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For: Orlando G, Soker S, Wood K. Operational tolerance after liver transplantation. J Hepatol 2009;50:1247-57. [PMID: 19394103 DOI: 10.1016/j.jhep.2009.03.006] [Citation(s) in RCA: 124] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]

For:	Orlando G, Soker S, Wood K. Operational tolerance after liver transplantation. J Hepatol 2009;50:1247-57. [PMID: 19394103 DOI: 10.1016/j.jhep.2009.03.006] [Citation(s) in RCA: 124] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]

Number

Cited by Other Article(s)

Ou LL, Jiang JL, Guo ML, Wu JH, Zhong WW, He YH. Research progress on the roles of complement in liver injury. World J Hepatol 2025;17:103839. [DOI: 10.4254/wjh.v17.i3.103839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/29/2025] [Accepted: 02/27/2025] [Indexed: 03/26/2025] Open

Costaguta AC, Costaguta GA, Rumbo C, Gondolesi G, D'Agostino D, Pallitto MB, Bottasso O, Álvarez F. Lack of differences in outcomes between 3 immunosuppression protocols in the first year after pediatric liver transplantation: A multicenter study. Liver Transpl 2025;31:201-210. [PMID: 38949782 DOI: 10.1097/lvt.0000000000000427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 06/17/2024] [Indexed: 07/02/2024]

Pan Z, Ye YS, Liu C, Li W. Role of liver-resident NK cells in liver immunity. Hepatol Int 2025:10.1007/s12072-025-10778-7. [PMID: 39893278 DOI: 10.1007/s12072-025-10778-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 01/10/2025] [Indexed: 02/04/2025]

Kim HS, Choi SJN, Lee HK, Lee S. Accidental ABO-incompatible pediatric liver transplantation with blood group antigen immune and operational tolerance: a case report with 21 years of follow-up. KOREAN JOURNAL OF TRANSPLANTATION 2023;37:306-309. [PMID: 38153256 PMCID: PMC10772265 DOI: 10.4285/kjt.23.0070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 12/18/2023] [Accepted: 12/19/2023] [Indexed: 12/29/2023] Open

Cardinale V, Lanthier N, Baptista PM, Carpino G, Carnevale G, Orlando G, Angelico R, Manzia TM, Schuppan D, Pinzani M, Alvaro D, Ciccocioppo R, Uygun BE. Cell transplantation-based regenerative medicine in liver diseases. Stem Cell Reports 2023;18:1555-1572. [PMID: 37557073 PMCID: PMC10444572 DOI: 10.1016/j.stemcr.2023.06.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 06/11/2023] [Accepted: 06/12/2023] [Indexed: 08/11/2023] Open

Affiliation(s)

Vincenzo Cardinale Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.
Nicolas Lanthier Service d'Hépato-gastroentérologie, Cliniques Universitaires Saint-Luc, Laboratory of Hepatogastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
Pedro M Baptista Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain; Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas (CIBERehd), Madrid, Spain; Fundación ARAID, Zaragoza, Spain; Department of Biomedical and Aerospace Engineering, Universidad Carlos III de Madrid, Madrid, Spain
Guido Carpino Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Italy
Gianluca Carnevale Department of Surgery, Medicine, Dentistry, and Morphological Sciences with Interest in Transplant, Oncology, and Regenerative Medicine, University of Modena and Reggio Emilia, 41125 Modena, Italy
Giuseppe Orlando Section of Transplantation, Department of Surgery, Wake Forest University School of Medicine, Winston Salem, NC, USA
Roberta Angelico Hepatobiliary Surgery and Transplant Unit, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy
Tommaso Maria Manzia Hepatobiliary Surgery and Transplant Unit, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy
Detlef Schuppan Institute of Translational Immunology, Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Massimo Pinzani UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Hospital, London, UK
Domenico Alvaro Department of Translation and Precision Medicine, "Sapienza" University of Rome, Rome, Italy
Rachele Ciccocioppo Gastroenterology Unit, Department of Medicine, A.O.U.I. Policlinico G.B. Rossi & University of Verona, Verona, Italy.
Basak E Uygun Center for Engineering in Medicine and Surgery, Massachusetts General Hospital, Harvard Medical School, Shriners Hospitals for Children, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.

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Sykes M. Leveraging the lymphohematopoietic graft-versus-host reaction (LGVHR) to achieve allograft tolerance and restore self tolerance with minimal toxicity. IMMUNOTHERAPY ADVANCES 2023;3:ltad008. [PMID: 37426630 PMCID: PMC10327628 DOI: 10.1093/immadv/ltad008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 05/12/2023] [Indexed: 07/11/2023] Open

Samala N, Wang RY, Auh S, Balla AK, Dakhoul L, Alter HJ, Farci P, Ghabril M, Lucey MR, Rangnekar AS, Reddy KR, Ghany MG. Hepatitis E prevalence and infection in solid-organ transplant recipients in the United States. J Viral Hepat 2022;29:1134-1142. [PMID: 36036116 DOI: 10.1111/jvh.13739] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 04/27/2022] [Accepted: 07/19/2022] [Indexed: 12/29/2022]

