Late Acute Liver Allograft Rejection; A Study of Its Natural History and Graft Survival in the Current Era

Thurairajah, Prem Harichander; Carbone, Marco; Bridgestock, H.; Thomas, Philip; Hebbar, Srisha; Gunson, Bridget K.; Shah, Tahir; Neuberger, James

doi:10.1097/tp.0b013e3182845f6c

Cited by 114 publications

(98 citation statements)

References 29 publications

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“…The role of late SCR remained unclear. However, late episodes of ACR were shown to be associated with poorer clinical outcome compared to early episodes of ACR …”

mentioning

confidence: 98%

Preferential accumulation of T helper cells but not cytotoxic T cells characterizes benign subclinical rejection of human liver allografts

Baumann

Schlué²,

Noyan

et al. 2016

Liver Transpl

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Subclinical rejection (SCR) is a common event in protocol biopsies after liver transplantation (LT). So far the interpretation of the underlying histological changes and clinical significance is limited. Previous studies were restricted to SCR manifestations within the first weeks after transplantation with limited follow-up. We analyzed clinical data from our prospective protocol biopsy program and found late SCR (at least 3 months after transplantation) to be a common event (41/94 patients). SCR manifested much later than acute cellular rejection (ACR). In the second year after transplantation, the SCR incidence in protocol biopsies reached a plateau of approximately 25% and remained at this level until the latest observed manifestations more than 5 years after transplantation. During a median follow-up of 32 months after SCR, no acute or chronic rejection, relevant graft fibrosis, graft loss, or liver-related death occurred even without specific therapy for SCR. Immunophenotyping of liver biopsies during SCR showed that similar to ACR, the composition of intrahepatic T cells depended on the severity of histological rejection. However, SCR showed a different pattern of infiltrating T cells with a stronger accumulation of CD4 1 cells, an increasing CD4 1 /CD8 1 ratio, and an increasing CD4 1 forkhead box P3 (FOXP3) 1 regulatory T cell (Treg)/CD8 1 ratio, which was not seen in ACR. These intrahepatic T cell patterns were not reflected in the peripheral blood. In conclusion, late SCR after LT has a good clinical prognosis, and it seems safe to leave it untreated. This benign clinical course compared to ACR is associated with intrahepatic T cell infiltration patterns showing less cytotoxic T cells and more CD4 1 FOXP3 1 Tregs.Liver Transplantation 22 943-955 2016 AASLD.Received November 13, 2015; accepted February 16, 2016. The liver is immunologically privileged and requires lower levels of immunosuppression (IS); it also shows relatively low rates of chronic rejection and the highest rates of spontaneous operational tolerance after transplantation. However, the rate of acute rejection is still at approximately 30%.(1-3)Acute cellular rejection (ACR) is characterized by the appearance of mixed portal infiltrates, venous endotheliitis, and bile duct lesions. It is categorized using the rejection activity index (RAI), (4) and it manifests mostly within the first weeks to months after liver transplantation (LT). Subclinical rejection (SCR) is defined as histological rejection without the accompanying biochemical abnormalities and can thus only be diagnosed in protocol biopsy programs. Previous studies described the role of early SCR weeks after transplantation. They found that it occurred in 1%-60% of patients and showed no stringent

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“…The role of late SCR remained unclear. However, late episodes of ACR were shown to be associated with poorer clinical outcome compared to early episodes of ACR …”

mentioning

confidence: 98%

Preferential accumulation of T helper cells but not cytotoxic T cells characterizes benign subclinical rejection of human liver allografts

Baumann

Schlué²,

Noyan

et al. 2016

Liver Transpl

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“…However, AR still remains a crucial determining factor which influences the short-term function and long-term outcome of both recipients and allografts [38]–[40]. To the best of our knowledge, this is the first meta-analysis focusing on the combined effects of TGFB1 +869 T/C and +915 G/C polymorphisms on AR risk.…”

