Premium
Immunosuppression Withdrawal in Liver Transplant Recipients on Sirolimus
Author(s) -
Levitsky Josh,
Burrell Bryna E.,
Kanaparthi Sai,
Turka Laurence A.,
Kurian Sunil,
SanchezFueyo Alberto,
Lozano Juan J.,
Demetris Anthony,
Lesniak Andrew,
Kirk Allan D.,
Stempora Linda,
Yang GuangYu,
Mathew James M.
Publication year - 2020
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31036
Subject(s) - immunosuppression , sirolimus , calcineurin , medicine , foxp3 , biopsy , cd8 , weaning , gastroenterology , immunology , immune system , transplantation
BACKGROUND AND AIMS As conversion from calcineurin inhibitor to sirolimus (SRL), a mechanistic target of rapamycin inhibitor (mTOR‐I), has been shown to enhance immunoregulatory profiles in liver transplant (LT) recipients (LTRs), mTOR‐I therapy might allow for increased success of immunosuppression (IS) withdrawal. Our aim was to determine if operational tolerance could be observed in LTRs withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal. APPROACH AND RESULTS We performed a prospective trial of SRL monotherapy withdrawal in nonimmune, nonviremic LTRs > 3 years post‐LT. SRL was weaned over ~6 months, and biopsies were performed 12 months postweaning or at concern for acute rejection. Twenty‐one LTRs consented; 6 were excluded due to subclinical acute rejection on baseline biopsy or other reasons, and 15 underwent weaning (age 61.3 ± 8.8 years; LT to SRL weaning 6.7 ± 3 years). Eight (53%) achieved operational tolerance (TOL). Of the 7 who were nontolerant (non‐TOL), 6 had mild acute rejection on biopsy near the end of weaning or at study end; 1 was removed from the trial due to liver cancer recurrence. At baseline preweaning, there were statistically increased blood tolerogenic dendritic cells and cell phenotypes correlating with chronic antigen presentation in the TOL versus non‐TOL groups. A previously identified biopsy gene signature accurately predicted TOL versus non‐TOL in 12/14 LTRs before weaning. At study end, biopsy staining revealed statistically significant increases in antigen‐presenting cell:leukocyte pairings, FOXP3 + /CD4 + T cells, Tbet + /CD8 + T cells, and lobular dendritic cells in the non‐TOL group. CONCLUSIONS This study evaluated IS withdrawal directly from mTOR‐I therapy in LTRs and achieved > 50% operational tolerance. Preweaning gene expression and peripheral blood mononuclear cell profiling may be useful as predictors of successful mTOR‐I therapy withdrawal. NCT02062944.