Abstract

Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide. An increased risk for HEV infection has been reported in organ-transplant recipients, mainly from Europe. Prospective data on HEV prevalence in the United States (U.S.) organ transplant population are limited. To determine the prevalence and factors associated with HEV infection among solid organ transplant-recipients, we conducted a prospective, cross-sectional, multicentre study among transplant-recipients and age- and organ-matched waitlist patients. Participants answered a risk-exposure questionnaire and were tested for HEV-RNA (in-house PCR), HEV-IgG, and IgM (ELISA, Wantai). Among 456 participants, 224 were transplant-recipients, and 232 were waitlist patients. The mean age was 58 years, 35% female, and 74% White. HEV seroprevalence of the entire cohort was 20.2% and associated with older age (p < 0.0001) and organ transplantation (p = 0.02). The HEV seropositivity was significantly higher among transplant-recipients compared with waitlist patients (24% vs. 16.4%, p = 0.042). Among transplant recipients, relative-risk of being HEV seropositive increased with older age (RR = 3.4 [1.07-10.74] in patients >70 years compared with ≤50 years, p = 0.037); history of graft hepatitis (2.2 [1.27-3.72], p = 0.005); calcineurin inhibitor use (RR = 1.9 [1.03-3.34], p = 0.02); and kidney transplantation (2.4 [1.15-5.16], p = 0.02). HEV-RNA, genotype 3 was detected in only two patients (0.4%), both transplant-recipients. HEV seroprevalence was higher among transplant-recipients than waitlist patients. HEV should be considered in transplant-recipients presenting with graft hepatitis. Detection of HEV-RNA was rare, suggesting that progression to chronic HEV infection is uncommon in transplant-recipients in the U.S.

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Cao W, Lu J, Li S, Song F, Xu J. Transcriptomic analysis of graft liver provides insight into the immune response of rat liver transplantation. Front Immunol 2022;13:947437. [DOI: 10.3389/fimmu.2022.947437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 10/07/2022] [Indexed: 11/05/2022] Open

Abstract BackgroundAs an “immune-privileged organ”, the liver has higher rates of both spontaneous tolerance and operational tolerance after being transplanted compared with other solid organs. Also, a large number of patients still need to take long-term immunosuppression regimens. Liver transplantation (LT) rejection involves varieties of pathophysiological processes and cell types, and a deeper understanding of LT immune response is urgently needed.MethodsHomogenic and allogeneic rat LT models were established, and recipient tissue was collected on postoperative day 7. The degree of LT rejection was evaluated by liver pathological changes and liver function. Differentially expressed genes (DEGs) were detected by transcriptome sequencing and confirmed by reverse transcription-polymerase chain reaction. The functional properties of DEGs were characterized by the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway analyses. The cells infiltrating the graft and recipient spleen and peripheral blood were evaluated by immunofluorescence and flow cytometry.ResultA total of 1,465 DEGs were screened, including 1,177 up-regulated genes and 288 down-regulated genes. GO enrichment and KEGG pathway analysis indicated that DEGs were involved in several immunobiological processes, including T cell activation, Th1, Th2 and Th17 cell differentiation, cytokine-cytokine receptor interaction and other immune processes. Reactome results showed that PD-1 signaling was enriched. Further research confirmed that mRNA expression of multiple immune cell markers increased and markers of T cell exhaustion significantly changed. Flow cytometry showed that the proportion of Treg decreased, and that of PD-1+CD4+ T cells and PD-1+CD8+ T cells increased in the allogeneic group.ConclusionUsing an omic approach, we revealed that the development of LT rejection involved multiple immune cells, activation of various immune pathways, and specific alterations of immune checkpoints, which would benefit risk assessment in the clinic and understanding of pathogenesis regarding LT tolerance. Further clinical validations are warranted for our findings. Collapse

Fitch ZW, Kang L, Li J, Knechtle SJ, Turek JW, Kirk AD, Markert ML, Kwun J. Introducing thymus for promoting transplantation tolerance. J Allergy Clin Immunol 2022;150:549-556. [PMID: 35690492 DOI: 10.1016/j.jaci.2022.05.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 04/29/2022] [Accepted: 05/04/2022] [Indexed: 10/18/2022]

Pesthy S, Wegener E, Ossami Saidy RR, Timmermann L, Uluk D, Aydin M, Dziodzio T, Schoening W, Lurje G, Öllinger R, Frost N, Fehrenbach U, Rückert JC, Neudecker J, Pratschke J, Eurich D. Reducing Immunosuppression in Patients with De Novo Lung Carcinoma after Liver Transplantation Could Significantly Prolong Survival. Cancers (Basel) 2022;14:cancers14112748. [PMID: 35681728 PMCID: PMC9179580 DOI: 10.3390/cancers14112748] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 02/01/2023] Open

Abstract

(1) Background: Liver transplantation (LT) is an established treatment for selected patients with end-stage liver disease resulting in a subsequent need for long-term immunosuppressive therapy. With cumulative exposure to immunosuppression (IS), the risk for the development of de novo lung carcinoma increases. Due to limited therapy options and prognosis after diagnosis of lung cancer, the question of the mode and extent of IS in this particular situation is raised. (2) Methods: All patients diagnosed with de novo lung cancer in the follow-up after LT were identified from the institution's register of liver allograft recipients (Charité-Universitätsmedizin Berlin, Germany) transplanted between 1988 and 2021. Survival analysis was performed based on the IS therapy following diagnosis of lung cancer and the oncological treatment approach. (3) Results: Among 3207 adult LTs performed in 2644 patients at our institution, 62 patients (2.3%) developed de novo lung carcinoma following LT. Lung cancer was diagnosed at a median interval of 9.7 years after LT (range 0.7-27.0 years). Median survival after diagnosis of lung carcinoma was 13.2 months (range 0-196 months). Surgical approach with curative intent significantly prolonged survival rates compared to palliative treatment (median 67.4 months vs. 6.4 months). Reduction of IS facilitated a significant improvement in survival (median 38.6 months vs. 6.7 months). In six patients (9.7%) complete IS weaning was achieved with unimpaired liver allograft function. (4) Conclusion: Reduction of IS therapy after the diagnosis of de novo lung cancer in LT patients is associated with prolonged survival. The risk of acute rejection does not appear to be increased with restrictive IS management. Therefore, strict reduction of IS should be an early intervention following diagnosis. In addition, surgical resection should be attempted, if technically feasible and oncologically meaningful.

