Effect of everolimus‐based drug regimens on CMV‐specific T‐cell functionality after renal transplantation: 12‐month ATHENA subcohort‐study results. Issue 4 (28th December 2020)

• Record Type: Journal Article
• Authors: Hauser, Ingeborg A.; Marx, Stefanie; Sommerer, Claudia; Suwelack, Barbara; Dragun, Duska; Witzke, Oliver; Lehner, Frank; Schiedel, Christiane; Porstner, Martina; Thaiss, Friedrich; Neudörfl, Christine; Falk, Christine S.; Nashan, Björn; Sester, Martina
• Is Part Of: European journal of immunology. Volume 51:Issue 4(2021)
• Page Start: 943
• Page End: 955
• Publication Date: 2020-12-28
• Subjects: CMV -- CD4 T cells -- CTLA‐4 -- Everolimus -- PD‐1; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.202048855
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: Post‐transplant cytomegalovirus (CMV) infections and increased viral replication are associated with CMV‐specific T‐cell anergy. In the ATHENA‐study, de‐novo everolimus (EVR) with reduced‐exposure tacrolimus (TAC) or cyclosporine (CyA) showed significant benefit in preventing CMV infections in renal transplant recipients as compared to standard TAC + mycophenolic acid (MPA). However, immunomodulatory mechanisms for this effect remain largely unknown. Ninety patients from the ATHENA‐study completing the 12‐month visit on‐treatment (EVR + TAC n = 28; EVR + CyA n = 19; MPA + TAC n = 43) were included in a posthoc analysis. Total lymphocyte subpopulations were quantified. CMV‐specific CD4 T cells were determined after stimulation with CMV‐antigen, and cytokine‐profiles and various T‐cell anergy markers were analyzed using flow cytometry. While 25.6% of MPA + TAC‐treated patients had CMV‐infections, no such events were reported in EVR‐treated patients. Absolute numbers of lymphocyte subpopulations were comparable between arms, whereas the percentage of regulatory T cells was significantly higher with EVR + CyA versus MPA + TAC ( p = 0.019). Despite similar percentages of CMV‐specific T cells, their median expression of CTLA‐4 and PD‐1 was lower with EVR + TAC ( p < 0.05 for both) or EVR + CyA ( p = 0.045 for CTLA‐4) compared with MPA + TAC. Moreover, mean percentages of multifunctional CMV‐specific T cells were higher with EVR + TAC (27.2%) and EVR + CyA (29.4%) than with MPA + TAC (19.0%). In conclusion, EVR‐treated patients retained CMV‐specific T‐cell functionality, which may contribute to enhanced protection against CMV infections. Abstract : The ATHENA substudy found that de novo treatment with an everolimus (EVR)/calcineurin inhibitor regimen resulted in protection from CMV infection after kidney transplantation. At 12 months, CMV‐specific CD4 T‐cell immunity was phenotypically and functionally more preserved in EVR‐treated patients than in patients on a standard drug regimen.