transplantologiyaТрансплантологияTransplantologiya. The Russian Journal of Transplantation2074-05062542-0909IPO Association of Transplantologists10.23873/2074-0506-2020-12-2-126-134transplantologiya-499Research ArticleОБЗОРНЫЕ СТАТЬИ И ЛЕКЦИИREVIEW ARTICLES AND LECTURESБиомаркеры толерантности и иммунологический мониторинг при трансплантации печениBiomarkers of tolerance and immunological monitoring in liver transplantationhttps://orcid.org/0000-0001-8391-5211СюткинВ. Е.SyutkinV. E.

Владимир Евгеньевич Сюткин, д-р мед. наук, ведущий научный сотрудник

Vladimir E. Syutkin, Dr. Med. Sci., Leading Research Associate

https://orcid.org/0000-0002-8897-7523БоровковаН. В.BorovkovaN. V.

Наталья Валерьевна Боровкова, д-р мед. наук, заведующая научным отделением биотехнологий и трансфузиологии

Natalya V. Borovkova, Dr. Med. Sci., Head of the Scientific Department of Biotechnology and Transfusiology,

https://orcid.org/0000-0002-6362-7914НоврузбековМ. С.NovruzbekovM. S.

Мурад Сафтарович Новрузбеков, д-р мед. наук, заведующий научным отделением трансплантации печени

Murad S. Novruzbekov, Dr. Med. Sci., Head of the Scientific Department for Liver Transplantation

ГБУЗ «НИИ скорой помощи им. Н.В. Склифосовского ДЗМ»РоссияN.V. Sklifosovsky Research Institute for Emergency MedicineRussian Federation202017062020122126134Copyright © Сюткин В.Е., Боровкова Н.В., Новрузбеков М.С., 20202020Сюткин В.Е., Боровкова Н.В., Новрузбеков М.С.Syutkin V.E., Borovkova N.V., Novruzbekov M.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.jtransplantologiya.ru/jour/article/view/499

Введение. В обзоре обобщены имеющиеся в литературе сведения о клинических и лабораторных показателях, позволяющих прогнозировать развитие операционной толерантности у реципиентов печени после полной отмены иммуносупрессивной терапии.

Цель обзора – выявить возможные биомаркеры толерантности у реципиентов печени с успешной полной отменой иммуносупрессии для последующего внедрения в повседневную клиническую практику. С позиций прогностической значимости оценены клеточные, гуморальные и молекулярные маркеры операционной толерантности реципиентов печени, которым была полностью отменена иммуносупрессивная терапия без развития дисфункции трансплантата. Обоснована необходимость проведения проспективных исследований для выявления биомаркеров, позволяющих до начала или в процессе снижения иммуносупрессии выявить реципиентов печени, у которых возможна полная ее отмена. 

Introduction. We reviewed the literature data on clinical and laboratory parameters that allow predicting the development of operational tolerance in liver transplant recipients after their complete weaning from immunosuppressive therapy.

The aim was to identify possible biomarkers of tolerance in liver transplant recipients with the successful complete weaning from immunosuppression for subsequent implementation in routine clinical practice. The cellular, humoral, and molecular markers of the liver transplant recipients who were completely withdrawn from immunosuppressive therapy without the development of graft dysfunction were estimated. The authors underlined the necessity of clinical trials for identifying biomarkers of the operational tolerance development. 