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Affiliation(s)

Sina Pesthy Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (E.W.); (R.R.O.S.); (L.T.); (D.U.); (M.A.); (T.D.); (W.S.); (G.L.); (R.Ö.); (J.-C.R.); (J.N.); (J.P.); (D.E.) Correspondence: ; Tel.: +49-30-450-652316
Elisa Wegener Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (E.W.); (R.R.O.S.); (L.T.); (D.U.); (M.A.); (T.D.); (W.S.); (G.L.); (R.Ö.); (J.-C.R.); (J.N.); (J.P.); (D.E.)
Ramin Raul Ossami Saidy Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (E.W.); (R.R.O.S.); (L.T.); (D.U.); (M.A.); (T.D.); (W.S.); (G.L.); (R.Ö.); (J.-C.R.); (J.N.); (J.P.); (D.E.)
Lea Timmermann Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (E.W.); (R.R.O.S.); (L.T.); (D.U.); (M.A.); (T.D.); (W.S.); (G.L.); (R.Ö.); (J.-C.R.); (J.N.); (J.P.); (D.E.)
Deniz Uluk Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (E.W.); (R.R.O.S.); (L.T.); (D.U.); (M.A.); (T.D.); (W.S.); (G.L.); (R.Ö.); (J.-C.R.); (J.N.); (J.P.); (D.E.)
Mustafa Aydin Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (E.W.); (R.R.O.S.); (L.T.); (D.U.); (M.A.); (T.D.); (W.S.); (G.L.); (R.Ö.); (J.-C.R.); (J.N.); (J.P.); (D.E.)
Tomasz Dziodzio Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (E.W.); (R.R.O.S.); (L.T.); (D.U.); (M.A.); (T.D.); (W.S.); (G.L.); (R.Ö.); (J.-C.R.); (J.N.); (J.P.); (D.E.) BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité—Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
Wenzel Schoening Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (E.W.); (R.R.O.S.); (L.T.); (D.U.); (M.A.); (T.D.); (W.S.); (G.L.); (R.Ö.); (J.-C.R.); (J.N.); (J.P.); (D.E.)
Georg Lurje Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (E.W.); (R.R.O.S.); (L.T.); (D.U.); (M.A.); (T.D.); (W.S.); (G.L.); (R.Ö.); (J.-C.R.); (J.N.); (J.P.); (D.E.)
Robert Öllinger Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (E.W.); (R.R.O.S.); (L.T.); (D.U.); (M.A.); (T.D.); (W.S.); (G.L.); (R.Ö.); (J.-C.R.); (J.N.); (J.P.); (D.E.)
Nikolaj Frost Department of Infectious Diseases and Pulmonary Medicine, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany;
Uli Fehrenbach Department of Radiology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany;
Jens-Carsten Rückert Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (E.W.); (R.R.O.S.); (L.T.); (D.U.); (M.A.); (T.D.); (W.S.); (G.L.); (R.Ö.); (J.-C.R.); (J.N.); (J.P.); (D.E.)
Jens Neudecker Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (E.W.); (R.R.O.S.); (L.T.); (D.U.); (M.A.); (T.D.); (W.S.); (G.L.); (R.Ö.); (J.-C.R.); (J.N.); (J.P.); (D.E.)
Johann Pratschke Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (E.W.); (R.R.O.S.); (L.T.); (D.U.); (M.A.); (T.D.); (W.S.); (G.L.); (R.Ö.); (J.-C.R.); (J.N.); (J.P.); (D.E.)
Dennis Eurich Department of Surgery, Campus Virchow-Klinikum and Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (E.W.); (R.R.O.S.); (L.T.); (D.U.); (M.A.); (T.D.); (W.S.); (G.L.); (R.Ö.); (J.-C.R.); (J.N.); (J.P.); (D.E.)

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Gudd CLC, Possamai LA. The Role of Myeloid Cells in Hepatotoxicity Related to Cancer Immunotherapy. Cancers (Basel) 2022;14:1913. [PMID: 35454819 PMCID: PMC9027811 DOI: 10.3390/cancers14081913] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/03/2022] [Accepted: 04/06/2022] [Indexed: 11/23/2022] Open

Duizendstra AA, van der Grift MV, Boor PP, Noordam L, de Knegt RJ, Peppelenbosch MP, Betjes MGH, Litjens NHR, Kwekkeboom J. Current Tolerance-Associated Peripheral Blood Gene Expression Profiles After Liver Transplantation Are Influenced by Immunosuppressive Drugs and Prior Cytomegalovirus Infection. Front Immunol 2022;12:738837. [PMID: 35087511 PMCID: PMC8787265 DOI: 10.3389/fimmu.2021.738837] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 12/16/2021] [Indexed: 12/14/2022] Open

Abstract

Spontaneous operational tolerance to the allograft develops in a proportion of liver transplant (LTx) recipients weaned off immunosuppressive drugs (IS). Several previous studies have investigated whether peripheral blood gene expression profiles could identify operational tolerance in LTx recipients. However, the reported gene expression profiles differed greatly amongst studies, which could be caused by inadequate matching of clinical parameters of study groups. Therefore, the purpose of this study was to validate differentially expressed immune system related genes described in previous studies that identified tolerant LTx recipients after IS weaning. Blood was collected of tolerant LTx recipients (TOL), a control group of LTx recipients with regular IS regimen (CTRL), a group of LTx recipients with minimal IS regimen (MIN) and healthy controls (HC), and groups were matched on age, sex, primary disease, time after LTx, and cytomegalovirus serostatus after LTx. Quantitative Polymerase Chain Reaction was used to determine expression of twenty selected genes and transcript variants in PBMCs. Several genes were differentially expressed between TOL and CTRL groups, but none of the selected genes were differentially expressed between HC and TOL. Principal component analysis revealed an IS drug dosage effect on the expression profile of these genes. These data suggest that use of IS profoundly affects gene expression in peripheral blood, and that these genes are not associated with operational tolerance. In addition, expression levels of SLAMF7 and NKG7 were affected by prior cytomegalovirus infection in LTx recipients. In conclusion, we found confounding effects of IS regimen and prior cytomegalovirus infection, on peripheral blood expression of several selected genes that were described as tolerance-associated genes by previous studies.

