T-cell allorecognition of donor glutathione S-transferase T1 in plasma cell-rich rejection
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摘要
AIM To investigate the role of glutathione S-transferase T1 donor-specific T lymphocytes in plasma cell-rich rejection of liver allografts.METHODS The study group included 22 liver transplant patients. Among them, 18 patients were mismatched for the glutathione S-transferase T1(GSTT1) alleles(don+/rec-), and 4 were matched(don+/rec+). Seven of the mismatched patients produced anti-GSTT1 antibodies and developed plasma cell-rich rejection(former de novo immune hepatitis). For the detection of specific Tlymphocytes, peripheral blood mononuclear cells were collected and stored in liquid nitrogen. The memory T cell response was studied by adding to the cell cultures to a mix of 39 custom-made, 15-mer overlapping peptides, which covered the entire GSTT1 amino acid sequence. The specific cellular response to peptides was analyzed by flow cytometry using the markers CD8, CD4, IL-4 and IFNγ.RESULTS Activation of CD8~+ T cells with different peptides was observed exclusively in the group of patients with plasma-cell rich rejection(3 out of 7), with production of IL-4 and/or IFNγ at a rate of 1%-4.92% depending on the peptides. The CD4~+ response was most common and not exclusive for patients with the disease, where 5 out of 7 showed percentages of activated cells from 1.24% to 31.34%. Additionally, two patients without the disease but with the mismatch had cells that became stimulated with some peptides(1.45%-5.18%). Highly unexpected was the finding of a double positive CD4~+CD8~(low) T cell population that showed the highest degree of activation with some of the peptides in 7 patients with the mismatch, in 4 patients with plasma cell-rich rejection and in 3 patients without the disease. Unfortunately, CD4~+CD8~(low) cells represent 1% of the total number of lymphocytes, and stimulation could not be analyzed in 9 patients due to the low number of gated cells. Cells from the 4 patients included as controls did not show activation with any of the peptides. CONCLUSION Patients with GSTT1 mismatch can develop a specific T-cell response, but the potential role of this response in the pathogenesis of plasma cell-rich rejection is unknown.
AIM To investigate the role of glutathione S-transferase T1 donor-specific T lymphocytes in plasma cell-rich rejection of liver allografts.METHODS The study group included 22 liver transplant patients. Among them, 18 patients were mismatched for the glutathione S-transferase T1(GSTT1) alleles(don+/rec-), and 4 were matched(don+/rec+). Seven of the mismatched patients produced anti-GSTT1 antibodies and developed plasma cell-rich rejection(former de novo immune hepatitis). For the detection of specific Tlymphocytes, peripheral blood mononuclear cells were collected and stored in liquid nitrogen. The memory T cell response was studied by adding to the cell cultures to a mix of 39 custom-made, 15-mer overlapping peptides, which covered the entire GSTT1 amino acid sequence. The specific cellular response to peptides was analyzed by flow cytometry using the markers CD8, CD4, IL-4 and IFNγ.RESULTS Activation of CD8~+ T cells with different peptides was observed exclusively in the group of patients with plasma-cell rich rejection(3 out of 7), with production of IL-4 and/or IFNγ at a rate of 1%-4.92% depending on the peptides. The CD4~+ response was most common and not exclusive for patients with the disease, where 5 out of 7 showed percentages of activated cells from 1.24% to 31.34%. Additionally, two patients without the disease but with the mismatch had cells that became stimulated with some peptides(1.45%-5.18%). Highly unexpected was the finding of a double positive CD4~+CD8~(low) T cell population that showed the highest degree of activation with some of the peptides in 7 patients with the mismatch, in 4 patients with plasma cell-rich rejection and in 3 patients without the disease. Unfortunately, CD4~+CD8~(low) cells represent 1% of the total number of lymphocytes, and stimulation could not be analyzed in 9 patients due to the low number of gated cells. Cells from the 4 patients included as controls did not show activation with any of the peptides. CONCLUSION Patients with GSTT1 mismatch can develop a specific T-cell response, but the potential role of this response in the pathogenesis of plasma cell-rich rejection is unknown.