операционная толерантностьтрансплантация печенибиомаркерыoperational toleranceliver transplantationbiomarkersReferencesStarzl TE. Cell migration and chimerism--a unifying concept in transplantation--with particular reference to HLA matching and tolerance induction. Transplant Proc. 1993;25(1 Pt 1):8–12. PMID: 8438487Starzl TE. Cell migration and chimerism--a unifying concept in transplantation--with particular reference to HLA matching and tolerance induction. Transplant Proc. 1993;25(1 Pt 1):8–12. PMID: 8438487Londono MC, Londoño MC, Rimola A, O'Grady J, Sanchez-Fueyo A. Immunosuppression minimization vs. complete drug withdrawal in liver transplantation. J Hepatol. 2013;59(4):872–879. PMID: 23578883 https://doi.org/10.1016/j. jhep.2013.04.003Londono MC, Londoño MC, Rimola A, O'Grady J, Sanchez-Fueyo A. Immunosuppression minimization vs. complete drug withdrawal in liver transplantation. J Hepatol. 2013;59(4):872–879. PMID: 23578883 https://doi.org/10.1016/j. jhep.2013.04.003Feng S. Spontaneous and induced tolerance for liver transplant recipients. Curr Opin Organ Transplant. 2016;21(1):53–8. PMID: 26709575 https://doi.org/10.1097/ mot.0000000000000268Feng S. Spontaneous and induced tolerance for liver transplant recipients. Curr Opin Organ Transplant. 2016;21(1):53–8. PMID: 26709575 https://doi.org/10.1097/ mot.0000000000000268Lerut J, Sanchez-Fueyo A. An appraisal of tolerance in liver transplantation. Am J Transplant. 2006;6(8):1774–1780. PMID: 16889539 https://doi.org/10.1111/j.16006143.2006.01396.xLerut J, Sanchez-Fueyo A. An appraisal of tolerance in liver transplantation. Am J Transplant. 2006;6(8):1774–1780. PMID: 16889539 https://doi.org/10.1111/j.16006143.2006.01396.xMazariegos GV, Reyes J, Marino IR, Demetris AJ, Flynn B, Irish W, et al. Weaning of immunosuppression in liver transplant recipients. Transplantation. 1997;63(2):243–249. PMID: 9020325 https://doi.org/10.1097/00007890199701270-00012Mazariegos GV, Reyes J, Marino IR, Demetris AJ, Flynn B, Irish W, et al. Weaning of immunosuppression in liver transplant recipients. Transplantation. 1997;63(2):243–249. PMID: 9020325 https://doi.org/10.1097/00007890199701270-00012Takatsuki M, Uemoto S, Inomata Y, Egawa H, Kiuchi T, Fujita S, et al., Wea ning of immunosuppression in living donor liver transplant recipients. Transplantation. 2001;72(3):449– 454. PMID: 11502975 https://doi. org/10.1097/00007890-200108150-00016Takatsuki M, Uemoto S, Inomata Y, Egawa H, Kiuchi T, Fujita S, et al., Wea ning of immunosuppression in living donor liver transplant recipients. Transplantation. 2001;72(3):449– 454. PMID: 11502975 https://doi. org/10.1097/00007890-200108150-00016Sawitzki B, Pascher A, Babel N, Reinke P, Volk HD. Can we use biomarkers and functional assays to implement personalized therapies in transplantation? Transplantation. 2009;87(11):1595– 1601. PMID: 19502949 https://doi. org/10.1097/tp.0b013e3181a6b2cfSawitzki B, Pascher A, Babel N, Reinke P, Volk HD. Can we use biomarkers and functional assays to implement personalized therapies in transplantation? Transplantation. 2009;87(11):1595– 1601. PMID: 19502949 https://doi. org/10.1097/tp.0b013e3181a6b2cfHeidt S, Wood KJ. Biomarkers of Operational Tolerance in Solid Organ Transplantation. Expert Opin Med Diagn. 2012;6(4):281–293. PMID: 22988481 https://doi.org/10.1517/17530059.2012. 680019Heidt S, Wood KJ. Biomarkers of Operational Tolerance in Solid Organ Transplantation. Expert Opin Med Diagn. 2012;6(4):281–293. PMID: 22988481 https://doi.org/10.1517/17530059.2012. 680019Benitez C, Londoño MC, Miquel R, Manzia TM, Abraldes JG, Lozano JJ, et al. Prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients. Hepatology. 