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Duizendstra AA, de Knegt RJ, Mancham S, Klepper M, Roelen DL, Brand‐Schaaf SH, Boor PP, Doukas M, de Man RA, Sprengers D, Peppelenbosch MP, Betjes MGH, Kwekkeboom J, Litjens NHR. Activated CD4⁺ T Cells and Highly Differentiated Alloreactive CD4⁺ T Cells Distinguish Operationally Tolerant Liver Transplantation Recipients. Liver Transpl 2022;28:98-112. [PMID: 34081828 PMCID: PMC9291234 DOI: 10.1002/lt.26188] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/20/2021] [Accepted: 05/31/2021] [Indexed: 02/06/2023]

Affiliation(s)

Aafke A. Duizendstra Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
Robert J. de Knegt Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
Shanta Mancham Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
Mariska Klepper Erasmus MC Transplant Institute, Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical CenterRotterdamthe Netherlands
Dave L. Roelen Department of Immunohematology and Blood TransfusionLeiden University Medical CenterLeidenthe Netherlands
Simone H. Brand‐Schaaf Department of Immunohematology and Blood TransfusionLeiden University Medical CenterLeidenthe Netherlands
Patrick P. Boor Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
Michail Doukas Department of PathologyErasmus MC University Medical CenterRotterdamthe Netherlands
Robert A. de Man Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
Dave Sprengers Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
Maikel P. Peppelenbosch Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
Michiel G. H. Betjes Erasmus MC Transplant Institute, Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical CenterRotterdamthe Netherlands
Jaap Kwekkeboom Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
Nicolle H. R. Litjens Erasmus MC Transplant Institute, Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC University Medical CenterRotterdamthe Netherlands

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Wang X, MacParland SA, Perciani CT. Immunological Determinants of Liver Transplant Outcomes Uncovered by the Rat Model. Transplantation 2021;105:1944-1956. [PMID: 33417410 PMCID: PMC8376267 DOI: 10.1097/tp.0000000000003598] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/12/2020] [Accepted: 11/14/2020] [Indexed: 02/07/2023]

Comparison of the characteristics of adult liver transplant recipients with prope (almost) tolerance and full immunosuppression regimen. Transpl Immunol 2021;68:101440. [PMID: 34343659 DOI: 10.1016/j.trim.2021.101440] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/27/2021] [Accepted: 07/30/2021] [Indexed: 11/20/2022]

Abstract

BACKGROUND

The liver transplant recipients are often subjected to excessive therapy by immunosuppressive drugs which produce several complications. Consequently, the minimization or even withdrawal of immunosuppression in selected patients is an attractive alternative. We investigated the frequency and characteristics of these near (or prope from Latin) tolerance in liver transplant recipients in Shiraz Organ Transplant Center.

MATERIAL AND METHODS

We reviewed the medical records of over 3800 adult liver transplant recipients to select a group treated with a low-dose tacrolimus monotherapy (n = 90) between 1994 and 2017 in our transplant center. The patients with the best liver function parameters were selected; then, the clinician arbitrarily decided to withdraw steroids first and then mycophenolate mofetil and maintain each patient on a low dose tacrolimus. We compared the characteristics of prope tolerant recipients on a low-dose tacrolimus with those on standard immunosuppression, namely full-dose tacrolimus plus steroids and mycophenolate mofetil (n = 233). Data were analyzed by t-test, chi-square test using SPSS software version 16.

RESULTS

Out of over 3800 liver transplant patients, 90 (2.34%) recipients were treated with a minimum dose of tacrolimus monotherapy. These recipients were compared to a selected group of 233 (6.1%) recipients treated with full-dose tacrolimus plus steroids and mycophenolate mofetil. In a prope tolerant group, there were 55 males (61.1%) and 35 females (38.9%) recipients. Mean age at the time of transplant was 39.92 ± (SD = 13.40) years with an average time from the transplantation time to completed weaning from triple immunosuppression to low-dose monotherapy of 41.35 months (SD = 17.27). The most common etiology of liver disease among both groups was viral hepatitis.

CONCLUSION

The achievement of prope (almost) immune tolerance was possible only in some liver transplant recipients with a relatively low risk of rejection. Our analysis suggests that there is a difference in the underlying diseases and recipients' age and the number of rejections between the two groups.

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Lee SJ, Kim HJ, Byun NR, Park CG. Donor-Specific Regulatory T Cell-Mediated Immune Tolerance in an Intrahepatic Murine Allogeneic Islet Transplantation Model with Short-Term Anti-CD154 mAb Single Treatment. Cell Transplant 2021;29:963689720913876. [PMID: 32216448 PMCID: PMC7586274 DOI: 10.1177/0963689720913876] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open

Affiliation(s)

Seok-Joo Lee Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Department of Oral Microbiology and Immunology, Seoul National University School of Dentistry, Seoul, Korea
Hyun-Je Kim Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea Department of Dermatology, Samsung Medical Center, Seoul, Korea
Na-ri Byun Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea Byun is now with the Hanmi R&D center, Hwaseong-si, Gyeonggi-do18469, Korea
Chung-Gyu Park Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Department of Dermatology, Samsung Medical Center, Seoul, Korea Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Korea Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea Chung-Gyu Park, MD, PhD, 103 Daehak-ro, Jongno-gu, 110-799 Seoul, South Korea. Emails: ;

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Chahal D, Hussaini T, Farnell D, Nador R, Yoshida EM. Isolated Liver Rejection After Lung and Combined Kidney-Liver Transplantation: A Case Report. Transplant Proc 2021;53:1333-1336. [PMID: 33750588 DOI: 10.1016/j.transproceed.2021.02.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 12/31/2020] [Accepted: 02/01/2021] [Indexed: 12/01/2022]