AIM To investigate the role of glutathione S-transferase T1 donor-specific T lymphocytes in plasma cell-rich rejection of liver allografts.METHODS The study group included 22 liver transplant patients. Among them, 18 patients were mismatched for the glutathione S-transferase T1(GSTT1) alleles(don+/rec-), and 4 were matched(don+/rec+). Seven of the mismatched patients produced anti-GSTT1 antibodies and developed plasma cell-rich rejection(former de novo immune hepatitis). For the detection of specific Tlymphocytes, peripheral blood mononuclear cells were collected and stored in liquid nitrogen. The memory T cell response was studied by adding to the cell cultures to a mix of 39 custom-made, 15-mer overlapping peptides, which covered the entire GSTT1 amino acid sequence. The specific cellular response to peptides was analyzed by flow cytometry using the markers CD8, CD4, IL-4 and IFNγ.RESULTS Activation of CD8~+ T cells with different peptides was observed exclusively in the group of patients with plasma-cell rich rejection(3 out of 7), with production of IL-4 and/or IFNγ at a rate of 1%-4.92% depending on the peptides. The CD4~+ response was most common and not exclusive for patients with the disease, where 5 out of 7 showed percentages of activated cells from 1.24% to 31.34%. Additionally, two patients without the disease but with the mismatch had cells that became stimulated with some peptides(1.45%-5.18%). Highly unexpected was the finding of a double positive CD4~+CD8~(low) T cell population that showed the highest degree of activation with some of the peptides in 7 patients with the mismatch, in 4 patients with plasma cell-rich rejection and in 3 patients without the disease. Unfortunately, CD4~+CD8~(low) cells represent 1% of the total number of lymphocytes, and stimulation could not be analyzed in 9 patients due to the low number of gated cells. Cells from the 4 patients included as controls did not show activation with any of the peptides. CONCLUSION Patients with GSTT1 mismatch can develop a specific T-cell response, but the potential role of this response in the pathogenesis of plasma cell-rich rejection is unknown.
引文
1 Aguilera I,Wichmann I,Sousa JM,Bernardos A,Franco E,García-Lozano JR,Nú?ez-Roldán A.Antibodies against glutathione S-transferase T1(GSTT1)in patients with de novo immune hepatitis following liver transplantation.Clin Exp Immunol 2001;126:535-539[PMID:11737073 DOI:10.1046/j.1365-2249.2001.01682.x]
2 Aguilera I,Sousa JM,Gavilán F,Bernardos A,Wichmann I,Nu?ez-Roldán A.Glutathione S-transferase T1 mismatch constitutes a risk factor for de novo immune hepatitis after liver transplantation.Liver Transpl 2004;10:1166-1172[PMID:15350010 DOI:10.1002/lt.20209]
3 Rodriguez-Mahou M,Salcedo M,Fernandez-Cruz E,Tiscar JL,Ba?ares R,Clemente G,Vicario JL,Alvarez E,Rodriguez-Sainz C.Antibodies against glutathione S-transferase T1(GSTT1)in patients with GSTT1 null genotype as prognostic marker:longterm follow-up after liver transplantation.Transplantation 2007;83:1126-1129[PMID:17452905 DOI:10.1097/01.tp.0000259963.47350.da]
