Tolerance studies in liver transplantation: are we fooling ourselves?
Journal
Current opinion in organ transplantation
ISSN: 1531-7013
Titre abrégé: Curr Opin Organ Transplant
Pays: United States
ID NLM: 9717388
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
pubmed:
20
2
2020
medline:
28
10
2020
entrez:
20
2
2020
Statut:
ppublish
Résumé
This article will summarize outcomes of prior immunosuppression withdrawal trials in pediatric and adult liver transplantation and provide updates on the current status of ongoing clinical tolerance studies including evolving strategies, such as identification of reliable biomarkers or immunomodulation to achieve an earlier onset and more robust level of operational tolerance. Clinical tolerance studies in liver transplantation have previously been limited by inconsistent and delayed success of immunosuppressive withdrawal, lack of substantial histological analysis from liver tissue biopsy, and the inability to translate mechanistic studies to reproducible clinical outcomes. Current clinical trials are attempting to overcome these hurdles through more comprehensive and guided immunosuppression withdrawal protocols. Novel and emerging technologies are enabling investigators to identify and validate potential biomarkers of tolerance in order to predict patient subpopulations disposed towards operational tolerance. Immune cell therapy using the adoptive transfer of various cell products have been shown to be feasible and well tolerated in early phase clinical trials and ongoing. Tolerance studies in liver transplantation are evolving and substantial progress has been made in overcoming the challenges that have prevented the widespread implementation of immunosuppression withdrawal protocols in the clinic. Identifying more sensitive and specific predictors of immunosuppression withdrawal success and tolerance induction strategies that will allow for early tolerance will advance the field tremendously towards the goal of promoting long-term allograft survival without immunosuppression.
Identifiants
pubmed: 32073482
doi: 10.1097/MOT.0000000000000738
pii: 00075200-202004000-00011
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
151-157Subventions
Organisme : NIAID NIH HHS
ID : T32 AI074490
Pays : United States
Références
Fine RN. Tolerance in solid-organ transplant. Exp Clin Transplant 2016; 14:1–5.
Dobbels F, van Damme-Lombaert R, Vanhaecke J, de Geest S. Growing pains: nonadherence with the immunosuppressive regimen in adolescent transplant recipients. Pediatr Transplant 2005; 9:381–390.
Mastoridis S, Martinez-Llordella M, Sanchez-Fueyo A. Immunotolerance in liver transplantation. Semin Liver Dis 2017; 37:95–108.
Ezekian B, Schroder PM, Freischlag K, et al. Contemporary strategies and barriers to transplantation tolerance. Transplantation 2018; 102:1213–1222.
Calne RY, Sells RA, Pena JR, et al. Induction of immunological tolerance by porcine liver allografts. Nature 1969; 223:472–476.
Kamada N, Wight DG. Antigen-specific immunosuppression induced by liver transplantation in the rat. Transplantation 1984; 38:217–221.
Feng S, Bucuvalas J. Tolerance after liver transplantation: where are we? Liver Transplant 2017; 23:1601–1614.
Levitsky J. Does the liver provide immunosuppressive advantage? Clin Liver Dis (Hoboken) 2019; 13:180–183.
Assy N, Adams PC, Myers P, et al. Randomized controlled trial of total immunosuppression, withdrawal in liver transplant recipients: role of ursodeoxycholic acid. Transplantation 2007; 83:1571–1576.
Devlin J, Doherty D, Thomson L, et al. Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology 1998; 27:926–933.
Ramos HC, Reyes J, Abu-Elmagd K, et al. Weaning of immunosuppression in long-term liver transplant recipients. Transplantation 1995; 59:212–217.
Hurwitz M, Desai DM, Cox KL, et al. Complete immunosuppressive withdrawal as a uniform approach to posttransplant lymphoproliferative disease in pediatric liver transplantation. Pediatr Transplant 2004; 8:267–272.