2013;58(5):1824–1835. PMID: 23532679 https://doi.org/10.1002/ hep.26426Benitez C, Londoño MC, Miquel R, Manzia TM, Abraldes JG, Lozano JJ, et al. Prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients. Hepatology. 2013;58(5):1824–1835. PMID: 23532679 https://doi.org/10.1002/ hep.26426Feng S, Ekong UD, Lobritto SJ, Demetris AJ, Roberts JP, Rosenthal P, et al. Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants. JAMA. 2012;307(3):283–293. PMID: 22253395 https://doi.org/10.1001/jama.2011.2014Feng S, Ekong UD, Lobritto SJ, Demetris AJ, Roberts JP, Rosenthal P, et al. Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants. JAMA. 2012;307(3):283–293. PMID: 22253395 https://doi.org/10.1001/jama.2011.2014Shaked A, DesMarais MR, Kopetskie H, Feng S, Punch JD, Levitsky J, et al. Outcomes of immunosuppression minimization and withdrawal early after liver transplantation. Am J Transplant. 2019;19(5):1397–1409. PMID: 30506630 https://doi.org/10.1111/ ajt.15205Shaked A, DesMarais MR, Kopetskie H, Feng S, Punch JD, Levitsky J, et al. Outcomes of immunosuppression minimization and withdrawal early after liver transplantation. Am J Transplant. 2019;19(5):1397–1409. PMID: 30506630 https://doi.org/10.1111/ ajt.15205Li Y, Koshiba T, Yoshizawa A, Yonekawa Y, Masuda K, Ito A, et al. Analyses of peripheral blood mononuclear cells in operational tolerance after pediatric living donor liver transplantation. Am J Transplant. 2004;4(12):2118– 2125. PMID: 15575917 https://doi. org/10.1111/j.1600-6143.2004.00611.xLi Y, Koshiba T, Yoshizawa A, Yonekawa Y, Masuda K, Ito A, et al. Analyses of peripheral blood mononuclear cells in operational tolerance after pediatric living donor liver transplantation. Am J Transplant. 2004;4(12):2118– 2125. PMID: 15575917 https://doi. org/10.1111/j.1600-6143.2004.00611.xZhao X, Li Y, Ohe H, NafadyHego H, Uemoto S, Bishop GA, et al. Intragraft Vdelta1 gammadelta T cells with a unique T-cell receptor are closely associated with pediatric semiallogeneic liver transplant tolerance. Transplantation. 2013;95(1):192–202. PMID: 23222896 https://doi.org/10.1097/tp.0b013e3182782f9fZhao X, Li Y, Ohe H, NafadyHego H, Uemoto S, Bishop GA, et al. Intragraft Vdelta1 gammadelta T cells with a unique T-cell receptor are closely associated with pediatric semiallogeneic liver transplant tolerance. Transplantation. 2013;95(1):192–202. PMID: 23222896 https://doi.org/10.1097/tp.0b013e3182782f9fLi Y, Zhao X, Cheng D, Haga H, Tsuruyama T, Wood K, et al. The presence of Foxp3 expressing T cells within grafts of tolerant human liver transplant recipients. Transplantation. 2008;86(12):1837– 1843. PMID: 19104431 https://doi. org/10.1097/tp.0b013e31818febc4Li Y, Zhao X, Cheng D, Haga H, Tsuruyama T, Wood K, et al. The presence of Foxp3 expressing T cells within grafts of tolerant human liver transplant recipients. Transplantation. 2008;86(12):1837– 1843. PMID: 19104431 https://doi. org/10.1097/tp.0b013e31818febc4Taubert R, Danger R, Londoño MC, Christakoudi S, Martinez-Picola M, Rimola A, et al. Hepatic infiltrates in operational tolerant patients after liver transplantation show enrichment of regulatory T cells before proinflammatory genes are downregulated. Am J Transplant. 2016;16(4):1285–1293. PMID: 26603835 https://doi.org/10.1111/ ajt.13617Taubert R, Danger R, Londoño MC, Christakoudi S, Martinez-Picola M, Rimola A, et al. Hepatic infiltrates in operational tolerant patients after liver transplantation show enrichment of regulatory T cells before proinflammatory genes are downregulated. Am J Transplant. 2016;16(4):1285–1293. PMID: 26603835 https://doi.org/10.1111/ ajt.13617Pons JA, Revilla-Nuin B, Baroja-Mazo A, Ramírez P, Martínez-Alarcón L, Sánchez-Bueno F, et al. FoxP3 in peripheral blood is associated with operational tolerance in liver transplant patients during immunosuppression with drawal. Transplantation. 