4 Demetris AJ,Bellamy C,Hübscher SG,O'Leary J,Randhawa PS,Feng S,Neil D,Colvin RB,Mc Caughan G,Fung JJ,Del Bello A,Reinholt FP,Haga H,Adeyi O,Czaja AJ,Schiano T,Fiel MI,Smith ML,Sebagh M,Tanigawa RY,Yilmaz F,Alexander G,Baiocchi L,Balasubramanian M,Batal I,Bhan AK,Bucuvalas J,Cerski CTS,Charlotte F,de Vera ME,El Monayeri M,Fontes P,Furth EE,Gouw ASH,Hafezi-Bakhtiari S,Hart J,Honsova E,Ismail W,Itoh T,Jhala NC,Khettry U,Klintmalm GB,Knechtle S,Koshiba T,Kozlowski T,Lassman CR,Lerut J,Levitsky J,Licini L,Liotta R,Mazariegos G,Minervini MI,Misdraji J,Mohanakumar T,M?lne J,Nasser I,Neuberger J,O'Neil M,Pappo O,Petrovic L,Ruiz P,Sa?ol?,Sanchez Fueyo A,Sasatomi E,Shaked A,Shiller M,Shimizu T,Sis B,Sonzogni A,Stevenson HL,Thung SN,Tisone G,Tsamandas AC,Wernerson A,Wu T,Zeevi A,Zen Y.2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology:Introduction of Antibody-Mediated Rejection.Am J Transplant 2016;16:2816-2835[PMID:27273869 DOI:10.1111/ajt.13909]
5 Aguilera I,Wichmann I,Gentil MA,Gonzalez-Escribano F,Nu?ez-Roldan A.Alloimmune response against donor glutathione S-transferase T1 antigen in renal transplant recipients.Am JKidney Dis 2005;46:345-350[PMID:16112055 DOI:10.1053/j.ajkd.2005.04.022]
6 Wichmann I,Aguilera I,Sousa JM,Bernardos A,García Nú?ez EJ,Vigil E,Magari?o R,Magari?o I,Torres A,Nú?ez-Roldán A.Antibodies against glutathione S-transferase T1 in non-solid organ transplanted patients.Transfusion 2006;46:1505-1509[PMID:16965576 DOI:10.1111/j.1537-2995.2006.00938.x]
7 Aguilera I,Espigado I,Martinez-Bravo MJ,Tallon I,UrbanoIspizua A,Nu?ez-Roldan A.Glutathione S-transferase T1 is a potential new target for the hepatic component of graft vs host disease after HSCT.Bone Marrow Transplant 2010;45:774-775[PMID:19684638 DOI:10.1038/bmt.2009.206]
8 Bogdanos DP,Gao B,Gershwin ME.Liver immunology.Compr Physiol 2013;3:567-598[PMID:23720323 DOI:10.1002/cphy.c120011]
9 Bumgardner GL,Orosz CG.Unusual patterns of alloimmunity evoked by allogeneic liver parenchymal cells.Immunol Rev 2000;174:260-279[PMID:10807522 DOI:10.1034/j.1600-0528.2002.017409.x]
10 Baker RJ,Hernandez-Fuentes MP,Brookes PA,Chaudhry AN,Cook HT,Lechler RI.Loss of direct and maintenance of indirect alloresponses in renal allograft recipients:implications for the pathogenesis of chronic allograft nephropathy.J Immunol 2001;167:7199-7206[PMID:11739543 DOI:10.4049/jimmunol.167.12.7199]
11 Martínez-Bravo MJ,Calderón-Cabrera C,Márquez-Malaver FJ,Rodríguez N,Guijarro M,Espigado I,Nú?ez-Roldán A,PérezSimón JA,Aguilera I.Mismatch on glutathione S-transferase T1 increases the risk of graft-versus-host disease and mortality after allogeneic stem cell transplantation.Biol Blood Marrow Transplant 2014;20:1356-1362[PMID:24844856 DOI:10.1016/j.bbmt.2014.05.008]
12 Rose ML.Activation of autoimmune B cells and chronic rejection.Transplantation 2005;79:S22-S24[PMID:15699740 DOI:10.1097/01.TP.0000153294.38939.5F]
13 Linton PJ,Harbertson J,Bradley LM.A critical role for B cells in the development of memory CD4 cells.J Immunol 2000;165:5558-5565[PMID:11067910 DOI:10.4049/jimmunol.165.10.5558]
14 Ng YH,Oberbarnscheidt MH,Chandramoorthy HC,Hoffman R,Chalasani G.B cells help alloreactive T cells differentiate into memory T cells.Am J Transplant 2010;10:1970-1980[PMID:20883532 DOI:10.1111/j.1600-6143.2010.03223.x]
15 Zeng Q,Ng YH,Singh T,Jiang K,Sheriff KA,Ippolito R,Zahalka S,Li Q,Randhawa P,Hoffman RA,Ramaswami B,Lund FE,Chalasani G.B cells mediate chronic allograft rejection independently of antibody production.J Clin Invest 2014;124:1052-1056[PMID:24509079 DOI:10.1172/JCI70084]
