The role of natural killer cells in hepatitis C infection

Antiviral Therapy

Volumn 18, Issue 7, 2013, Pages 853-865

  Howell, Jessica ^a,b,c   Visvanathan, Kumar ^c  

^a AUSTIN HOSPITAL   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

^c MONASH UNIVERSITY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; NATURAL KILLER CELL RECEPTOR;

ACCESSORY CELL; ADAPTIVE IMMUNITY; CELL FUNCTION; CYTOTOXICITY; DEGRANULATION; DRUG RESPONSE; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; INNATE IMMUNITY; LIVER FIBROSIS; NATURAL KILLER CELL; NONHUMAN; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE ACTIVATION; VIRAL CLEARANCE; VIRUS INFECTION;

ADAPTIVE IMMUNITY; HEPACIVIRUS; HEPATITIS C; HEPATITIS C, CHRONIC; HUMANS; IMMUNITY, INNATE; KILLER CELLS, NATURAL; LIVER; LIVER CIRRHOSIS; LYMPHOCYTE ACTIVATION; NATURAL KILLER T-CELLS; RECEPTORS, NATURAL KILLER CELL; RECEPTORS, PATTERN RECOGNITION;

EID: 84892689414     PISSN: 13596535     EISSN: 20402058     Source Type: Journal    
DOI: 10.3851/IMP2565     Document Type: Review

References (117)

1. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997;349:825-832.
2. He XS, Rehermann B, Lopez-Labrador FX, et al. Quantitative analysis of hepatitis C virus-specific CD8 (*) T cells in peripheral blood and liver using peptide-MHC tetramers. Proc Natl Acad Sci U S A 1999;96:5692-5697.
3. Shackel NA, Jamias J, Rahman W, et al. Early high peak hepatitis C viral load levels independently predict hepatitis C-related liver failure post-liver transplantation. Liver Transpl 2009;15:709-718.
4. Flodstrom-Tullberg M, Bryceson YT, Shi FD, Hoglund P, Ljunggren HG. Natural killer cells in human autoimmunity. Curr Opin Immunol 2009;21:634-640.
5. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol 2008;9:503-510.
6. Malmberg KJ, Bryceson YT, Carlsten M, et al. NK cellmediated targeting of human cancer and possibilities for new means of immunotherapy. Cancer Immunol Immunother 2008;57:1541-1552.
7. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G. Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 2002;195:327-333.
8. Piccioli D, Sbrana S, Melandri E, Valiante NM. Contactdependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med 2002;195:335-341.
9. Raulet DH. Interplay of natural killer cells and their receptors with the adaptive immune response. Nat Immunol 2004;5:996-1002.
10. Cheent K, Khakoo SI. Natural killer cells and hepatitis C: action and reaction. Cut 2011;60:268-278.
11. Corado J, Toro F, Rivera H, Bianco NE, Deibis L, De Sanctis JB. Impairment of natural killer (NK) cytotoxic activity in hepatitis C virus (HCV) infection. Clin Exp Immunol 1997;109:451-457.
12. Ahlenstiel G, Edlich B, Hogdal LJ, et al. Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C. Gastroenterology 2011;141:1231-1239.
13. Harrison RJ, Ettorre A, Little AM, Khakoo SI. Association of NKG2A with treatment for chronic hepatitis C virus infection. Clin Exp Immunol 2010;161:306-314.
14. Gerosa F, Gobbi A, Zorzi P, et al. The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions. J Immunol 2005;174:727-734.
15. Bryceson YT, Chiang SC, Darmanin S, et al. Molecular mechanisms of natural killer cell activation. J Innate Immun 2011;3:216-226.
16. Cooper MA, Fehniger TA, Turner SC, et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56 (bright) subset. Blood 2001;97:3146-3151.
17. Chan A, Hong DL, Atzberger A, et al. CD56bright human NK cells differentiate into CD56dim cells: role of contact with peripheral fibroblasts. J Immunol 2007;179:89-94.
18. Bjorkstrom NK, Riese P, Heuts F, et al. Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education. Blood 2010;116:3853-3864.
19. + NK-cell subset. Blood 2010;116:3865-3874.
20. + natural T cells with distinct cytotoxic activities and Thl, Th2, and ThO cytokine secretion patterns. J Immunol 1999;163:2314-2321.
21. Wisse E, Van't Noordende JM, Van Der Meulen J, Daems WT. The pit cell: description of a new type of cell occurring in rat liver sinusoids and peripheral blood. Cell Tissue Res 1976;173:423-435.
22. Lassen MG, Lukens JR, Dolina JS, Brown MG, Hahn YS. Intrahepatic IL-10 maintains NKG2A*Ly49 liver NK cells in a functionally hyporesponsive state. J Immunol 2010;184:2693-2701.
23. Melhem A, Muhanna N, Bishara A, et al. Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J Hepatol 2006;45:60-71.
24. Gao B, Radaeva S, Jeong WI. Activation of natural killer cells inhibits liver fibrosis: a novel strategy to treat liver fibrosis. Expert Rev Gastroenterol Hepatol 2007;1:173-180.
25. Morishima C, Paschal DM, Wang CC, et al. Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. Hepatology 2006;43:573-580.
26. Gregoire C, Chasson L, Luci C, et al. The trafficking of natural killer cells. Immunol Rev 2007;220:169-182.
27. Bryceson YT, Ljunggren HG, Long EO. Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood 2009;114:2657-2666.
28. Lee SH, Yun S, Piao ZH, et al. Suppressor of cytokine signaling 2 regulates IL-15-primed human NK cell function via control of phosphorylated Pyk2. J Immunol 2010;185:917-928.
29. Golden-Mason L, Madrigal-Estebas L, McGrath E, et al. Altered natural killer cell subset distributions in resolved and persistent hepatitis C virus infection following single source exposure. Gut 2008;57:1121-1128.
30. Siegal FP, Kadowaki N, Shodell M, et al. The nature of the principal type 1 interferon-producing cells in human blood. Science 1999;284:1835-1837.
31. Trinchieri G, Santoli D. Anti-viral activity induced by culturing lymphocytes with tumor-derived or virustransformed cells. Enhancement of human natural killer cell activity by interferon and antagonistic inhibition of susceptibility of target cells to lysis. J Exp Med 1978;147:1314-1333.