Kroemer A, Khan K, Kaufman SS, Kang J, Weiner J, Duttargi A, Belyayev L, Ashokkumar C, Sindhi R, Timofeeva OA, Zasloff M, Matsumoto CS, Fishbein TM. Operational tolerance in intestinal transplantation. Am J Transplant 2021;21:876-882. [PMID: 32721092 PMCID: PMC8274367 DOI: 10.1111/ajt.16224] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 06/29/2020] [Accepted: 07/15/2020] [Indexed: 01/25/2023]

Affiliation(s)

Alexander Kroemer Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
Khalid Khan Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
Stuart S Kaufman Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
Jiman Kang Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
Joshua Weiner Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
Anju Duttargi Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
Leonid Belyayev Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
Chethan Ashokkumar The Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
Rakesh Sindhi The Hillman Center for Pediatric Transplantation, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
Olga A Timofeeva Department of Pathology and Laboratory Medicine, Georgetown University Medical Center, Washington, District of Columbia, USA
Michael Zasloff Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
Cal S Matsumoto Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA
Thomas M Fishbein Center for Translational Transplant Medicine, MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Georgetown University Medical Center, Washington, District of Columbia, USA

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Induction of Allograft Tolerance While Maintaining Immunity Against Microbial Pathogens: Does Coronin 1 Hold a Key? Transplantation 2020;104:1350-1357. [PMID: 31895336 DOI: 10.1097/tp.0000000000003101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]

Dai H, Zheng Y, Thomson AW, Rogers NM. Transplant Tolerance Induction: Insights From the Liver. Front Immunol 2020;11:1044. [PMID: 32582167 PMCID: PMC7289953 DOI: 10.3389/fimmu.2020.01044] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 04/30/2020] [Indexed: 12/13/2022] Open

Chimerism, Transplant Tolerance, and Beyond. Transplantation 2020;103:1556-1567. [PMID: 30896678 DOI: 10.1097/tp.0000000000002711] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]

Edgar L, Pu T, Porter B, Aziz JM, La Pointe C, Asthana A, Orlando G. Regenerative medicine, organ bioengineering and transplantation. Br J Surg 2020;107:793-800. [DOI: 10.1002/bjs.11686] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 04/17/2020] [Indexed: 12/21/2022]

Abstract Abstract Background Organ transplantation is predicted to increase as life expectancy and the incidence of chronic diseases rises. Regenerative medicine-inspired technologies challenge the efficacy of the current allograft transplantation model. Methods A literature review was conducted using the PubMed interface of MEDLINE from the National Library of Medicine. Results were examined for relevance to innovations of organ bioengineering to inform analysis of advances in regenerative medicine affecting organ transplantation. Data reports from the Scientific Registry of Transplant Recipient and Organ Procurement Transplantation Network from 2008 to 2019 of kidney, pancreas, liver, heart, lung and intestine transplants performed, and patients currently on waiting lists for respective organs, were reviewed to demonstrate the shortage and need for transplantable organs. Results Regenerative medicine technologies aim to repair and regenerate poorly functioning organs. One goal is to achieve an immunosuppression-free state to improve quality of life, reduce complications and toxicities, and eliminate the cost of lifelong antirejection therapy. Innovative strategies include decellularization to fabricate acellular scaffolds that will be used as a template for organ manufacturing, three-dimensional printing and interspecies blastocyst complementation. Induced pluripotent stem cells are an innovation in stem cell technology which mitigate both the ethical concerns associated with embryonic stem cells and the limitation of other progenitor cells, which lack pluripotency. Regenerative medicine technologies hold promise in a wide array of fields and applications, such as promoting regeneration of native cell lines, growth of new tissue or organs, modelling of disease states, and augmenting the viability of existing ex vivo transplanted organs. Conclusion The future of organ bioengineering relies on furthering understanding of organogenesis, in vivo regeneration, regenerative immunology and long-term monitoring of implanted bioengineered organs. Collapse

The role of complement activation in autoimmune liver disease. Autoimmun Rev 2020;19:102534. [PMID: 32234403 DOI: 10.1016/j.autrev.2020.102534] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 12/20/2019] [Indexed: 12/12/2022]

Abstract

INTRODUCTION

The complement system, an essential part of the innate immune system, is involved in various autoimmune diseases. Activation of the complement system by autoantibodies results in immune activation and tissue damage. At the moment little is known about the role of the complement system in autoimmune liver disease, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). Since inhibition of the complement system is currently being tested in several autoimmune diseases as a therapeutic option, its role in autoimmune liver disease requires further clarification.

METHODS

A review of the literature was performed on studies investigating complement activation in PBC, PSC and AIH. Since data on AIH were lacking immunohistochemical staining for IgG, C1q, C3d, C4d and C5b9 was performed on liver tissue of nine AIH patients, two healthy controls and one positive control (acute liver failure caused by paracetamol intoxication).

RESULTS

Immunohistochemical analysis in AIH revealed increased production of C3 and C4 by hepatocytes. Despite a strong staining for IgG in the immune infiltrate in AIH, C3d, C4d and C5b9 deposition was only present in one AIH patient and the deposition was restricted to the interface between portal tracts and liver parenchyma. No deposition was found in all other AIH patients or healthy controls. Literature review showed raised plasma C3 and C4 levels in AIH, PBC and PSC patients compared to healthy controls. For PBC and PSC no complement depositions at the bile ducts were reported.

CONCLUSION AND DISCUSSION

Although complement is involved in various autoimmune diseases, the role of complement in autoimmune liver disease seems limited. Therefore it is unlikely that complement inhibition will become a novel treatment option for these diseases.

