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 Our aim was to determine if operational tolerance could be observed in LTRs withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal.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.
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 Our aim was to determine if operational tolerance could be observed in LTRs withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal.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.
Authors: Kylie M Quinn; Annette Fox; Kim L Harland; Brendan E Russ; Jasmine Li; Thi H O Nguyen; Liyen Loh; Moshe Olshanksy; Haroon Naeem; Kirill Tsyganov; Florian Wiede; Rosela Webster; Chantelle Blyth; Xavier Y X Sng; Tony Tiganis; David Powell; Peter C Doherty; Stephen J Turner; Katherine Kedzierska; Nicole L La Gruta Journal: Cell Rep Date: 2018-06-19 Impact factor: 9.423
Authors: Sandy Feng; Anthony J Demetris; Katharine M Spain; Sai Kanaparthi; Bryna E Burrell; Udeme D Ekong; Estella M Alonso; Philip Rosenthal; Laurence A Turka; David Ikle; Nadia K Tchao Journal: Hepatology Date: 2016-07-27 Impact factor: 17.425
Authors: George V Mazariegos; Alan F Zahorchak; Jorge Reyes; Lynn Ostrowski; Bridget Flynn; Adriana Zeevi; Angus W Thomson Journal: Am J Transplant Date: 2003-06 Impact factor: 8.086
Authors: Jaap Kwekkeboom; Nicolle H R Litjens; Aafke A Duizendstra; Robert J de Knegt; Shanta Mancham; Mariska Klepper; Dave L Roelen; Simone H Brand-Schaaf; Patrick P Boor; Michail Doukas; Robert A de Man; Dave Sprengers; Maikel P Peppelenbosch; Michiel G H Betjes Journal: Liver Transpl Date: 2021-07-21 Impact factor: 6.112
Authors: Aafke A Duizendstra; Michelle V van der Grift; Patrick P Boor; Lisanne Noordam; Robert J de Knegt; Maikel P Peppelenbosch; Michiel G H Betjes; Nicolle H R Litjens; Jaap Kwekkeboom Journal: Front Immunol Date: 2022-01-11 Impact factor: 7.561