16 Shiu KY,Mc Laughlin L,Rebollo-Mesa I,Zhao J,Semik V,Cook HT,Roufosse C,Brookes P,Bowers RW,Galliford J,Taube D,Lechler RI,Hernandez-Fuentes MP,Dorling A.B-lymphocytes support and regulate indirect T-cell alloreactivity in individual patients with chronic antibody-mediated rejection.Kidney Int2015;88:560-568[PMID:25830760 DOI:10.1038/ki.2015.100]
17 Gaughan A,Wang J,Pelletier RP,Nadasdy T,Brodsky S,Roy S,Lodder M,Bobek D,Mofatt-Bruce S,Fairchild RL,Henry ML,Hadley GA.Key role for CD4 T cells during mixed antibodymediated rejection of renal allografts.Am J Transplant 2014;14:284-294[PMID:24410909 DOI:10.1111/ajt.12596]
18 Honjo K,Xu Xy,Bucy RP.CD4+T-cell receptor transgenic Tcells alone can reject vascularized heart transplants through the indirect pathway of alloantigen recognition.Transplantation 2004;77:452-455[PMID:14966425 DOI:10.1097/01.TP.0000112937.12491.42]
19 Herkel J,Jagemann B,Wiegard C,Lazaro JF,Lueth S,Kanzler S,Blessing M,Schmitt E,Lohse AW.MHC class II-expressing hepatocytes function as antigen-presenting cells and activate specific CD4 T lymphocyutes.Hepatology 2003;37:1079-1085[PMID:12717388 DOI:10.1053/jhep.2003.50191]
20 Longhi MS,Hussain MJ,Bogdanos DP,Quaglia A,Mieli-Vergani G,Ma Y,Vergani D.Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2.Hepatology 2007;46:472-484[PMID:17559153 DOI:10.1002/hep.21658]
21 Nascimbeni M,Shin EC,Chiriboga L,Kleiner DE,Rehermann B.Peripheral CD4(+)CD8(+)T cells are differentiated effector memory cells with antiviral functions.Blood 2004;104:478-486[PMID:15044252 DOI:10.1182/blood-2003-12-4395]
22 Nascimbeni M,Pol S,Saunier B.Distinct CD4+CD8+doublepositive T cells in the blood and liver of patients during chronic hepatitis B and C.PLo S One 2011;6:e20145[PMID:21647449DOI:10.1371/journal.pone.0020145]
23 Giraldo NA,Bola?os NI,Cuellar A,Guzman F,Uribe AM,Bedoya A,Olaya N,CucunubáZM,Roa N,Rosas F,Velasco V,Puerta CJ,González JM.Increased CD4+/CD8+double-positive T cells in chronic Chagasic patients.PLo S Negl Trop Dis 2011;5:e1294[PMID:21886854 DOI:10.1371/journal.pntd.0001294]
24 Suni MA,Ghanekar SA,Houck DW,Maecker HT,Wormsley SB,Picker LJ,Moss RB,Maino VC.CD4(+)CD8(dim)T lymphocytes exhibit enhanced cytokine expression,proliferation and cytotoxic activity in response to HCMV and HIV-1 antigens.Eur J Immunol2001;31:2512-2520[PMID:11500836 DOI:10.1002/1521-4141(200108)31:8<2512::AID-IMMU2512>3.0.CO;2-M]
25 Hübscher SG.What is the long-term outcome of the liver allograft?J Hepatol 2011;55:702-717[PMID:21426919 DOI:10.1016/j.jhep.2011.03.005]
26 Sebagh M,Castillo-Rama M,Azoulay D,Coilly A,Delvart V,Allard MA,Dos Santos A,Johanet C,Roque-Afonso AM,Saliba F,Duclos-Vallée JC,Samuel D,Demetris AJ.Histologic findings predictive of a diagnosis of de novo autoimmune hepatitis after liver transplantation in adults.Transplantation 2013;96:670-678[PMID:23982338 DOI:10.1097/TP.0b013e31829eda7f]
2 Aguilera I,Sousa JM,Gavilán F,Bernardos A,Wichmann I,Nu?ez-Roldán A.Glutathione S-transferase T1 mismatch constitutes a risk factor for de novo immune hepatitis after liver transplantation.Liver Transpl 2004;10:1166-1172[PMID:15350010 DOI:10.1002/lt.20209]
3 Rodriguez-Mahou M,Salcedo M,Fernandez-Cruz E,Tiscar JL,Ba?ares R,Clemente G,Vicario JL,Alvarez E,Rodriguez-Sainz C.Antibodies against glutathione S-transferase T1(GSTT1)in patients with GSTT1 null genotype as prognostic marker:longterm follow-up after liver transplantation.Transplantation 2007;83:1126-1129[PMID:17452905 DOI:10.1097/01.tp.0000259963.47350.da]
