[en] Introduction: Mesenchymal stromal cells (MSCs) have particular properties that are of interest in organ transplantation, including the expansion of regulatory T cells (Tregs), a key factor in transplant tolerance induction. However, the most effective immunosuppressive drug to associate with MSCs has yet to be defined. Additionally, the impact of the association of everolimus with MSCs on Treg expansion, and on the induction of liver graft tolerance, has never been studied. The aim of this study was to evaluate the effects of MSCs in combination, or not, with everolimus on Treg expansion and in a model of rejection after liver transplantation (LT) in the rat.
Methods: Firstly, 24 Lewis rats were assigned to 4 groups (n=6 in each group) receiving intravenous MSCs or saline injection at day (D)9 with/without subcutaneous everolimus from D0 to D14. Analysis of circulating Tregs was performed at D0, D14 and D28. In a second set of experiment, 30 Lewis rats were randomized in 3 groups 48hours after LT with a Dark Agouti rat liver: everolimus (subcutaneous for 14 days), MSCs (intravenous injection at post-operative day 2 and 9), or both everolimus and MSCs. Rejection of the liver graft was assessed by liver tests, histology and survival.
Results: Individually, MSC infusion and everolimus promoted Treg expansion in rats, and everolimus had no negative impact on Treg expansion in combination with MSCs. However, in the LT model, injections of MSCs two and nine days following LT were not effective at preventing acute rejection, and the combination of MSCs with everolimus failed to show any synergistic effect when compared to everolimus alone.
Conclusion: Everolimus may be used in association with MSCs. However, in our model of LT in the rat, post-transplant MSC injections did not prevent acute rejection, and the association of MSCs with everolimus did not show any synergistic effect.
Disciplines :
Urology & nephrology
Author, co-author :
VANDERMEULEN, Morgan ; Centre Hospitalier Universitaire de Liège - CHU > > Service de chirurgie abdo, sénologique, endocrine et de transplantation
ERPICUM, Pauline ; Centre Hospitalier Universitaire de Liège - CHU > > Service de néphrologie
BLETARD, Noëlla ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'anatomie et cytologie pathologiques
POMA, Laurence ; Centre Hospitalier Universitaire de Liège - CHU > > Service de néphrologie
JOURET, François ; Centre Hospitalier Universitaire de Liège - CHU > > Service de néphrologie
DETRY, Olivier ; Centre Hospitalier Universitaire de Liège - CHU > > Service de chirurgie abdo, sénologique, endocrine et de transplantation
Language :
English
Title :
Effect of the Combination of Everolimus and Mesenchymal Stromal Cells on Regulatory T Cells Levels and in a Liver Transplant Rejection Model in Rats.
Dominici M Le Blanc K Mueller I Slaper-Cortenbach I Marini F Krause D et al. Minimal Criteria for Defining Multipotent Mesenchymal Stromal Cells. The International Society for Cellular Therapy Position Statement. Cytotherapy (2006) 8(4):315–7. doi: 10.1080/14653240600855905
Zuk PA Zhu M Ashjian P De Ugarte DA Huang JI Mizuno H et al. Human Adipose Tissue Is a Source of Multipotent Stem Cells. Mol Biol Cell (2002) 13(12):4279–95. doi: 10.1091/mbc.e02-02-0105
Majore I Moretti P Stahl F Hass R Kasper C. Growth and Differentiation Properties of Mesenchymal Stromal Cell Populations Derived From Whole Human Umbilical Cord. Stem Cell Rev Rep (2011) 7(1):17–31. doi: 10.1007/s12015-010-9165-y
Vandermeulen M Erpicum P Weekers L Briquet A Lechanteur C Detry O et al. Mesenchymal Stromal Cells in Solid Organ Transplantation. Transplantation (2020) 104(5):923–36. doi: 10.1097/TP.0000000000003077
