Distinct Immune imprints of post‐Liver transplantation hepatitis C persist despite viral clearance

BACKGROUND Recurrence or de novo infection of hepatitis C virus (HCV) after liver-transplantation 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 hepatitis C after liver-transplantation is unknown. METHODS We here studied 74 protein biomarkers in plasma of liver-transplanted 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. RESULTS We found that liver-transplanted patients with active HCV infection displayed distinct alterations of inflammatory protein biomarkers such as CXCL10, CASP-8, CCL20, CCL19, IFN-gamma, CDCP1, IL-18R1, CXCL11, CCL3, IL8, IL12B, TNFB, CXCL6, OPG, IL10, Flt3L, HGF, uPA, NT-3, CCL4, IL6, TNFRSF9, PD-L1, IL18 and MCP-1 and enrichment of peripheral immune cell subsets unlike transplanted patients without HCV infection. Interestingly, patients that cleared HCV post liver-transplantation 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. CONCLUSION Overall, these data indicate that HCV-specific imprints on inflammatory analytes and immune cell subsets post liver-transplantation are not completely normalized by therapy-induced HCV elimination. This is in line with the clinical observation that cure of HCV post-transplantation did not trigger rejection episodes in many patients.