4 Demetris AJ,Bellamy C,Hübscher SG,O'Leary J,Randhawa PS,Feng S,Neil D,Colvin RB,Mc Caughan G,Fung JJ,Del Bello A,Reinholt FP,Haga H,Adeyi O,Czaja AJ,Schiano T,Fiel MI,Smith ML,Sebagh M,Tanigawa RY,Yilmaz F,Alexander G,Baiocchi L,Balasubramanian M,Batal I,Bhan AK,Bucuvalas J,Cerski CTS,Charlotte F,de Vera ME,El Monayeri M,Fontes P,Furth EE,Gouw ASH,Hafezi-Bakhtiari S,Hart J,Honsova E,Ismail W,Itoh T,Jhala NC,Khettry U,Klintmalm GB,Knechtle S,Koshiba T,Kozlowski T,Lassman CR,Lerut J,Levitsky J,Licini L,Liotta R,Mazariegos G,Minervini MI,Misdraji J,Mohanakumar T,M?lne J,Nasser I,Neuberger J,O'Neil M,Pappo O,Petrovic L,Ruiz P,Sa?ol?,Sanchez Fueyo A,Sasatomi E,Shaked A,Shiller M,Shimizu T,Sis B,Sonzogni A,Stevenson HL,Thung SN,Tisone G,Tsamandas AC,Wernerson A,Wu T,Zeevi A,Zen Y.2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology:Introduction of Antibody-Mediated Rejection.Am J Transplant 2016;16:2816-2835[PMID:27273869 DOI:10.1111/ajt.13909]
5 Aguilera I,Wichmann I,Gentil MA,Gonzalez-Escribano F,Nu?ez-Roldan A.Alloimmune response against donor glutathione S-transferase T1 antigen in renal transplant recipients.Am JKidney Dis 2005;46:345-350[PMID:16112055 DOI:10.1053/j.ajkd.2005.04.022]
6 Wichmann I,Aguilera I,Sousa JM,Bernardos A,García Nú?ez EJ,Vigil E,Magari?o R,Magari?o I,Torres A,Nú?ez-Roldán A.Antibodies against glutathione S-transferase T1 in non-solid organ transplanted patients.Transfusion 2006;46:1505-1509[PMID:16965576 DOI:10.1111/j.1537-2995.2006.00938.x]
7 Aguilera I,Espigado I,Martinez-Bravo MJ,Tallon I,UrbanoIspizua A,Nu?ez-Roldan A.Glutathione S-transferase T1 is a potential new target for the hepatic component of graft vs host disease after HSCT.Bone Marrow Transplant 2010;45:774-775[PMID:19684638 DOI:10.1038/bmt.2009.206]
8 Bogdanos DP,Gao B,Gershwin ME.Liver immunology.Compr Physiol 2013;3:567-598[PMID:23720323 DOI:10.1002/cphy.c120011]
9 Bumgardner GL,Orosz CG.Unusual patterns of alloimmunity evoked by allogeneic liver parenchymal cells.Immunol Rev 2000;174:260-279[PMID:10807522 DOI:10.1034/j.1600-0528.2002.017409.x]
10 Baker RJ,Hernandez-Fuentes MP,Brookes PA,Chaudhry AN,Cook HT,Lechler RI.Loss of direct and maintenance of indirect alloresponses in renal allograft recipients:implications for the pathogenesis of chronic allograft nephropathy.J Immunol 2001;167:7199-7206[PMID:11739543 DOI:10.4049/jimmunol.167.12.7199]
11 Martínez-Bravo MJ,Calderón-Cabrera C,Márquez-Malaver FJ,Rodríguez N,Guijarro M,Espigado I,Nú?ez-Roldán A,PérezSimón JA,Aguilera I.Mismatch on glutathione S-transferase T1 increases the risk of graft-versus-host disease and mortality after allogeneic stem cell transplantation.Biol Blood Marrow Transplant 2014;20:1356-1362[PMID:24844856 DOI:10.1016/j.bbmt.2014.05.008]
12 Rose ML.Activation of autoimmune B cells and chronic rejection.Transplantation 2005;79:S22-S24[PMID:15699740 DOI:10.1097/01.TP.0000153294.38939.5F]
13 Linton PJ,Harbertson J,Bradley LM.A critical role for B cells in the development of memory CD4 cells.J Immunol 2000;165:5558-5565[PMID:11067910 DOI:10.4049/jimmunol.165.10.5558]