2008;86(10):1370– 1378. PMID: 19034005 https://doi. org/10.1097/tp.0b013e318188d3e6Pons JA, Revilla-Nuin B, Baroja-Mazo A, Ramírez P, Martínez-Alarcón L, Sánchez-Bueno F, et al. FoxP3 in peripheral blood is associated with operational tolerance in liver transplant patients during immunosuppression with drawal. Transplantation. 2008;86(10):1370– 1378. PMID: 19034005 https://doi. org/10.1097/tp.0b013e318188d3e6Stegmann KA, Björkström NK, Veber H, Ciesek S, Riese P, Wiegand J, et al. Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection. Gastroenterology. 2010;138(5):1885–1897. PMID: 20334827 https://doi.org/10.1053/j.gastro.2010.01.051Stegmann KA, Björkström NK, Veber H, Ciesek S, Riese P, Wiegand J, et al. Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection. Gastroenterology. 2010;138(5):1885–1897. PMID: 20334827 https://doi.org/10.1053/j.gastro.2010.01.051Jinushi M, Takehara T, Tatsumi T, Yamaguchi S, Sakamori R, Hiramatsu N, et al. Natural killer cell and hepatic cell interaction via NKG2A leads to dendritic cell-mediated induction of CD4 CD25 T cells with PD-1-dependent regulatory activities. Immunology. 2007;120(1):73– 82. PMID: 17052247 https://doi. org/10.1111/j.1365-2567.2006.02479.xJinushi M, Takehara T, Tatsumi T, Yamaguchi S, Sakamori R, Hiramatsu N, et al. Natural killer cell and hepatic cell interaction via NKG2A leads to dendritic cell-mediated induction of CD4 CD25 T cells with PD-1-dependent regulatory activities. Immunology. 2007;120(1):73– 82. PMID: 17052247 https://doi. org/10.1111/j.1365-2567.2006.02479.xХубутия М.Ш., Гуляев В.А., Хватов В.Б., Леменёв В.Л., Кабанова С.А., Новрузбеков М.С. и др. Иммунологическая толерантность при трансплантации органов. Трансплантология. 2017;9(3):211–225.Khubutiya MSh, Gulyaev VA, Khvatov VB, Lemenev VL, Kabanova SA, Novruzbekov MS, et al. Immunological tolerance in organ transplantation. Transplantologiya. The Russian Journal of Transplantation. 2017;9(3):211–225. (In Russ.) https:// doi.org/10.23873/2074-0506-2017-9-3211-225Ciuffreda D, Codarri L, Buhler L, Vallotton L, Giostra E, Mentha G, et al. Hepa titis C virus infection after liver transplantation is associated with lower levels of activated CD4(+)CD25(+) CD45RO(+)IL-7ralpha(high) T cells. Liver Transpl. 2010;16(1):49–55. PMID: 19866484 https://doi.org/10.1002/lt.21959Ciuffreda D, Codarri L, Buhler L, Vallotton L, Giostra E, Mentha G, et al. Hepa titis C virus infection after liver transplantation is associated with lower levels of activated CD4(+)CD25(+) CD45RO(+)IL-7ralpha(high) T cells. Liver Transpl. 2010;16(1):49–55. PMID: 19866484 https://doi.org/10.1002/lt.21959Carpentier A, Conti F, Stenard F, Aoudjehane L, Miroux C, Podevin P, et al. Increased expression of regulatory Tr1 cells in recurrent hepatitis C after liver transplantation. Am J Transplant. 2009;9(9):2102–2112. PMID: 19624566 https://doi.org/10.1111/j.16006143.2009.02743.xCarpentier A, Conti F, Stenard F, Aoudjehane L, Miroux C, Podevin P, et al. Increased expression of regulatory Tr1 cells in recurrent hepatitis C after liver transplantation. Am J Transplant. 2009;9(9):2102–2112. PMID: 19624566 https://doi.org/10.1111/j.16006143.2009.02743.xXie XJ, Ye YF, Zhou L, Xie HY, Jiang GP, Feng XW, et al. Th17 promotes acute rejection following liver transplantation in rats. J Zhejiang Univ Sci B. 2010;11(11):819–827. PMID: 21043049 https://doi.org/10.1631/jzus.b1000030Xie XJ, Ye YF, Zhou L, Xie HY, Jiang GP, Feng XW, et al. Th17 promotes acute rejection following liver transplantation in rats. J Zhejiang Univ Sci B. 2010;11(11):819–827. PMID: 21043049 https://doi.org/10.1631/jzus.b1000030Fan H, Li LX, Han DD, Kou JT, Li P, He Q, et al. Increase of peripheral Th17 lymphocytes during acute cellular rejection in liver transplant recipients. Hepatobiliary Pancreat Dis Int. 2012;11(6):606– 611. PMID: 23232631 https://doi.org/10.1016/s1499-3872(12)60231-8Fan H, Li LX, Han DD, Kou JT, Li P, He Q, et al. Increase of peripheral Th17 lymphocytes during acute cellular rejection in liver transplant recipients. Hepatobiliary Pancreat Dis Int. 2012;11(6):606– 611. PMID: 23232631 https://doi.org/10.1016/s1499-3872(12)60231-8Germani G, Rodriguez-Castro K, Russo FP, Senzolo M, Zanetto A, Ferrarese A, et al. Markers of acute rejection and graft acceptance in liver transplantation. World J Gastroenterol. 