Section: Discussionmentioning

confidence: 95%

Combined Effects of TGFB1 +869 T/C and +915 G/C Polymorphisms on Acute Rejection Risk in Solid Organ Transplant Recipients: A Systematic Review and Meta-Analysis

et al. 2014

PLoS ONE

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BackgroundTransforming growth factor-beta 1(TGF-β1) is involved in the development of acute rejection (AR) episodes in solid organ transplant recipients; and a number of studies have been conducted to investigate the combined effects of human TGF-β1 gene (TGFB1) +869 T/C and +915 G/C polymorphisms on AR risk. However, the results obtained are inconclusive.MethodsEligible studies that investigated the haplotypic association between TGFB1 +869 T/C and +915 G/C polymorphisms and AR risk were comprehensively searched in the PUBMED, EMBASE, China National Knowledge Infrastructure, and Wanfang Database. Statistical analyses were performed by using STATA 12.0 and Review Manager 5.0.ResultsFourteen eligible studies with 565 AR cases and 1219 non-AR cases were included. Overall, a significantly decreased risk was detected in patients carried with intermediate producer (IP) haplotypes (T/C G/C, T/T G/C, and C/C G/G) and/or low producer (LP) haplotypes (C/C G/C, C/C C/C, T/T C/C, and T/C C/C) compared with high producer (HP) haplotypes (T/T G/G and T/C G/G; IP vs. HP: OR = 0.75, 95% CI, 0.58–0.96, P heterogeneity = 0.238; IP/LP vs. HP: OR = 0.77, 95% CI, 0.61–0.98, P heterogeneity = 0.144). In addition, subgroup analysis by transplant types demonstrated a similar association in patients receiving heart transplant (IP vs. HP: OR = 0.32, 95% CI, 0.14–0.73, P heterogeneity = 0.790; IP/LP vs. HP: OR = 0.41, 95% CI, 0.20–0.85, P heterogeneity = 0.320).ConclusionsThe current meta-analysis and systematic review indicated that recipient TGFB1 HP haplotypes were significantly associated with an increased risk for AR in solid organ transplant recipients, particularly patients receiving cardiac allograft.

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“…In this study, patients with high-risk disease tended to have a higher Scheuer score at their first biopsy, although there was no clear-cut off point. The cholangitis component of the Nakanuma score (Carbone et al, 2013, Thurairajah et al, 2013) appeared to enable a degree of differentiation between high- and low-risk disease, but the hepatitis component did not. It was notable, however, that all patients with high-risk disease had evidence of ductopenia on biopsy, only present in one low risk patient.…”

Section: Discussionmentioning

confidence: 97%

Early Molecular Stratification of High-risk Primary Biliary Cholangitis

et al. 2016

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High-risk primary biliary cholangitis (PBC), defined by inadequate response at one year to Ursodeoxycholic acid (UDCA), is associated with disease progression and liver transplantation. Stratifying high-risk patients early would facilitate improved approaches to care. Using long-term follow-up data to define risk at presentation, 6 high-risk PBC patients and 8 low-risk patients were identified from biopsy, transplant and biochemical archival records. Formalin-fixed paraffin-embedded (FFPE) liver biopsies taken at presentation were graded (Scheuer and Nakanuma scoring) and gene expression analysed using the NanoString® nCounter PanCancer Immunity 770-gene panel. Principle component analysis (PCA) demonstrated discrete gene expression clustering between controls and high- and low-risk PBC. High-risk PBC was characterised by up-regulation of genes linked to T-cell activation and apoptosis, INF-γ signalling and leukocyte migration and down-regulation of those linked to the complement pathway. CDKN1a, up-regulated in high-risk PBC, correlated with significantly increased expression of its gene product, the senescence marker p21WAF1/Cip, by biliary epithelial cells. Our findings suggest high- and low-risk PBC are biologically different from disease outset and senescence an early feature in high-risk disease. Identification of a high-risk ‘signal’ early from standard FFPE tissue sections has clear clinical utility allowing for patient stratification and second-line therapeutic intervention.

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Late Acute Liver Allograft Rejection; A Study of Its Natural History and Graft Survival in the Current Era

Abstract: LAR continues to provide a risk to patient and graft survival: understanding risk factors may allow an improvement in monitoring and early intervention and so prevent early graft loss.

Cited by 114 publications

References 29 publications

Preferential accumulation of T helper cells but not cytotoxic T cells characterizes benign subclinical rejection of human liver allografts

Preferential accumulation of T helper cells but not cytotoxic T cells characterizes benign subclinical rejection of human liver allografts

Combined Effects of TGFB1 +869 T/C and +915 G/C Polymorphisms on Acute Rejection Risk in Solid Organ Transplant Recipients: A Systematic Review and Meta-Analysis

Early Molecular Stratification of High-risk Primary Biliary Cholangitis

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