14 Ng YH,Oberbarnscheidt MH,Chandramoorthy HC,Hoffman R,Chalasani G.B cells help alloreactive T cells differentiate into memory T cells.Am J Transplant 2010;10:1970-1980[PMID:20883532 DOI:10.1111/j.1600-6143.2010.03223.x]
15 Zeng Q,Ng YH,Singh T,Jiang K,Sheriff KA,Ippolito R,Zahalka S,Li Q,Randhawa P,Hoffman RA,Ramaswami B,Lund FE,Chalasani G.B cells mediate chronic allograft rejection independently of antibody production.J Clin Invest 2014;124:1052-1056[PMID:24509079 DOI:10.1172/JCI70084]
16 Shiu KY,Mc Laughlin L,Rebollo-Mesa I,Zhao J,Semik V,Cook HT,Roufosse C,Brookes P,Bowers RW,Galliford J,Taube D,Lechler RI,Hernandez-Fuentes MP,Dorling A.B-lymphocytes support and regulate indirect T-cell alloreactivity in individual patients with chronic antibody-mediated rejection.Kidney Int2015;88:560-568[PMID:25830760 DOI:10.1038/ki.2015.100]
17 Gaughan A,Wang J,Pelletier RP,Nadasdy T,Brodsky S,Roy S,Lodder M,Bobek D,Mofatt-Bruce S,Fairchild RL,Henry ML,Hadley GA.Key role for CD4 T cells during mixed antibodymediated rejection of renal allografts.Am J Transplant 2014;14:284-294[PMID:24410909 DOI:10.1111/ajt.12596]
18 Honjo K,Xu Xy,Bucy RP.CD4+T-cell receptor transgenic Tcells alone can reject vascularized heart transplants through the indirect pathway of alloantigen recognition.Transplantation 2004;77:452-455[PMID:14966425 DOI:10.1097/01.TP.0000112937.12491.42]
19 Herkel J,Jagemann B,Wiegard C,Lazaro JF,Lueth S,Kanzler S,Blessing M,Schmitt E,Lohse AW.MHC class II-expressing hepatocytes function as antigen-presenting cells and activate specific CD4 T lymphocyutes.Hepatology 2003;37:1079-1085[PMID:12717388 DOI:10.1053/jhep.2003.50191]
20 Longhi MS,Hussain MJ,Bogdanos DP,Quaglia A,Mieli-Vergani G,Ma Y,Vergani D.Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2.Hepatology 2007;46:472-484[PMID:17559153 DOI:10.1002/hep.21658]
21 Nascimbeni M,Shin EC,Chiriboga L,Kleiner DE,Rehermann B.Peripheral CD4(+)CD8(+)T cells are differentiated effector memory cells with antiviral functions.Blood 2004;104:478-486[PMID:15044252 DOI:10.1182/blood-2003-12-4395]
22 Nascimbeni M,Pol S,Saunier B.Distinct CD4+CD8+doublepositive T cells in the blood and liver of patients during chronic hepatitis B and C.PLo S One 2011;6:e20145[PMID:21647449DOI:10.1371/journal.pone.0020145]
23 Giraldo NA,Bola?os NI,Cuellar A,Guzman F,Uribe AM,Bedoya A,Olaya N,CucunubáZM,Roa N,Rosas F,Velasco V,Puerta CJ,González JM.Increased CD4+/CD8+double-positive T cells in chronic Chagasic patients.PLo S Negl Trop Dis 2011;5:e1294[PMID:21886854 DOI:10.1371/journal.pntd.0001294]
24 Suni MA,Ghanekar SA,Houck DW,Maecker HT,Wormsley SB,Picker LJ,Moss RB,Maino VC.CD4(+)CD8(dim)T lymphocytes exhibit enhanced cytokine expression,proliferation and cytotoxic activity in response to HCMV and HIV-1 antigens.Eur J Immunol2001;31:2512-2520[PMID:11500836 DOI:10.1002/1521-4141(200108)31:8<2512::AID-IMMU2512>3.0.CO;2-M]
25 Hübscher SG.What is the long-term outcome of the liver allograft?J Hepatol 2011;55:702-717[PMID:21426919 DOI:10.1016/j.jhep.2011.03.005]
26 Sebagh M,Castillo-Rama M,Azoulay D,Coilly A,Delvart V,Allard MA,Dos Santos A,Johanet C,Roque-Afonso AM,Saliba F,Duclos-Vallée JC,Samuel D,Demetris AJ.Histologic findings predictive of a diagnosis of de novo autoimmune hepatitis after liver transplantation in adults.Transplantation 2013;96:670-678[PMID:23982338 DOI:10.1097/TP.0b013e31829eda7f]
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