptosis of the liver.  J Hepatol. 2004;  40 874-875
• 177 Spierings D C, de Vries E G, Vellenga E et al.. Tissue distribution of the death ligand TRAIL and its receptors.  J Histochem Cytochem. 2004;  52 821-831
• 178 Mori E, Thomas M, Motoki K et al.. Human normal hepatocytes are susceptible to apoptosis signal mediated by both TRAIL-R1 and TRAIL-R2.  Cell Death Differ. 2004;  11 203-207
• 179 Almasan A, Ashkenazi A. Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy.  Cytokine Growth Factor Rev. 2003;  14 337-348
• 180 Wang S, El-Deiry W S. TRAIL and apoptosis induction by TNF-family death receptors.  Oncogene. 2003;  22 8628-8633
• 181 Mundt B, Kuhnel F, Zender L et al.. Involvement of TRAIL and its receptors in viral hepatitis.  FASEB J. 2003;  17 94-96
• 182 Zender L, Hutker S, Mundt B et al.. NFkappaB-mediated upregulation of bcl-xl restrains TRAIL-mediated apoptosis in murine viral hepatitis.  Hepatology. 2005;  41 280-288
• 183 Higuchi H, Bronk S F, Takikawa Y et al.. The bile acid glycochenodeoxycholate induces trail-receptor 2/DR5 expression and apoptosis.  J Biol Chem. 2001;  276 38610-38618
• 184 Colell A, Coll O, Garcia-Ruiz C et al.. Tauroursodeoxycholic acid protects hepatocytes from ethanol-fed rats against tumor necrosis factor-induced cell death by replenishing mitochondrial glutathione.  Hepatology. 2001;  34 964-971
• 185 Higuchi H, Gores G J. Mechanisms of liver injury: an overview.  Curr Mol Med. 2003;  3 483-490
• 186 Jaeschke H, Gores G J, Cederbaum A I, Hinson J A, Pessayre D, Lemasters J J. Mechanisms of hepatotoxicity.  Toxicol Sci. 2002;  65 166-176
• 187 Graca L, Honey K, Adams E, Cobbold S P, Waldmann H. Cutting edge: anti-CD154 therapeutic antibodies induce infectious transplantation tolerance.  J Immunol. 2000;  165 4783-4786
• 188 Harlan D M, Kirk A D. The future of organ and tissue transplantation: can T-cell costimulatory pathway modifiers revolutionize the prevention of graft rejection?.  JAMA. 1999;  282 1076-1082
• 189 Swain M G et al.. Hepatology.  2005;  , (in press)