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Suresh S, Upton J, Green M, Pham-Huy A, Posfay-Barbe KM, Michaels MG, Top KA, Avitzur Y, Burton C, Chong PP, Danziger-Isakov L, Dipchand AI, Hébert D, Kumar D, Morris SK, Nalli N, Ng VL, Nicholas SK, Robinson JL, Solomon M, Tapiero B, Verma A, Walter JE, Allen UD. Live vaccines after pediatric solid organ transplant: Proceedings of a consensus meeting, 2018. Pediatr Transplant 2019;23:e13571. [PMID: 31497926 DOI: 10.1111/petr.13571] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 07/12/2019] [Accepted: 07/26/2019] [Indexed: 12/11/2022]

Affiliation(s)

Sneha Suresh Division of Infectious Disease and IHOPE, Department of Pediatrics, Stollery Children's Hospital, University of Alberta, Edmonton, AB, Canada
Julia Upton Division of Immunology and Allergy, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Michael Green Division of Infectious Diseases, Department of Pediatrics, Pediatric Transplant Infectious Diseases, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
Anne Pham-Huy Division of Infectious Diseases, Immunology and Allergy, Department of Paediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada
Klara M Posfay-Barbe Division of Pediatric Infectious Diseases, Department of Paediatrics, University Hospitals of Geneva, Geneva, Switzerland
Marian G Michaels Division of Infectious Diseases, Department of Pediatrics, Pediatric Transplant Infectious Diseases, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
Karina A Top Division of Infectious Diseases, Department of Pediatrics, Dalhousie University, Canadian Center for Vaccinology IWK Health Centre, Halifax, NS, Canada
Yaron Avitzur Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Transplant and Regenerative Medicine Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Catherine Burton Division of Infectious Diseases, Department of Paediatrics, Stollery Children's Hospital, University of Alberta, Edmonton, AB, Canada
Pearlie P Chong Division of Infectious Diseases, Department of Medicine, UT Southwestern Medical Center, Dallas, Texas
Lara Danziger-Isakov Division of Infectious Diseases, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio
Anne I Dipchand Department of Paediatrics, Labatt Family Heart Centre, Transplant and Regenerative Medicine Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Diane Hébert Division of Nephrology, Department of Paediatrics, Transplant and Regenerative Medicine Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Deepali Kumar Department of Medicine, Transplant Infectious Diseases, University Health Network, Toronto, ON, Canada
Shaun K Morris Division of Infectious Diseases, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Nadya Nalli Department of Pharmacy, Department of Paediatrics, Transplant and Regenerative Medicine Centre, Hospital for Sick Children, Toronto, ON, Canada
Vicky Lee Ng Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Transplant and Regenerative Medicine Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Sarah Kogan Nicholas Division of Immunology, Allergy and Rheumatology, Department of Pediatrics, Texas Children's Hospital, Houston, Texas
Joan L Robinson Division of Infectious Diseases and Immunology, Department of Pediatrics, Stollery Children's Hospital, University of Alberta, Edmonton, AB, Canada
Melinda Solomon Division of Respiratory Medicine, Department of Paediatrics, Transplant and Regenerative Medicine Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Bruce Tapiero Division of Infectious Diseases, Department of Paediatrics, CHU Sainte Justine, University of Montreal, Montreal, QC, Canada
Anita Verma Department of Infection Science, Kings College Hospital, London, UK
Jolan E Walter Division of Pediatric Allergy/Immunology, Department of Pediatrics, University of South Florida, John's Hopkins All Children's Hospital, St. Petersburg, Florida.,Division of Pediatric Allergy/Immunology, Massachusetts General Hospital for Children, Boston, Massachusetts
Upton D Allen Division of Infectious Diseases, Department of Paediatrics, Transplant and Regenerative Medicine Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

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Immunosuppressive drug withdrawal late after liver transplantation improves the lipid profile and reduces infections. Eur J Gastroenterol Hepatol 2019;31:1444-1451. [PMID: 31095525 DOI: 10.1097/meg.0000000000001435] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]

Hepatic Stellate Cells Enhance Liver Cancer Progression by Inducing Myeloid-Derived Suppressor Cells through Interleukin-6 Signaling. Int J Mol Sci 2019;20:ijms20205079. [PMID: 31614930 PMCID: PMC6834132 DOI: 10.3390/ijms20205079] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 10/05/2019] [Accepted: 10/11/2019] [Indexed: 01/07/2023] Open

Manzia TM, Angelico R, Gazia C, Lenci I, Milana M, Ademoyero OT, Pedini D, Toti L, Spada M, Tisone G, Baiocchi L. De novo malignancies after liver transplantation: The effect of immunosuppression-personal data and review of literature. World J Gastroenterol 2019;25:5356-5375. [PMID: 31558879 PMCID: PMC6761240 DOI: 10.3748/wjg.v25.i35.5356] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 08/08/2019] [Accepted: 08/24/2019] [Indexed: 02/06/2023] Open

Abstract

BACKGROUND

Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with critical systemic morbidities. De novo malignancies following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between immunosuppression and de novo malignancies in liver transplant patients.

AIM

To study the role of immunosuppression on the incidence of de novo malignancies in liver transplant recipients.

METHODS

A systematic literature examination about de novo malignancies and immunosuppression weaning in adult and pediatric OLT recipients was described in the present review. Worldwide data were collected from highly qualified institutions performing OLTs. Patient follow-up, immunosuppression discontinuation and incidence of de novo malignancies were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted immunosuppression regimens and the different type of diagnosed solid and blood malignancy.

RESULTS

Emerging evidence suggests that the liver is an immunologically privileged organ able to support immunosuppression discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily immunosuppression regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected de novo malignancies in the pediatric and adult OLT population, respectively. To date, immunosuppression withdrawal has been achieved in up to 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of immunosuppression weaning protocols on de novo malignancies is difficult to ascertain because data have not been specified in most of the clinical experiences.