2015;21(4):1061–1068. PMID: 25632178 https://doi.org/10.3748/wjg.v21.i4.1061Germani G, Rodriguez-Castro K, Russo FP, Senzolo M, Zanetto A, Ferrarese A, et al. Markers of acute rejection and graft acceptance in liver transplantation. World J Gastroenterol. 2015;21(4):1061–1068. PMID: 25632178 https://doi.org/10.3748/wjg.v21.i4.1061Jhun J, Lee SH, Lee SK, Kim HY, Jung ES, Kim DG, et al. Serial monitoring of immune markers being represented regulatory T cell/T helper 17 cell ratio: indicating tolerance for tapering immunosuppression after liver transplantation. Front Immunol. 2018;9:352. PMID: 29545795 https://doi.org/10.3389/ fimmu.2018.00352Jhun J, Lee SH, Lee SK, Kim HY, Jung ES, Kim DG, et al. Serial monitoring of immune markers being represented regulatory T cell/T helper 17 cell ratio: indicating tolerance for tapering immunosuppression after liver transplantation. Front Immunol. 2018;9:352. PMID: 29545795 https://doi.org/10.3389/ fimmu.2018.00352Mazariegos GV, Zahorchak AF, Reyes J, Chapman H, Zeevi A, Thomson AW, et al. Dendritic cell subset ratio in tolerant, weaning and nontolerant liver recipients is not affected by extent of immunosuppression. Am J Transplant. 2005;5(2): 314–322. PMID: 15643991 https://doi.org/10.1111/j.16006143.2004.00672.xMazariegos GV, Zahorchak AF, Reyes J, Chapman H, Zeevi A, Thomson AW, et al. Dendritic cell subset ratio in tolerant, weaning and nontolerant liver recipients is not affected by extent of immunosuppression. Am J Transplant. 2005;5(2): 314–322. PMID: 15643991 https://doi.org/10.1111/j.16006143.2004.00672.xBattaglia M, Battaglia M, Stabilini A, Migliavacca B, HorejsHoeck J, Kaupper T, et al. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol. 2006;177(12): 8338–8347. PMID: 17142730 https://doi. org/10.4049/jimmunol.177.12.8338Battaglia M, Battaglia M, Stabilini A, Migliavacca B, HorejsHoeck J, Kaupper T, et al. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol. 2006;177(12): 8338–8347. PMID: 17142730 https://doi. org/10.4049/jimmunol.177.12.8338Levitsky J, Mathew JM, Abecassis M, Tambur A, Leventhal J, Chandrasekaran D, et al. Systemic immunoregulatory and proteogenomic effects of tacrolimus to sirolimus conversion in liver transplant recipients. Hepatology. 2013;57(1):239–248. PMID: 22234876 https://doi.org/10.1002/hep.25579Levitsky J, Mathew JM, Abecassis M, Tambur A, Leventhal J, Chandrasekaran D, et al. Systemic immunoregulatory and proteogenomic effects of tacrolimus to sirolimus conversion in liver transplant recipients. Hepatology. 2013;57(1):239–248. PMID: 22234876 https://doi.org/10.1002/hep.25579Levitsky J, Miller J, Wang E, Rosen A, Flaa C, Abecassis M, et al. Immunoregulatory profiles in liver transplant recipients on different immunosuppressive agents. Hum immunol. 2009;70(3):146– 150. PMID: 19141306 https://doi. org/10.1016/j.humimm.2008.12.008Levitsky J, Miller J, Wang E, Rosen A, Flaa C, Abecassis M, et al. Immunoregulatory profiles in liver transplant recipients on different immunosuppressive agents. Hum immunol. 2009;70(3):146– 150. PMID: 19141306 https://doi. org/10.1016/j.humimm.2008.12.008Ghazal K, Stenard F, Dahlqvist G, Barjon C, Aoudjehane L, Scatton O, et al. Treatment with mTOR inhibitors after liver transplantation enables a sustained increase in regulatory T-cells while preserving their suppressive capacity. Clin Res Hepatol Gastroenterol. 