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Title: Defining and interpreting tolerance and rejection biomarkers in liver transplantation
Author: Bonaccorsi Riani, Eliano
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Liver transplantation has become a well-established therapy for end-stage liver diseases over the last decades. Despite the huge progress in perioperative care of liver recipients, which led to an exponential increase on early graft and recipient survival rates, patients are doomed to stay under long-term immunosuppression treatment, being exposed to the consequences of its late side effects. Recently, supported by experimental animal studies and clinical observations, which have endorsed the hepatic tolerogenic trend, attempts to completely wean the patient off immunosuppressive drugs have been made. In a recent published study, 41 (42%) of the 98 enrolled liver recipients could be completely weaned off from immunosuppressive drugs, achieving the operational tolerance status, defined by normal maintenance of clinical graft function without immunological damage in the absence of immunosuppression treatment. On the other hand, eventual rejection episodes were mainly mild and easily treated mostly with reintroduction of the baseline immunosuppression regimen with complete normalization of liver function tests and no graft loss as a consequence of the rejection episode (1). Furthermore, functional analyses performed on baseline liver biopsies suggested that operational tolerance was associated with a differential expression of genes related to iron metabolism (2). In the current study, we checked the influence of iron levels on the immune response using a murine model of ConcanavalinA induced T cell mediate acute liver hepatitis. Iron deficiency significantly blunted the inflammatory liver damage, which was associated with less T cell and NKT cell activation. Aiming to decipher the iron effect on liver tolerance establishment, we set up a fully vascularized rat liver transplant model in the context of iron restriction. Furthermore, taking advantage of the opportunity provided by the sequential liver biopsies and blood samples collected from rejecting recipients in the aforementioned clinical trial, we conducted an extensive molecular analysis trying to identify biomarkers of acute cellular rejection during the immunosuppression withdrawal. Rejection episodes produced distinct blood and liver tissue transcriptional changes independent of HCV status and pharmacological immunosuppression. Gene expression profiles were used to build a blood predictive rejection model in HCV-negative patients. The model identified molecular changes associated with rejection, which were detected 1-2 months before its clinical diagnostic during the clinical trial. Altogether, our results provided insights on the effect that iron has on the tolerance process and in the understanding of molecular rejection biomarkers; which could improve the patient selection and the safety of the future immunosuppression withdrawal clinical trials.
Supervisor: Sanchez Fueyo, Alberto Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available