Abstract
Recurrence or de novo infection of hepatitis C virus (HCV) after liver transplantation (LT) has been associated with progressive graft hepatitis that can be improved by treatment with novel direct-acting antivirals. Cases of rejection episodes have been described during and after HCV treatment. The evolution of innate and adaptive immune response during and after cure of HCV LT is unknown. We studied 74 protein biomarkers in the plasma of LT patients receiving antiviral therapy. In addition, deep immune phenotyping of both the myeloid and lymphoid immune cell subsets in peripheral blood mononuclear cells was performed. We found that LT patients with active HCV infection displayed distinct alterations of inflammatory protein biomarkers, such as C-X-Cmotif chemokine 10 (CXCL10), caspase 8, C-C motif chemokine 20 (CCL20), CCL19, interferon γ, CUB domain-containing protein 1 (CDCP1), interleukin (IL)-18R1, CXCL11, CCL3, IL8, IL12B, tumor necrosis factor-beta, CXCL6, osteoprotegerin, IL10, fms-related tyrosine kinase 3 ligand, hepatocyte growth factor, urokinase-type plasminogen activator, neurotrophin-3, CCL4, IL6, tumornecrosis factor receptor superfamily member 9, programmed death ligand 1, IL18, and monocyte chemotactic protein 1, and enrichment of peripheral immune cell subsets unlike patients without HCV infection who received transplants. Interestingly, patients who cleared HCV after LT did not normalize the altered inflammatory milieu nor did the peripheral immune cell subsets normalize to what would be seen in the absence of HCV recurrence. Overall, these data indicate that HCV-specific imprints on inflammatory analytes and immune cell subsets after LT are not completely normalized by therapy-induced HCV elimination. This is in line with the clinical observation that cure of HCV after LT did not trigger rejection episodes in many patients.
Highlights
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
We found that liver transplantation (LT) patients with active hepatitis C virus (HCV) infection displayed distinct alterations of inflammatory protein biomarkers, such as C-X-Cmotif chemokine 10 (CXCL10), caspase 8, C-C motif chemokine 20 (CCL20), CCL19, interferon γ, CUB domain-containing protein 1 (CDCP1), interleukin (IL) -18R1, CXCL11, CCL3, IL8, IL12B, tumor necrosis factor-β, CXCL6, osteoprotegerin, IL10, fms-related tyrosine kinase 3 ligand, hepatocyte growth factor, urokinase-type plasminogen activator, neurotrophin-3, CCL4, IL6, tumornecrosis factor receptor superfamily member 9, programmed death ligand 1, IL18, and monocyte chemotactic protein 1, and enrichment of peripheral immune cell subsets unlike patients without HCV infection who received transplants
HCV clearance led to significant reduction of some of the upregulated mediators, including CXCL10, caspase 8 (CASP-8), CCL20, CCL19, CDCP1, IFNγ, IL-18R1, CXCL11, IL10, and programmed death ligand 1 (PD-L1) (Fig. 2A,C)
Summary
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Hepatitis C virus (HCV)–associated end-stage liver diseases are major indications for liver transplantation (LT).(1) The recurrence of HCV after LT is Abbreviations: ANOVA, analysis of variance; CASP-8, caspase 8; CD, clusters of differentiation; CCL, C-C motif chemokine; CDCP, CUB domain-containing protein; CM, central memory; Cq, quantitation cycle; CXCL, C-X-Cmotif chemokine; DAA, direct-acting antiviral; DC, dendritic cell; EDTA, ethylene diamine tetraacetic acid; EM, effector memory; FGF, fibroblast growth factor; Flt3L, Fmsrelated tyrosine kinase 3 ligand; GT, genotype; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HCV + LT, HCV recurrence after LT; HGF, hepatocyte growth factor; HLA, human leukocyte antigen; IFN, interferon; IL, interleukin; LT, liver transplantation; MMP1, matrixmetalloproteinase-1; MAIT, mucosal-associated invariant T cell; MCP, monocyte chemoattractant protein; mDC, myeloid-derived ubiquitously observed in almost all patients who are viremic at the time of LT.[2] The disease prognosis following HCV recurrence or de novo infection has been rapid, leading to fibrosis and cirrhosis in less than 5 years and associated with worse outcomes compared with LTs performed for other indications.(3-5) treatment with recently approved direct- acting antiviral (DAA) regimens against HCV are shown to be effective and safe as in patients who did not receive transplants with almost all posttransplant patients achieving sustained virological response (SVR).(6) Importantly, HCV treatment after LT improved the outcome of graft hepatitis C.(7,8) Still, it is not yet known to what extent a slightly higher risk for disease progression persists despite viral clearance. We and others previously reported that several of the innate and adaptive immune responses remain dendritic cell; MMP, matrix metalloproteinase; NK, cell natural killer cell; non-HCV LT, LT without persistent HCV infection; NT-3, neurotrophin-3; OPG, osteoprotegerin; PBMC, peripheral blood mononuclear cell; PCA, principal component analysis; pDC, plasmacytoid dendritic cells; PD-L1, programmed death ligand 1; SCF, stem cell factor; SEM, standard error of the mean; SVR, sustained virological response; SVR-LT, LT with cleared HCV after sustained virological response; TGF-α , transforming growth factor α; TGF- β-1, transforming growth factor β 1; TNFB, tumor necrosis factorbeta; TNFRSF9, tumornecrosis factor receptor superfamily member 9; TRAIL, tumor necrosis factor–related apoptosis-inducing ligand; Tregs, regulatory T cells; t-SNE, t-distributed stochastic neighbor embedding; uPA, urokinase-type plasminogen activator
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