2018;42(3):237–244. PMID: 29175009 https://doi.org/10.1016/j. clinre.2017.10.001Ghazal K, Stenard F, Dahlqvist G, Barjon C, Aoudjehane L, Scatton O, et al. Treatment with mTOR inhibitors after liver transplantation enables a sustained increase in regulatory T-cells while preserving their suppressive capacity. Clin Res Hepatol Gastroenterol. 2018;42(3):237–244. PMID: 29175009 https://doi.org/10.1016/j. clinre.2017.10.001Cuadrado A, San Segundo D, LópezHoyos M, Crespo J, Fábrega E, et al. Clinical significance of donor-specific human leukocyte antigen antibodies in liver transplantation. World J Gastroenterol. 2015;21(39):11016–11026. PMID: 26494958 https://doi.org/10.3748/wjg. v21.i39.11016Cuadrado A, San Segundo D, LópezHoyos M, Crespo J, Fábrega E, et al. Clinical significance of donor-specific human leukocyte antigen antibodies in liver transplantation. World J Gastroenterol. 2015;21(39):11016–11026. PMID: 26494958 https://doi.org/10.3748/wjg. v21.i39.11016Jucaud V, Shaked A, DesMarais M, Sayre P, Feng S, Levitsky J, et al. Prevalence and impact of de novo donor-specific antibodies during a multicenter immunosuppression withdrawal trial in adult liver transplant recipients. Hepatology. 2019;69(3):1273–1286. PMID: 30229989 https://doi.org/10.1002/hep.30281Jucaud V, Shaked A, DesMarais M, Sayre P, Feng S, Levitsky J, et al. Prevalence and impact of de novo donor-specific antibodies during a multicenter immunosuppression withdrawal trial in adult liver transplant recipients. Hepatology. 2019;69(3):1273–1286. PMID: 30229989 https://doi.org/10.1002/hep.30281Martinez-Llordella M, Puig-Pey I, Orlando G, Ramoni M, Tisone G, Rimola A, et al. Multiparameter immune profiling of operational tolerance in liver transplantation. Am J Transplant. 2007;7(2):309–319. PMID: 17241111 https://doi.org/10.1111/j.16006143.2006.01621.xMartinez-Llordella M, Puig-Pey I, Orlando G, Ramoni M, Tisone G, Rimola A, et al. Multiparameter immune profiling of operational tolerance in liver transplantation. Am J Transplant. 2007;7(2):309–319. PMID: 17241111 https://doi.org/10.1111/j.16006143.2006.01621.xMartinez-Llordella M, Lozano JJ, Puig-Pey I, Orlando G, Tisone G, Lerut J, et al. Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients. J Clin Invest. 2008;118(8):2845– 2857. PMID: 18654667 https://doi. org/10.1172/jci35342Martinez-Llordella M, Lozano JJ, Puig-Pey I, Orlando G, Tisone G, Lerut J, et al. Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients. J Clin Invest. 2008;118(8):2845– 2857. PMID: 18654667 https://doi. org/10.1172/jci35342Bohne F, Martínez-Llordella M, Lozano JJ, Miquel R, Benítez C, Londoño MC, et al. Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation. J Clin Invest. 2012;122(1):368–382. PMID: 22156196 https://doi.org/10.1172/ jci59411Bohne F, Martínez-Llordella M, Lozano JJ, Miquel R, Benítez C, Londoño MC, et al. Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation. J Clin Invest. 2012;122(1):368–382. PMID: 22156196 https://doi.org/10.1172/ jci59411Li L, Wozniak LJ, Rodder S, Heish S, Talisetti A, Wang Q, et al. A common peripheral blood gene set for diagnosis of operational tolerance in pediatric and adult liver transplantation. Am J Transplant. 2012;12(5):1218–1228. PMID: 22300520 https://doi.org/10.1111/j.16006143.2011.03928.xLi L, Wozniak LJ, Rodder S, Heish S, Talisetti A, Wang Q, et al. A common peripheral blood gene set for diagnosis of operational tolerance in pediatric and adult liver transplantation. Am J Transplant. 2012;12(5):1218–1228. PMID: 22300520 https://doi.org/10.1111/j.16006143.2011.03928.x

The authors declare that there are no conflicts of interest present.