TY - JOUR
T1 - Preformed T cell alloimmunity and HLA eplet mismatch to guide immunosuppression minimization with tacrolimus monotherapy in kidney transplantation
T2 - Results of the CELLIMIN trial
AU - Bestard, Oriol
AU - Meneghini, Maria
AU - Crespo, Elena
AU - Bemelman, Frederike
AU - Koch, Martina
AU - Volk, Hans D.
AU - Viklicky, Ondrej
AU - Giral, Magali
AU - Banas, Bernhard
AU - Ruiz, Juan C.
AU - Melilli, Edoardo
AU - Hu, Liu
AU - van Duivenvoorden, Raphael
AU - Nashan, Björn
AU - Thaiss, Friedrich
AU - Otto, Natalie M.
AU - Bold, Gantuja
AU - Stein, Maik
AU - Sefrin, Anett
AU - Lachmann, Nils
AU - Hruba, Petra
AU - Stranavova, Lucia
AU - Brouard, Sophie
AU - Braudeau, Cécile
AU - Blancho, Gilles
AU - Banas, Miriam
AU - Irure, Juan
AU - Christakoudi, Sophia
AU - Sanchez-Fueyo, Alberto
AU - Wood, Kathryn J.
AU - Reinke, Petra
AU - Grinyó, Josep M.
N1 - Funding Information:
This work was funded by a European Union FP7 grant (FP7‐HEALTH‐2012 INNOVATION‐1, grant agreement nº 305147). OB was also supported by an intensification grant from the Instituto de Salud Carlos III (ISCIII) (ICI14/00242 and PI16/01321) and the SLT002/16/00183 grant, funded by the Department of Health of the Generalitat de Catalunya by the call “Acció instrumental: Intensificació de professionals de la salut, modalitat de professionals sanitaris (infermeria i fisioteràpia).” We thank CERCA Programme/Generalitat de Catalunya for institutional support. MM received a grant from the European Society of Transplantation (ESOT). We thank all the patients who participated in the study, without whom this work would not have been possible. We thank all biobank units from each center for sample processing. We would also like to thank Ms Rosemarie Preyer from AID for their constant technical support in the ELISPOT assays. Participating centers, investigators, and staff for the CELLIMIN trial: Study coordinators: Hilke Schmidts, Carolina Polo, Eulàlia Molina, Dorien Standaar, Ester Remmerswaal, Grégoire Couvrat‐Desvergnes, and Khuzama El Nasser. Immunological ELISPOT assessment: Alba Torija, Marta Jarque, Nelly van der Bom‐Baylon, Simone Reichelt‐Wurm, Marcos Lopez‐Hoyos, and David San Segundo. Patient care: Anna Manonelles, Nuria Montero, Alexandre Favà, Joan Torras, Josep M Cruzado, Montserrat Gomà, Thomas Schachtner, Peter Nickel, Astrid Wilke, Hanna Zobel, Silvia Fischer, Cordula Giesler, Joris Roelofs, Emilio Rodrigo, Rosalía Valero, Julien Branchereau, Diego Cantarovich, Anne Cesbron, Agnès Chapelet, Jacques Dantal, Florent Delbos, Claire Garandeau, Maryvonne Hourmant, Régis Josien, Georges Karam, Aurélie Meurette, Clément Deltombe, Lucile Figueres, Caroline Gourraud‐Vercel, Cécile Guillot‐Gueguen, Christophe Masset, Karine Renaudin, Simon Ville, Franz J Putz, Janka Slatinska, Mariana Wohlfahrtova, Marie Kolarova, and Jana Maluskova.
Funding Information:
The CELLIMIN trial was a prospective, multi‐center, biomarker‐driven, randomized trial performed within the European BIO‐DRIM research consortium, sponsored by the European Union Seventh Framework Program (FP7‐HEALTH‐2012‐INNOVATION‐1, grant agreement nº 305147). Eight kidney transplant centers across Europe participated in the trial, Bellvitge University Hospital (Barcelona, Spain), Charité (Berlin, Germany), Amsterdam University Medical Centers (Amsterdam, the Netherlands), Universitätsklinikum Hamburg‐Eppendorf (Hamburg, Germany), Institute for Clinical and Experimental Medicine (Prague, Czech Republic), Centre Hospitalier Universitaire Nantes (Nantes, France), University Hospital Regensburg (Regensburg, Germany), and University Hospital Marqués de Valdecilla (Santander, Spain). Each center participated under the approval of the Europe‐wide voluntary harmonization process (VHP). An external Data Safety Monitoring Board (DSMB) was responsible for periodic safety review and guided by predetermined protocol–defined stopping criteria.
Publisher Copyright:
© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/8
Y1 - 2021/8
N2 - Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E−) were randomized to LI (n = 48) or SOC (n = 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E− (4/35 [13%] vs. 1/43 [2%], p =.15 and 12/48 [25%] vs. 6/53 [11.3%], p =.073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocol analyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E− patients, notably E−/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p =.043). Eplet mismatch also predicted anti-class-I (p =.05) and anti-DQ (p <.001) de novo DSA. Adverse events were similar, but E−/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p =.021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.
AB - Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E−) were randomized to LI (n = 48) or SOC (n = 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E− (4/35 [13%] vs. 1/43 [2%], p =.15 and 12/48 [25%] vs. 6/53 [11.3%], p =.073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocol analyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E− patients, notably E−/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p =.043). Eplet mismatch also predicted anti-class-I (p =.05) and anti-DQ (p <.001) de novo DSA. Adverse events were similar, but E−/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p =.021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.
KW - biomarker
KW - clinical decision-making
KW - clinical research/practice
KW - clinical trial
KW - immunobiology
KW - immunosuppression/immune modulation
KW - immunosuppressive regimens - minimization/withdrawal
KW - kidney transplantation/nephrology
KW - rejection: acute
UR - http://www.scopus.com/inward/record.url?scp=85104306305&partnerID=8YFLogxK
U2 - 10.1111/ajt.16563
DO - 10.1111/ajt.16563
M3 - Article
C2 - 33725408
AN - SCOPUS:85104306305
SN - 1600-6135
VL - 21
SP - 2833
EP - 2845
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 8
ER -