CONCLUSION

The selected populations of tolerant pediatric and adult liver transplant recipients greatly benefit from immunosuppression weaning. There is still no strong clinical evidence on the usefulness of immunosuppression withdrawal in OLT recipients on malignancies. An interesting focus is represented by the complete reconstitution of the immunological pathways that could help in decreasing the incidence of de novo malignancies and may also help in treating liver transplant patients suffering from cancer.

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Thorgersen EB, Barratt‐Due A, Haugaa H, Harboe M, Pischke SE, Nilsson PH, Mollnes TE. The Role of Complement in Liver Injury, Regeneration, and Transplantation. Hepatology 2019;70:725-736. [PMID: 30653682 PMCID: PMC6771474 DOI: 10.1002/hep.30508] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 01/10/2019] [Indexed: 12/20/2022]

Rethinking Regenerative Medicine From a Transplant Perspective (and Vice Versa). Transplantation 2019;103:237-249. [DOI: 10.1097/tp.0000000000002370] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]

Honeyman C, Fries CA. Vascularised Composite Allotransplantation – Basic Science and Clinical Applications. ACTA ACUST UNITED AC 2019. [DOI: 10.29337/ijops.28] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]

Manzia TM, Gazia C, Baiocchi L, Lenci I, Milana M, Santopaolo F, Angelico R, Tisone G. Clinical Operational Tolerance and Immunosuppression Minimization in Kidney Transplantation: Where Do We Stand? Rev Recent Clin Trials 2019;14:189-202. [PMID: 30868959 DOI: 10.2174/1574887114666190313170205] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 02/27/2019] [Accepted: 03/05/2019] [Indexed: 06/09/2023]

Wood KJ, Shankar S, Hester J, Issa F. Concepts and Challenges in Organ Transplantation. Clin Immunol 2019. [DOI: 10.1016/b978-0-7020-6896-6.00081-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]

Black CK, Termanini KM, Aguirre O, Hawksworth JS, Sosin M. Solid organ transplantation in the 21^st century. ANNALS OF TRANSLATIONAL MEDICINE 2018;6:409. [PMID: 30498736 PMCID: PMC6230860 DOI: 10.21037/atm.2018.09.68] [Citation(s) in RCA: 175] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 09/29/2018] [Indexed: 12/20/2022]

Cell Therapy as a Tool for Induction of Immunological Tolerance after Liver Transplantation. Bull Exp Biol Med 2018;165:554-563. [PMID: 30121913 DOI: 10.1007/s10517-018-4213-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Indexed: 12/13/2022]

Litjens NHR, van der Wagen L, Kuball J, Kwekkeboom J. Potential Beneficial Effects of Cytomegalovirus Infection after Transplantation. Front Immunol 2018;9:389. [PMID: 29545802 PMCID: PMC5838002 DOI: 10.3389/fimmu.2018.00389] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 02/12/2018] [Indexed: 01/03/2023] Open

Abstract

Cytomegalovirus (CMV) infection can cause significant complications after transplantation, but recent emerging data suggest that CMV may paradoxically also exert beneficial effects in two specific allogeneic transplant settings. These potential benefits have been underappreciated and are therefore highlighted in this review. First, after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) using T-cell and natural killer (NK) cell-replete grafts, CMV reactivation is associated with protection from leukemic relapse. This association was not observed for other hematologic malignancies. This anti-leukemic effect might be mediated by CMV-driven expansion of donor-derived memory-like NKG2C⁺ NK and Vδ2^negγδ T-cells. Donor-derived NK cells probably recognize recipient leukemic blasts by engagement of NKG2C with HLA-E and/or by the lack of donor (self) HLA molecules. Vδ2^negγδ T cells probably recognize as yet unidentified antigens on leukemic blasts via their TCR. Second, immunological imprints of CMV infection, such as expanded numbers of Vδ2^negγδ T cells and terminally differentiated TCRαβ⁺ T cells, as well as enhanced NKG2C gene expression in peripheral blood of operationally tolerant liver transplant patients, suggest that CMV infection or reactivation may be associated with liver graft acceptance. Mechanistically, poor alloreactivity of CMV-induced terminally differentiated TCRαβ⁺ T cells and CMV-induced IFN-driven adaptive immune resistance mechanisms in liver grafts may be involved. In conclusion, direct associations indicate that CMV reactivation may protect against AML relapse after allogeneic HSCT, and indirect associations suggest that CMV infection may promote allograft acceptance after liver transplantation. The causative mechanisms need further investigations, but are probably related to the profound and sustained imprint of CMV infection on the immune system.

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ImmunoCloak as a Paradigm of the Biomaterial Approach to Immunomodulation: Where Regenerative Medicine Meets Organ Transplantation. Transplantation 2018;101:234-235. [PMID: 27798511 DOI: 10.1097/tp.0000000000001551] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]

Chimerism: A Clinical Guide to Tolerance Induction. CHIMERISM 2018. [DOI: 10.1007/978-3-319-89866-7_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]

Geng L, Liu J, Huang J, Lin B, Yu S, Shen T, Wang Z, Yang Z, Zhou L, Zheng S. A high frequency of CD8⁺CD28^- T-suppressor cells contributes to maintaining stable graft function and reducing immunosuppressant dosage after liver transplantation. Int J Med Sci 2018;15:892-899. [PMID: 30008601 PMCID: PMC6036103 DOI: 10.7150/ijms.24042] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 02/27/2018] [Indexed: 01/15/2023] Open

Affiliation(s)

Lei Geng Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Division of Liver Transplantation, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
Jingfeng Liu Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Division of Liver Transplantation, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
Junjie Huang Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Division of Liver Transplantation, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
Bingyi Lin Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Division of Liver Transplantation, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
Songfeng Yu Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Division of Liver Transplantation, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
Tian Shen Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Division of Liver Transplantation, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
Zhuoyi Wang Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Division of Liver Transplantation, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
Zhe Yang Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Division of Liver Transplantation, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
Lin Zhou Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Division of Liver Transplantation, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
Shuseng Zheng Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Division of Liver Transplantation, Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China