32. Perussia B, Fanning V, Trinchieri G. A leukocyte subset bearing HLA-DR antigens is responsible for in vitro alpha interferon production in response to viruses. Nat Immun Cell Growth Regul 1985;4:120-137.
33. Dolganiuc A, Chang S, Kodys K, et al. Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol 2006;177:6758-6768.
34. Szabo G, Chang S, Dolganiuc A. Altered innate immunity in chronic hepatitis C infection: cause or effect? Hepatology 2007;46:1279-1290.
35. Khakoo SI, Carrington M. KIR and disease: a model system or system of models? Immunol Rev 2006;214:186-201.
36. Vilches C, Parham P. KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol 2002;20:217-251.
37. Boyington JC, Sun PD. A structural perspective on MHC class I recognition by killer cell immunoglobulin-like receptors. Mol Immunol 2002;38:1007-1021.
38. Faridi RM, Agrawal S. Killer immunoglobulin-like receptors (KIRs) and HLA-C allorecognition patterns implicative of dominant activation of natural killer cells contribute to recurrent miscarriages. Hum Reprod 2011;26:491-497.
39. Seich Al Basatena NK, Macnamara A, Vine AM, et al. KIR2DL2 enhances protective and detrimental HLA class I-mediated immunity in chronic viral infection. PLoS Pathog 2011;7:el002270.
40. Khakoo SI, Thio CL, Martin MP, et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 2004;305:872-874.
41. Ohira M, Ishiyama K, Tanaka Y, et al. Adoptive immunotherapy with liver allograft-derived lymphocytes induces anti-HCV activity after liver transplantation in humans and humanized mice. J Clin Invest 2009;119:3226-3235.
42. + regulatory T cells. J Leukoc Biol 2007;81:144-153.
43. Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 2008;9:495-502.
44. + T-cells or B-cells in parallel with CD4*CDC25high T-cells control potentially viremia in blood donors with HCV. J Med Virol 2009;81:49-59.
45. Ma X, Chow JM, Gri G, et al. The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells. J Exp Med 1996;183:147-157.
46. Cooper MA, Colonna M, Yokoyama WM. Hidden talents of natural killers: NK cells in innate and adaptive immunity. EMBO Rep 2009;10:1103-1110.
47. Dustin ML, Long EO. Cytotoxic immunological synapses. Immunol Rev 2010;235:24-34.
48. Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant 2006;6:783-790.
49. Lucin P, Jonjic S, Messerle M, Polic B, Hengel H, Koszinowski UH. Late phase inhibition of murine cytomegalovirus replication by synergistic action of interferon-gamma and tumour necrosis factor. J Gen Virol 1994;75:101-110.
50. Heise MT, Virgin HW, IV The T-cell-independent role of gamma interferon and tumor necrosis factor alpha in macrophage activation during murine cytomegalovirus and herpes simplex virus infections. J Virol 1995;69:904-909.
51. MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol 1997;15:323-350.
52. Orange JS, Biron CA. An absolute and restricted requirement for IL-12 in natural killer cell IFN-gamma production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections. J Immunol 1996;156:1138-1142.
53. Wang SH, Huang CX, Ye L, et al. Natural killer cells suppress full cycle HCV infection of human hepatocytes. J Viral Hepat 2008;15:855-864.
54. Coccia EM, Uze G, Pellegrini S. Negative regulation of type I interferon signaling: facts and mechanisms. Cell Mol Biol 2006;52:77-87.
55. Hart OM, Athie-Morales V, O'Connor GM, Gardiner CM. TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-gamma production. J Immunol 2005;175:1636-1642.
56. Qiu F, Maniar A, Diaz MQ, Chapoval AI, Medvedev AE. Activation of cytokine-producing and antitumor activities of natural killer cells and macrophages by engagement of Toll-like and NOD-like receptors. Innate Immun 2011;17:375-387.
57. Aste-Amezaga M, D'Andrea A, Kubin M, Trinchieri G. Cooperation of natural killer cell stimulatory factor/interleukin-12 with other stimuli in the induction of cytokines and cytotoxic cell-associated molecules in human T and NK cells. Cell Immunol 1994;156:480-492.
58. Ebihara T, Azuma M, Oshiumi H, et al. Identification of a polyl:C-inducible membrane protein that participates in dendritic cell-mediated natural killer cell activation. J Exp Med 2010;207:2675-2687.
59. Matsumoto M, Funami K, Tanabe M, et al. Subcellular localization of Toll-like receptor 3 in human dendritic cells. J Immunol 2003;171:3154-3162.
60. McCartney S, Vermi W, Gilfillan S, et al. Distinct and complementary functions of MDA5 and TLR3 in poly (I:C) - mediated activation of mouse NK cells. J Exp Med 2009;206:2967-2976.
61. Foy E, Li K, Sumpter R, Jr., et al. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc Natl Acad Sci USA 2005;102:2986-2991.
62. Loo YM, Owen DM, Li K, et al. Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. Proc Natl Acad Sci USA 2006;103:6001-6006.
63. Godfrey DI, Hammond KJ, Poulton LD, Smyth MJ, Baxter AG. NKT cells: facts, functions and fallacies. Immunol Today 2000;21:573-583.