Mazariegos GV, Reyes J, Marino IR, et al. Weaning of immunosuppression in liver transplant recipients. Transplantation 1997; 63:243–249.
Takatsuki M, Uemoto S, Inomata Y, et al. Weaning of immunosuppression in living donor liver transplant recipients. Transplantation 2001; 72:449–454.
Tisone G, Orlando G, Cardillo A, et al. Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence. J Hepatol 2006; 44:702–709.
Pons JA, Y_elamos J, Ram_ırez P, et al. Endothelial cell chimerism does not influence allograft tolerance in liver transplant patients after withdrawal of immunosuppression. Transplantation 2003; 75:1045–1047.
Eason JD, Cohen AJ, Nair S, et al. Tolerance: is it worth the risk? Transplantation 2005; 79:1157–1159.
de la Garza RG, Sarobe P, Merino J, et al. Trial of complete weaning from immunosuppression for liver transplant recipients: factors predictive of tolerance. Liver Transpl 2013; 19:937–944.
Manzia TM, Angelico R, Ciano P, et al. Impact of immunosuppression minimization andwithdrawal in long-term hepatitis C virus liver transplant recipients. World J Gastroenterol 2014; 20:12217–12225.
Tryphonopoulos P, Ruiz P, Weppler D, et al. Long-term follow-up of 23 operational tolerant liver transplant recipients. Transplantation 2010; 90:1556–1561.
Tryphonopoulos P, Tzakis AG, Weppler D, et al. The role of donor bone marrow infusions in withdrawal of immunosuppression in adult liver allotransplantation. Am J Transplant 2005; 5:608–613.
Oike F, Yokoi A, Nishimura E, et al. Complete withdrawal of immunosuppression in living donor liver transplantation. Transplant Proc 2002; 34:1521.
Girlanda R, Rela M, Williams R, et al. Long-term outcome of immunosuppression withdrawal after liver transplantation. Transplant Proc 2005; 37:1708–1709.
Mazariegos GV, Sindhi R, Thomson AW, Marcos A. Clinical tolerance following liver transplantation: long term results and future prospects. Transpl Immunol 2007; 17:114–119.
Orlando G, Manzia T, Baiocchi L, et al. The Tor Vergata weaning off immunosuppression protocol in stable HCV liver transplant patients: the updated follow up at 78 months. Transpl Immunol 2008; 20:43–47.
Lee JH, Lee SK, Lee HJ, et al. Withdrawal of immunosuppression in pediatric liver transplant recipients in Korea. Yonsei Med J 2009; 50:784–788.
Lin NC, Wang HK, Yeh YC, et al. Minimization or withdrawal of immunosuppressants in pediatric liver transplant recipients. J Pediatr Surg 2015; 50:2128–2133.
Koshiba T, Li Y, Takemura M, et al. Clinical, immunological, and pathological aspects of operational tolerance after pediatric living-donor liver transplantation. Transpl Immunol 2007; 17:94–97.
Levitsky J, Feng S. Tolerance in clinical liver transplantation. Hum Immunol 2018; 79:283–287.
Benıtez C, Londo∼no MC, Miquel R, et al. Prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients. Hepatology 2013; 58:1824–1835.
Feng S, Ekong UD, Lobritto SJ, et al. Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants. JAMA 2012; 307:283–293.
Shaked A, DesMarais MR, Kopetskie H, et al. Outcomes of immunosuppression minimization and withdrawal early after liver transplantation. Am J Transplant 2019; 19:1397–1409.
Bohne F, Londoño MC, Benítez C, et al. HCV-induced immune responses influence the development of operational tolerance after liver transplantation in humans. Sci Transl Med 2014; 6:242ra81.
Feng S, Demetris AJ, Spain KM, et al. Five-year histological and serological follow-up of operationally tolerant pediatric liver transplant recipients enrolled in WISP-R. Hepatology 2017; 65:647–660.