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Anti-donor regulatory T cell therapy in liver transplantation. Hum Immunol 2017;79:288-293. [PMID: 29292027 DOI: 10.1016/j.humimm.2017.12.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 12/14/2017] [Accepted: 12/21/2017] [Indexed: 12/14/2022]

Mechanisms of liver-induced tolerance. Curr Opin Organ Transplant 2017;22:71-78. [PMID: 27984276 DOI: 10.1097/mot.0000000000000380] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]

Geng L, Huang JJ, Lin BY, Chen TC, Shen T, Zheng SS. Characteristics of recipients with complete immunosuppressant withdrawal after adult liver transplantation. Hepatobiliary Pancreat Dis Int 2017;16:437-439. [PMID: 28823376 DOI: 10.1016/s1499-3872(17)60043-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]

Affiliation(s)

Lei Geng Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
Jun-Jie Huang Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
Bing-Yi Lin Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
Tian-Chi Chen Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
Tian Shen Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
Shu-Sen Zheng Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China.

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Kullberg-Lindh C, Saalman R, Olausson M, Herlenius G, Lindh M. Epstein-Barr virus DNA monitoring in serum and whole blood in pediatric liver transplant recipients who do or do not discontinue immunosuppressive therapy. Pediatr Transplant 2017;21. [PMID: 28039929 DOI: 10.1111/petr.12875] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/23/2016] [Indexed: 12/17/2022]

Behnam Sani K, Sawitzki B. Immune monitoring as prerequisite for transplantation tolerance trials. Clin Exp Immunol 2017;189:158-170. [PMID: 28518214 DOI: 10.1111/cei.12988] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2017] [Indexed: 02/06/2023] Open

Clavien PA, Muller X, de Oliveira ML, Dutkowski P, Sanchez-Fueyo A. Can immunosuppression be stopped after liver transplantation? Lancet Gastroenterol Hepatol 2017;2:531-537. [PMID: 28606879 DOI: 10.1016/s2468-1253(16)30208-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 11/30/2016] [Accepted: 11/30/2016] [Indexed: 12/22/2022]

Romano M, Tung SL, Smyth LA, Lombardi G. Treg therapy in transplantation: a general overview. Transpl Int 2017;30:745-753. [PMID: 28012226 DOI: 10.1111/tri.12909] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 09/26/2016] [Accepted: 12/19/2016] [Indexed: 12/23/2022]

Miloh T, Barton A, Wheeler J, Pham Y, Hewitt W, Keegan T, Sanchez C, Bulut P, Goss J. Immunosuppression in pediatric liver transplant recipients: Unique aspects. Liver Transpl 2017;23:244-256. [PMID: 27874250 DOI: 10.1002/lt.24677] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 11/03/2016] [Indexed: 02/07/2023]

Yolcu ES, Shirwan H, Askenasy N. Mechanisms of Tolerance Induction by Hematopoietic Chimerism: The Immune Perspective. Stem Cells Transl Med 2017;6:700-712. [PMID: 28186688 PMCID: PMC5442770 DOI: 10.1002/sctm.16-0358] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 09/02/2016] [Accepted: 10/10/2016] [Indexed: 01/05/2023] Open

Conti F, Dahlqvist G, Brisson H, Miyara M, Calmus Y, Gorochov G. Regulatory T cell therapy: An option to induce operational tolerance in liver transplantation. Clin Res Hepatol Gastroenterol 2016;40:660-665. [PMID: 27288298 DOI: 10.1016/j.clinre.2016.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 04/26/2016] [Accepted: 05/02/2016] [Indexed: 02/04/2023]

Todo S, Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T, Watanabe M, Aoyagi T, Suzuki T, Shimamura T, Kamiyama T, Sato N, Sugita J, Hatanaka K, Bashuda H, Habu S, Demetris AJ, Okumura K. A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology 2016;64:632-43. [PMID: 26773713 DOI: 10.1002/hep.28459] [Citation(s) in RCA: 321] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 01/07/2016] [Indexed: 12/11/2022]

Abstract

UNLABELLED

Potent immunosuppressive drugs have significantly improved early patient survival after liver transplantation (LT). However, long-term results remain unsatisfactory because of adverse events that are largely associated with lifelong immunosuppression. To solve this problem, different strategies have been undertaken to induce operational tolerance, for example, maintenance of normal graft function and histology without immunosuppressive therapy, but have achieved limited success. In this pilot study, we aimed to induce tolerance using a novel regulatory T-cell-based cell therapy in living donor LT. Adoptive transfer of an ex vivo-generated regulatory T-cell-enriched cell product was conducted in 10 consecutive adult patients early post-LT. Cells were generated using a 2-week coculture of recipient lymphocytes with irradiated donor cells in the presence of anti-CD80/86 monoclonal antibodies. Immunosuppressive agents were tapered from 6 months, reduced every 3 months, and completely discontinued by 18 months. After the culture, the generated cells displayed cell-number-dependent donor-specific inhibition in the mixed lymphocyte reaction. Infusion of these cells caused no significant adverse events. Currently, all patients are well with normal graft function and histology. Seven patients have completed successful weaning and cessation of immunosuppressive agents. At present, they have been drug free for 16-33 months; 4 patients have been drug free for more than 24 months. The other 3 recipients with autoimmune liver diseases developed mild rejection during weaning and then resumed conventional low-dose immunotherapy.

CONCLUSIONS

A cell therapy using an ex vivo-generated regulatory T-cell-enriched cell product is safe and effective for drug minimization and operational tolerance induction in living donor liver recipients with nonimmunological liver diseases. (Hepatology 2016;64:632-643).

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Issa F. Vascularized composite allograft-specific characteristics of immune responses. Transpl Int 2016;29:672-81. [PMID: 26927941 DOI: 10.1111/tri.12765] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 07/03/2015] [Accepted: 02/24/2016] [Indexed: 01/31/2023]