64. Lee PT, Benlagha K, Teyton L, Bendelac A. Distinct functional lineages of human V (alpha) 24 natural killer T cells. J Exp Med 2002;195:637-641.
65. Kanto T, Hayashi N. Innate immunity in hepatitis C virus infection: Interplay among dendritic cells, natural killer cells and natural killer T cells. Hepatol Res 2007;37 Suppl 3:S319-S326.
66. Amadei B, Urbani S, Cazaly A, et al. Activation of natural killer cells during acute infection with hepatitis C virus. Gastroenterology 2010;138:1536-1545.
67. Golden-Mason L, Cox AL, Randall JA, Cheng L, Rosen HR. Increased natural killer cell cytotoxicity and NKp30 expression protects against hepatitis C virus infection in high-risk individuals and inhibits replication in vitro. Hepatology 2010;52:1581-1589.
68. Pelletier S, Drouin C, Bedard N, Khakoo SI, Bruneau J, Shoukry NH. Increased degranulation of natural killer cells during acute HCV correlates with the magnitude of virusspecific T cell responses. J Hepatol 2010;53:805-816.
69. Bonorino P, Ramzan M, Camous X, et al. Fine characterization of intrahepatic NK cells expressing natural killer receptors in chronic hepatitis B and C. J Hepatol 2009;51:458-467.
70. + NK cells in acute HCV infection may predict viral clearance. J Hepatol 2011;55:278-288.
71. Miyagi T, Takehara T, Nishio K, et al. Altered interferonalpha-signaling in natural killer cells from patients with chronic hepatitis C virus infection. J Hepatol 2010;53:424-430.
72. Knapp S, Warshow U, Hegazy D, et al. Consistent beneficial effects of killer cell immunoglobulin-like receptor 2DL3 and group 1 human leukocyte antigen-C following exposure to hepatitis C virus. Hepatology 2010;51:1168-1175.
73. Romero V, Azocar J, Zuniga J, et al. Interaction of NK inhibitory receptor genes with HLA-C and MHC class II alleles in hepatitis C virus infection outcome. Mol Immunol 2008;45:2429-2436.
74. Kim AY, Kuntzen T, Timm J, et al. Spontaneous control of HCV is associated with expression of HLA-B 57 and preservation of targeted epitopes. Gastroenterology 2011;140:686-696.
75. Strong RK, Holmes MA, Li P, Braun L, Lee N, Geraghty DE. HLA-E allelic variants. Correlating differential expression, peptide affinities, crystal structures, and thermal stabilities. J Biol Chem 2003;278:5082-5090.
76. Dessouki O, Kamiya Y, Nagahama H, et al. Chronic hepatitis C viral infection reduces NK cell frequency and suppresses cytokine secretion: reversion by antiviral treatment. Biochem Biophys Res Commun 2010;393:331-337.
77. +) T cells and natural killer cells in cirrhotic livers with hepatitis C may be involved in their susceptibility to hepatocellular carcinoma. Hepatology 2000;32:962-969.
78. Crotta S, Stilla A, Wack A, et al. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J Exp Med 2002;195:35-41.
79. Bonavita MS, Franco A, Paroli M, et al. Normalization of depressed natural killer activity after interferon-alpha therapy is associated with a low frequency of relapse in patients with chronic hepatitis C. Int J Tissue React 1993;15:11-16.
80. + peripheral blood lymphocyte counts, low perforin expression and the impairment of natural killer cell activity is associated with chronic hepatitis C virus infection. J Hepatol 2002;37:514-522.
81. Yoon JC, Shiina M, Ahlenstiel G, Rehermann B. Natural killer cell function is intact after direct exposure to infectious hepatitis C virions. Hepatology 2009;49:12-21.
82. Düesberg U, Schneiders AM, Flieger D, Inchauspe G, Sauerbruch T, Spengler U. Natural cytotoxicity and antibodydependent cellular cytotoxicity (ADCC) is not impaired in patients suffering from chronic hepatitis C. J Hepatol 2001;35:650-657.
83. +) innate lymphocyte populations associated with severity of hepatitis C virus recurrence. Liver Transpl 2008;14:31-40.
84. Meier UC, Owen RE, Taylor E, et al. Shared alterations in NK cell frequency, phenotype, and function in chronic human immunodeficiency virus and hepatitis C virus infections. J Virol 2005;79:12365-12374.
85. Jinushi M, Takehara T, Tatsumi T, et al. Autocrine/paracrine IL-15 that is required for type I IFN-mediated dendritic cell expression of MHC class I-related chain A and B is impaired in hepatitis C virus infection. J Immunol 2003;171:5423-5429.
86. Nattermann J, Feldmann G, Ahlenstiel G, Langhans B, Sauerbruch T, Spengler U. Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut 2006;55:869-877.
87. De Maria A, Fogli M, Mazza S, et al. Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients. Eur J Immunol 2007;37:445-455.
88. Crotta S, Brazzoli M, Piccioli D, Valiante NM, Wack A. Hepatitis C virions subvert natural killer cell activation to generate a cytokine environment permissive for infection. J Hepatol 2010;52:183-190.