Casiraghi F Noris M Remuzzi G. Immunomodulatory Effects of Mesenchymal Stromal Cells in Solid Organ Transplantation. Curr Opin Organ Transplant (2010) 15(6):731–7. doi: 10.1097/MOT.0b013e328340172c
Negi N Griffin MD. Effects of Mesenchymal Stromal Cells on Regulatory T Cells: Current Understanding and Clinical Relevance. Stem Cells (2020) 38(5):596–605. doi: 10.1002/stem.3151
Erpicum P Detry O Weekers L Bonvoisin C Lechanteur C Briquet A et al. Mesenchymal Stromal Cell Therapy in Conditions of Renal Ischaemia/Reperfusion. Nephrol Dial Transplant (2014) 29(8):1487–93. doi: 10.1093/ndt/gft538
Selmani Z Naji A Zidi I Favier B Gaiffe E Obert L et al. Human Leukocyte Antigen-G5 Secretion by Human Mesenchymal Stem Cells Is Required to Suppress T Lymphocyte and Natural Killer Function and to Induce CD4 + CD25 High FOXP3 + Regulatory T Cells. Stem Cells (2008) 26(1):212–22. doi: 10.1634/stemcells.2007-0554
Atif M Conti F Gorochov G Oo YH Miyara M. Regulatory T Cells in Solid Organ Transplantation. Clin Transl Immunol (2020) 9(2):1–15. doi: 10.1002/cti2.1099
Reinders MEJ van Kooten C Rabelink TJ de Fijter JW. Mesenchymal Stromal Cell Therapy for Solid Organ Transplantation. Transplantation (2018) 102(1):35–43. doi: 10.1097/TP.0000000000001879
Vandermeulen M Mohamed-Wais M Erpicum P Delbouille MH Lechanteur C Briquet A et al. Infusion of Allogeneic Mesenchymal Stromal Cells After Liver Transplantation: A 5-Year Follow-Up. Liver Transplant (2021) 67(1):47–55. doi: 10.1002/lt.26323
Hoogduijn MJ Crop MJ Korevaar SS Peeters AMA Eijken M Maat LPWM et al. Susceptibility of Human Mesenchymal Stem Cells to Tacrolimus, Mycophenolic Acid, and Rapamycin. Transplantation (2008) 86(9):1283–91. doi: 10.1097/TP.0b013e31818aa536
Vandermeulen M Grégoire C Briquet A Lechanteur C Beguin Y Detry O. Rationale for the Potential Use of Mesenchymal Stromal Cells in Liver Transplantation. World J Gastroenterol (2014) 20(44):16418–32. doi: 10.3748/wjg.v20.i44.16418
Furukawa A Wisel SA Tang Q. Impact of Immune-Modulatory Drugs on Regulatory T Cell. Transplantation (2016) 100(11):2288–300. doi: 10.1097/TP.0000000000001379
Zeiser R Nguyen VH Beilhack A Buess M Schulz S Baker J et al. Inhibition of CD4+CD25+ Regulatory T-Cell Function by Calcineurin-Dependent Interleukin-2 Production. Blood (2006) 108(1):390–9. doi: 10.1182/blood-2006-01-0329
Detry O Vandermeulen M Delbouille MH Somja J Bletard N Briquet A et al. Infusion of Mesenchymal Stromal Cells After Deceased Liver Transplantation: A Phase I–II, Open-Label, Clinical Study. J Hepatol (2017) 67(1):47–55. doi: 10.1016/j.jhep.2017.03.001
Mondino A Mueller DL. mTOR at the Crossroads of T Cell Proliferation and Tolerance. Semin Immunol (2007) 19(3):162–72. doi: 10.1016/j.smim.2007.02.008
Buron F Perrin H Malcus C Héquet O Thaunat O Kholopp-Sarda MN et al. Human Mesenchymal Stem Cells and Immunosuppressive Drug Interactions in Allogeneic Responses: An In Vitro Study Using Human Cells. Transplant Proc (2009) 41(8):3347–52. doi: 10.1016/j.transproceed.2009.08.030
Ge W Jiang J Baroja ML Arp J Zassoko R Liu W et al. Infusion of Mesenchymal Stem Cells and Rapamycin Synergize to Attenuate Alloimmune Responses and Promote Cardiac Allograft Tolerance. Am J Transplant (2009) 9(8):1760–72. doi: 10.1111/j.1600-6143.2009.02721.x
Duan W Yu X Ma D Yang B Li Y Huang L et al. Mesenchymal Stem Cells in Combination With Low-Dose Rapamycin Significantly Prolong Islet Allograft Survival Through Induction of Regulatory T Cells. Biochem Biophys Res Commun (2018) 506(3):619–25. doi: 10.1016/j.bbrc.2018.10.070
