Khaldoun Ghazal1, Fabien Stenard2, Géraldine Dahlqvist3, Clément Barjon2, Lynda Aoudjehane2, Olivier Scatton4, Filomena Conti5. 1. Sorbonne universités, UPMC université Paris 06, UMR_S 938, CDR Saint-Antoine, 75005 Paris, France; Laboratoire de biochimie, hôpital Bicêtre, AP-HP, 94275 Le Kremlin-Bicêtre cedex, France. Electronic address: khaldoun.ghazal@aphp.fr. 2. Sorbonne universités, UPMC université Paris 06, UMR_S 938, CDR Saint-Antoine, 75005 Paris, France. 3. Sorbonne universités, UPMC université Paris 06, UMR_S 938, CDR Saint-Antoine, 75005 Paris, France; Cliniques universitaires Saint-Luc, 1200 Bruxelles, Belgium. 4. Service de chirurgie et de transplantation hépatique, UPMC Paris 6, hôpital Pitié-Salpêtrière, AP-HP, boulevard de l'Hôpital, 75013 Paris, France. 5. Sorbonne universités, UPMC université Paris 06, UMR_S 938, CDR Saint-Antoine, 75005 Paris, France; Unité médicale de transplantation hépatique, UPMC Paris 6, hôpital Pitié-Salpêtrière, AP-HP, boulevard de l'Hôpital, 75013 Paris, France.
Abstract
BACKGROUND: The mammalian targets of rapamycin (mTOR) inhibitors (sirolimus [SRL] and everolimus [EVR]) are used after transplantation for their immunosuppressive activity. Regulatory T-cells (Tregs) play a crucial role in immune tolerance. mTOR inhibitors appear to preserve Tregs, unlike Tacrolimus (Tac). AIM: The aim of this study was to evaluate the number and function of Tregs in liver transplant recipients before and after conversion from Tac to mTOR inhibitors. METHODS: Fifteen patients with stable graft function where converted to SRL (n=5) or EVR (n=10). Tregs (CD4+ CD25+ FoxP3+ CD127low) number and activity were analysed prospectively in blood cells using flow cytometry, and functional assay. RESULTS: Patients of both groups displayed a sustained rise in Treg levels after introduction of mTOR inhibitors (Treg levels at 3 months: 6.45±0.38% of CD4 T-cells, vs. baseline level of 3.61±0.37%, P<0.001; mean fold increase 2.04±0.73). In SRL group, 3-month Treg levels were 6.01±0.53 vs. 3.79±0.39; P=0.037, while in EVR group they were 6.63±0.67 vs. 3.54±0.51; P=0.001. By contrast, no statistical change was observed in an unconverted Tac control group. Tregs also preserved their functional ability to suppress activated T-cells. CONCLUSION: These results suggest that mTOR inhibitors induce a significant increase in Tregs while maintaining suppressive activity after LT.
BACKGROUND: The mammalian targets of rapamycin (mTOR) inhibitors (sirolimus [SRL] and everolimus [EVR]) are used after transplantation for their immunosuppressive activity. Regulatory T-cells (Tregs) play a crucial role in immune tolerance. mTOR inhibitors appear to preserve Tregs, unlike Tacrolimus (Tac). AIM: The aim of this study was to evaluate the number and function of Tregs in liver transplant recipients before and after conversion from Tac to mTOR inhibitors. METHODS: Fifteen patients with stable graft function where converted to SRL (n=5) or EVR (n=10). Tregs (CD4+ CD25+ FoxP3+ CD127low) number and activity were analysed prospectively in blood cells using flow cytometry, and functional assay. RESULTS:Patients of both groups displayed a sustained rise in Treg levels after introduction of mTOR inhibitors (Treg levels at 3 months: 6.45±0.38% of CD4 T-cells, vs. baseline level of 3.61±0.37%, P<0.001; mean fold increase 2.04±0.73). In SRL group, 3-month Treg levels were 6.01±0.53 vs. 3.79±0.39; P=0.037, while in EVR group they were 6.63±0.67 vs. 3.54±0.51; P=0.001. By contrast, no statistical change was observed in an unconverted Tac control group. Tregs also preserved their functional ability to suppress activated T-cells. CONCLUSION: These results suggest that mTOR inhibitors induce a significant increase in Tregs while maintaining suppressive activity after LT.
Authors: Beatriz Díaz-Molina; Paula Diaz-Bulnes; Reyes Carvajal Palao; Maria José Bernardo; Ramón M Rodriguez; Viviana Corte-Iglesias; Cesar Moris de la Tassa; Jose Luis Lambert; Beatriz Suarez-Alvarez Journal: Front Immunol Date: 2018-09-26 Impact factor: 7.561
Authors: Felix Oldhafer; Eva-Maria Wittauer; Christine S Falk; Daphne E DeTemple; Oliver Beetz; Kai Timrott; Moritz Kleine; Florian W R Vondran Journal: Ann Transplant Date: 2019-08-13 Impact factor: 1.530