Immunosuppression Withdrawal in Liver Transplant Recipients on Sirolimus

Abstract

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 Our aim was to determine if operational tolerance could be observed in LTRs withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal.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.

Strategies for Deliberate Induction of Immune Tolerance in Liver Transplantation: From Preclinical Models to Clinical Application

“…Pittsburgh group reported that the increase in the ratio of plasmacytoid DCs to monocytoid DCs in peripheral blood was associated with successful withdrawal ( 90 ). Consistent with this finding, a study with a mammalian target of rapamycin (mTOR) inhibitor showed a higher proportion of tolerogenic DCs in tolerant recipients ( 74 ). An increasing number of regulatory T cell subsets (Tregs and gamma-delta T cells) and NK cells in peripheral blood are associated with tolerant recipients, which is consistent with their gene signatures ( 58 , 65 , 74 , 91 ).…”

“…Consistent with this finding, a study with a mammalian target of rapamycin (mTOR) inhibitor showed a higher proportion of tolerogenic DCs in tolerant recipients ( 74 ). An increasing number of regulatory T cell subsets (Tregs and gamma-delta T cells) and NK cells in peripheral blood are associated with tolerant recipients, which is consistent with their gene signatures ( 58 , 65 , 74 , 91 ). A recent report has shown the kinetics of increasing Tregs/Th17 cell ratio over the clinical course as a predictor of the development of tolerance ( 92 ).…”

“…Another topic in the transplantation field of mTOR signaling is the impact on Treg stability and function, usually mTOR inhibition recognized as favorable effects ( 131 ). One recent IS withdrawal trial has been conducted expecting this “Treg friendly effect” to induce operational tolerance ( 74 ). Further investigation is required to elucidate the clinical application of mTOR inhibitors for transplantation tolerance.…”

Progress in Liver Transplant Tolerance and Tolerance-Inducing Cellular Therapies

“…After 12 months from sirolimus withdraw, it showed that 8 recipients (53%) achieved OT. Of the other 7 patients, 3 failed IS withdrawal, 3 developed moderate cellular rejection (TCMR) on liver biopsies at the end of the study, and 1 was withdrawn from the trial owing to adrenal metastasis of hepatocellular carcinoma ( 32 ). The current result showed the OT rate of sirolimus was comparable to CNI-withdrawal studies.…”

“…Levitsky et al also found that, compared with the baseline, the tolerogenic dendritic cells (tolDC), regulatory B cells (Breg), and cell phenotypes associated with chronic antigen presentation in peripheral blood of the OT group was significantly higher than that of the non-OT group. In addition, gene signatures in peripheral blood/biopsy tissue showed that 12/14 LTR could accurately predict tolerance ( 32 ). Chruscinski et al performed a clinical trial (NCT02541916) for the predictive value of gene signatures in peripheral blood/biopsy tissue.…”