Erpicum P Rowart P Poma L Krzesinski J-M Detry O Jouret F. Administration of Mesenchymal Stromal Cells Before Renal Ischemia/Reperfusion Attenuates Kidney Injury and may Modulate Renal Lipid Metabolism in Rats. Sci Rep (2017) 7(1):8687. doi: 10.1038/s41598-017-08726-z
Oldani G Lacotte S Morel P Mentha G Toso C. Orthotopic Liver Transplantation in Rats. J Vis Exp (2012) 65):1–7. doi: 10.3791/4143
Oldani G Lacotte S Orci LA Delaune V Slits F Gex Q et al. Efficient Nonarterialized Mouse Liver Transplantation Using 3-Dimensional–Printed Instruments. Liver Transplant (2016) 22(12):1688–96. doi: 10.1002/lt.24637
Demetris AJ Batts KP Dhillon AP Ferrell L Fung J Geller SA et al. Banff Schema for Grading Liver Allograft Rejection: An International Consensus Document. Hepatology (1997) 25(3):658–63. doi: 10.1002/hep.510250328
Erpicum P Weekers L Detry O Bonvoisin C Delbouille MH Grégoire C et al. Infusion of Third-Party Mesenchymal Stromal Cells After Kidney Transplantation: A Phase I-II, Open-Label, Clinical Study. Kidney Int (2019) 95(3):693–707. doi: 10.1016/j.kint.2018.08.046
Pu LY Wang XH Zhang F Li XC Yao AH Yu Y et al. Adoptive Transfusion of Ex Vivo Donor Alloantigen-Stimulated CD4+CD25+ Regulatory T Cells Ameliorates Rejection of DA-To-Lewis Rat Liver Transplantation. Surgery (2007) 142(1):67–73. doi: 10.1016/j.surg.2007.02.014
De Simone P Fagiuoli S Cescon M De Carlis L Tisone G Volpes R et al. Use of Everolimus in Liver Transplantation: Recommendations From a Working Group. Transplantation (2017) 101(2):239–51. doi: 10.1097/TP.0000000000001438
Battaglia M Stabilini A Roncarolo MG. Rapamycin Selectively Expands CD4+CD25+FoxP3 + Regulatory T Cells. Blood (2005) 105:4743–8. doi: 10.1182/blood-2004-10-3932
Ruggenenti P Perico N Gotti E Cravedi P D’Agati V Gagliardini E et al. Sirolimus Versus Cyclosporine Therapy Increases Circulating Regulatory T Cells, But Does Not Protect Renal Transplant Patients Given Alemtuzumab Induction From Chronic Allograft Injury. Transplantation (2007) 84(8):956–64. doi: 10.1097/01.tp.0000284808.28353.2c
Ghazal K Stenard F Dahlqvist G Barjon C Aoudjehane L Scatton O et al. Treatment With mTOR Inhibitors After Liver Transplantation Enables a Sustained Increase in Regulatory T-Cells While Preserving Their Suppressive Capacity. Clin Res Hepatol Gastroenterol (2018) 42(3):237–44. doi: 10.1016/j.clinre.2017.10.001
Di Ianni M Del Papa B De Ioanni M Moretti L Bonifacio E Cecchini D et al. Mesenchymal Cells Recruit and Regulate T Regulatory Cells. Exp Hematol (2008) 36(3):309–18. doi: 10.1016/j.exphem.2007.11.007
Gedaly R De Stefano F Turcios L Hill M Mitov MI Alstott MC et al. mTOR Inhibitor Everolimus in Regulatory T Cell Expansion for Clinical Application in Transplantation. Transplantation (2019) 103(4):705–15. doi: 10.1097/TP.0000000000002495
Dreyer GJ Groeneweg KE Heidt S Roelen DL van Pel M Roelofs H et al. Human Leukocyte Antigen Selected Allogeneic Mesenchymal Stromal Cell Therapy in Renal Transplantation: The Neptune Study, a Phase I Single-Center Study. Am J Transplant (2020) 20(10):2905–15. doi: 10.1111/ajt.15910
You Y Zhang J Gong J Chen Y Li Y Yang K et al. Mesenchymal Stromal Cell-Dependent Reprogramming of Kupffer Cells Is Mediated by TNF-Alpha and and PGE2 and Is Crucial for Liver Transplant Tolerance. Immunol Res (2015) 62(3):292–305. doi: 10.1007/s12026-015-8660-2
Tang J Yang R Lv L Yao A Pu L Yin A et al. Transforming Growth Factor-β-Expressing Mesenchymal Stem Cells Induce Local Tolerance in a Rat Liver Transplantation Model of Acute Rejection. Stem Cells (2016) 34(11):2681–92. doi: 10.1002/stem.2437
Sun Z Li T Wen H Wang H Ji W Ma Y. Immunological Effect Induced by Mesenchymal Stem Cells in a Rat Liver Transplantation Model. Exp Ther Med (2015) 10(2):401–6. doi: 10.3892/etm.2015.2551