Immunosuppression withdrawal in liver transplant recipients on sirolimus

: As conversion from calcineurin inhibitor (CNI) to sirolimus (SRL), an mTOR-inhibitor (mTOR-I), has been shown to enhance immunoregulatory profiles in liver transplant recipients (LTR), mTOR-I therapy might allow for increased success with immunosuppression withdrawal. Our aim was to determine if operational tolerance could be observed in LTR withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal. We performed a prospective trial of SRL monotherapy withdrawal in non-immune, non-viremic LTR > 3 years post-LT. Sirolimus was weaned over ~6 months and biopsies performed 12 months post-weaning or at concern for acute rejection (AR). Twenty-one LTR were consented; 6 were excluded due to subclinical AR on baseline biopsy or other reasons; 15 underwent weaning (age 61.3±8.8 yrs; LT to SRL weaning 6.7±3 yrs). Eight (53%) achieved operational tolerance (TOL). Of the 7 non-TOL, 6 had mild AR on biopsy near the end of weaning or at study end; 1 was removed due to liver cancer recurrence. At baseline preweaning, there were statistically higher blood tolerogenic dendritic cells, regulatory B cells, and cell phenotypes correlating with chronic antigen presentation in the TOL vs. non-TOL groups. At baseline preweaning, a previously identified biopsy gene signature accurately predicted TOL vs. non-TOL in 12/14 LTR. At study end, biopsy staining revealed statistically significant increases in antigen presenting cell:leukocyte pairings, Foxp3+CD4+ T cells, T-bet+CD8+ T cells, and lobular dendritic cells in the non-TOL group. CONCLUSION: This study is the first to evaluate IS withdrawal directly from mTOR-I therapy in LTR and achieved >50% operational tolerance. Pre-weaning blood/graft gene expression and PBMC profiling may be useful as predictors of successful mTOR-I therapy withdrawal. NCT02062944.