Hepatic Infiltrates in Operational Tolerant Patients After Liver Transplantation Show Enrichment of Regulatory T Cells Before Proinflammatory Genes Are Downregulated

Abstract

These authors contributed equally as a senior author. ‡ Equal first authors.Immunosuppression can be discontinued from selected and stable patients after liver transplantation resulting in spontaneous operational tolerance (SOT), although the underlying mechanisms remain elusive. Thus, we analyzed serial liver biopsy specimens from adult liver recipients enrolled in a prospective multicenter immunosuppression withdrawal trial that used immunophenotyping and transcriptional profiling. Liver specimens were collected before the initiation of weaning, at the time of rejection, or at 1 and 3 years after complete drug discontinuation. Unexpectedly, the tolerated grafts developed portal tract expansion with increased T cell infiltration after immunosuppression withdrawal. This was associated with transient and preferential accumulation of CD4 + FOXP3 + cells and a trend toward upregulation of immune activation and regulatory genes, without signs of rejection. At the same time, no markers of endothelial damage or activation were noted. Portal infiltrates persisted at 3 years but were characterized by decreased expression of genes associated with chronic immunological damage. Further, SOT was not associated with a progressive liver fibrosis up to 5 years. These data suggest that SOT involves several mechanisms: a long-lasting local immune cell persistence with a transient regulatory T cells accumulation followed by a downregulation of immune-activated genes over years. These results have important implications for designs and follow-up of weaning trials.

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“…Operational tolerance is a rare phenomenon after LT [18]. Tregs have been proposed to be key in strategies aiming for tolerance and immunomodulation after SOT [35]. In a recent paper, Todo et al demonstrated that a single Treg injection might promote operational tolerance after living-related LT [36].…”

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“…This is very interesting and somehow unexpected, especially in relation to findings from other IS weaning trials, but in accordance with previous observations in preclinical models. In contrast to the findings presented by Taubert et al (4), increase in portal tract infiltration has rarely been observed; however, most of the published data came from weaning trials with pediatric liver transplant patients (5). In addition, the presence of Foxp3 + T cells in graft infiltrates is controversial because it may enhance fibrosis development at later time points and has been associated with development of chronic rejection.…”

“…In this issue of the American Journal of Transplantation, Taubert et al (4) have engaged this matter and studied the sequence and phenotype of infiltrating leukocytes following IS withdrawal in patients with OT (5). Apart from quantifying the changes of total portal tract infiltrate, Taubert et al concentrated on the balance of Foxp3 + regulatory and Foxp3…”

“…Before jumping to conclusions, one must carefully discuss the findings and limitations of the presented study (4). As mentioned, 24 patients with OT were included in this investigation, but preweaning and 1-and 3-year biopsies and PBMCs were available for complete analysis from only seven.…”

Regulatory T cell therapy: An option to induce operational tolerance in liver transplantation

“…Some immunosuppressive regimens might also affect effector cells, and in that way facilitate tolerance induction. Therefore, it remains unknown whether Treg are mandatory in OT following LT. Several groups are working on identifying biomarkers of tolerance that would help the clinician detecting tolerant individuals [7] or clinical complications such as recurrent hepatitis C [19][20][21]. Most studies have utilized peripheral blood mononuclear cells, but liver samples may be more relevant to identify such markers [19,22].…”