O’Leary JG, Kaneku H, Jennings LW, et al. Preformed class II donor-specific antibodies are associated with an increased risk of early rejection after liver transplantation. Liver Transpl 2013; 19:973–980.
Kozlowski T, Rubinas T, Nickeleit V, et al. Liver allograft antibody-mediated rejection with demonstration of sinusoidal C4d staining and circulating donor-specific antibodies. Liver transpl 2013; 17:357–368.
O’Leary JG, Cai J, Freeman R, et al. Proposed diagnostic criteria for chronic antibody-mediated rejection in liver allografts. Am J Transpl 2016; 16:603–614.
Wozniak LJ, et al. Donor-specific HLA antibodies are associated with late allograft dysfunction after pediatric liver transplantation. Transplantation 2015; 99:1416–1422. doi:10.1097/TP.0000000000000796.
doi: 10.1097/tp.0000000000000796
Jucaud V, Shaked A, DesMarais M, et al. Prevalence and impact of de novo donor-specific antibodies during a multicenter immunosuppression withdrawal trial in adult liver transplant recipients. Hepatology 2019; 69:1273–1286.
Martínez-Llordella M, Lozano JJ, Puig-Pey I, et al. Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients. J Clin Invest 2008; 118:2845–2857.
Li Y, Koshiba T, Yoshizawa A, et al. Analyses of peripheral blood mononuclear cells in operational tolerance after pediatric living donor liver transplantation. Am J Transplant 2004; 4:2118–2125.
Zhao X, Li Y, Ohe H, et al. Intragraft Vdelta1 gammadelta T cells with a unique T-cell receptor are closely associated with pediatric semi-allogeneic liver transplant tolerance. Transplantation 2003; 95:192.
Li Y, Zhao X, Cheng D, et al. The presence of Foxp3 expressing T cells within grafts of tolerant human liver transplant recipients. Transplantation 2008; 86:1837–1843.
Li L, Wozniak LJ, Rodder S, et al. A common peripheral blood gene set for diagnosis of operational tolerance in pediatric and adult liver transplantation. Am J Transplant 2012; 12:1218–1228.
Vionnet J, Sánchez-Fueyo A. Biomarkers of immune tolerance in liver transplantation. Hum Immunol 2018; 79:388–394.
Bohne F, Martínez-Llordella M, Lozano JJ, 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; 122:368–382.
Revilla-Nuin B, de Bejar Á, Martínez-Alarcón L, et al. Differential profile of activated regulatory T cell subsets and microRNAs in tolerant liver transplant recipients. Liver Transpl 2017; 23:933–945.
Vitalone MJ, Wei L, Fujiki M, et al. Liver microRNA profile of induced allograft tolerance. Transplantation 2016; 100:781–790.
Lau AH, Vitalone MJ, Haas K, et al. Mass cytometry reveals a distinct immunoprofile of operational tolerance in pediatric liver transplantation. Pediatr Transplant 2016; 20:1072–1080.
Mathew JM, Ansari MJ, Gallon L, Leventhal JR. Cellular and functional biomarkers of clinical transplant tolerance. Hum Immunol 2018; 79:322–333.
Todo S, Yamashita K, Goto R, et al. A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology 2016; 64:632–643.
Thomson AW, Humar A, Lakis F, Metes D. Dendritic cells for promotion of liver transplant operational tolerance: rationale for a clinical trial and accompanying mechanistic studies. Hum Immunol 2018; 79:314–321.
You Y, Wen D, Gong J, Liu Z. Research status of mesenchymal stem cells in liver transplantation. Cell Transplant 2019; 28:1490–1506.
Detry O, Vandermeulen M, Delbouille MH, et al. Infusion of mesenchymal stromal cells after deceased liver transplantation: a phase I–II, open-label, clinical study. J Hepatol 2017; 67:47–55.
Thomson AW, Zahorchak AF, Ezzelarab MB, et al. Prospective clinical testing of regulatory dendritic cells in organ transplantation. Front Immunol 2016; 7:15.