89. Abel M, Sene D, Pol S, et al. Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection. Hepatology 2006;44:1607-1616.
90. +) T cell population in chronic hepatitis C virus infection. J Clin Invest 2004;113:963-972.
91. Tseng CT, Klimpel GR. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J Exp Med 2002;195:43-49.
92. Eid AJ, Brown RA, Paya CV, Razonable RR. Association between toll-like receptor polymorphisms and the outcome of liver transplantation for chronic hepatitis C virus. Transplantation 2007;84:511-516.
93. Farag MM, Weigand K, Encke J, Momburg F. Activation of natural killer cells by hepatitis C virus particles in vitro. Clin Exp Immunol 2011;165:352-362.
94. Jinushi M, Takehara T, Tatsumi T, et al. Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol 2004;173:6072-6081.
95. Jinushi M, Takehara T, Tatsumi T, et al. Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. J Immunol 2004;173:6072-6081.
96. Jinushi M, Takehara T, Tatsumi T, et al. Impairment of natural killer cell and dendritic cell functions by the soluble form of MHC class I-related chain A in advanced human hepatocellular carcinomas. J Hepatol 2005;43:1013-1020.
97. Andrade CF, Waddell TK, Keshavjee S, Liu M. Innate immunity and organ transplantation: the potential role of toll-like receptors. Am J Transplant 2005;5:969-975.
98. Ahlenstiel G, Titerence RH, Koh C, et al. Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa- dependent manner. Gastroenterology 2010;138:325-335.
99. Nattermann J, Nischalke HD, Hofmeister V, et al. The HLA-A2 restricted T cell epitope HCV core 35-44 stabilizes HLA-E expression and inhibits cytolysis mediated by natural killer cells. Am J Pathol 2005;166:443-453.
100. Sene D, Levasseur F, Abel M, et al. Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines. PLoS Pathog 2010;6:el001184.
101. Ebihara T, Masuda H, Akazawa T, et al. Induction of NKG2D ligands on human dendritic cells by TLR ligand stimulation and RNA virus infection. Int Immunol 2007;19:1145-1155.
102. Wen C, He X, Ma H, et al. Hepatitis C virus infection downregulates the ligands of the activating receptor NKG2D. Cell Mol Immunol 2008;5:475-478.
103. Oliviero B, Varchetta S, Paudice E, et al. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 2009;137:1151-1160.
104. Layden TJ, Mika B, Wiley TE. Hepatitis C kinetics: mathematical modeling of viral response to therapy. Semin Liver Dis 2000;20:173-183.
105. Vidal-Castineira JR, Lopez-Vazquez A, Diaz-Pena R, et al. Effect of killer immunoglobulin-like receptors in the response to combined treatment in patients with chronic hepatitis C virus infection. J Virol 2010;84:475-481.
106. Carneiro VL, Lemaire DC, Bendicho MT, et al. Natural killer cell receptor and HLA-C gene polymorphisms among patients with hepatitis C: a comparison between sustained virological responders and non-responders. Liver Int 2010;30:567-573.
107. Golden-Mason L, Bambha KM, Cheng L, et al. Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C. Hepatology 2011;54:1559-1569.
108. Lee S, Watson MW, Flexman JP, Cheng W, Hammond T, Price P. Increased proportion of the CD56 (bright) NK cell subset in patients chronically infected with hepatitis C virus (HCV) receiving interferon-alpha and ribavirin therapy. J Med Virol 2010;82:568-574.
109. Charlton M, Wiesner R. Natural history and management of hepatitis C infection after liver transplantation. Semin Liver Dis 2004;24 Suppl 2:79-88.
110. Berenguer M. What determines the natural history of recurrent hepatitis C after liver transplantation? J Hepatol 2005;42:448-456.
111. Varchetta S, Oliviero B, Francesca Donato M, et al. Prospective study of natural killer cell phenotype in recurrent hepatitis C virus infection following liver transplantation. J Hepatol 2009;50:314-322.
112. De Arias AE, Haworth SE, Belli LS, et al. Killer cell immunoglobulin-like receptor genotype and killer cell immunoglobulin-like receptor-human leukocyte antigen C ligand compatibility affect the severity of hepatitis C virus recurrence after liver transplantation. Liver Transpl 2009;15:390-399.
113. Li Y, Zhang T, Ho C, Orange JS, Douglas SD, Ho WZ. Natural killer cells inhibit hepatitis C virus expression. J Leukoc Biol 2004;76:1171-1179.
114. Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 2006;130:435-452.
115. Hanvesakul R, Spencer N, Cook M, et al. Donor HLA-C genotype has a profound impact on the clinical outcome following liver transplantation. Am J Transplant 2008;8:1931-1941.
116. Parham P. Immunology. NK cells lose their inhibition. Science 2004;305:786-787.
117. Tran TH, Middleton D, Dohler B, et al. Reassessing the impact of donor HLA-C genotype on long-term liver transplant survival. Am J Transplant 2009;9:1674-1678.