Effect of everolimus‐based drug regimens on CMV‐specific T‐cell functionality after renal transplantation: 12‐month ATHENA subcohort‐study results

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.

Incidence of cytomegalovirus infection in seropositive kidney transplant recipients treated with everolimus: A randomized, open-label, multicenter phase 4 trial

“…of acute lymphocytic choriomeningitis virus infection 26 and the number of CMV-specific T cells in R+ KTRs. [8][9][10][11]27 Our quantiFERON-CMV data indicate that the quantity of gamma-interferon produced by CMV-specific T cells increased rapidly after the initiation of EVR.…”

Ways to boost cellular immunity in solid organ transplant recipients – The case of letermovir

“…Of note, immunosuppressive treatment with mammalian target of rapamycin-inhibitors is superior to calcineurin inhibitor therapy in preventing CMV infection and disease 8 and was shown to be associated with preserved CMV-specific T-cell functionality. 9 In the current study, immunosuppression was already tapered prior to initiation of secondary prophylaxis with letermovir (Figure 1), which may indicate that this had not contributed to the induction of specific immunity in these cases. However, six out of seven patients had also received intravenous immunoglobulins (Figure 1), which may reduce the viral load by passively conferring neutralizing activity towards CMV.…”

mTOR-Inhibition and COVID-19 in Kidney Transplant Recipients: Focus on Pulmonary Fibrosis

“…Compelling data suggest an antivirial role of mTOR-I by blocking cellular proliferation and impairing pathways critical for infection, signaling, and replication ( Liacini et al, 2010 ; Clippinger et al, 2011 ). In addition, mTOR-I may have a direct anti-viral activity by increasing the percentage of multifunctional virus-specific CD4 T cells ( Hauser et al, 2021 ).…”

“…Several clinical trials have reported a reduced rate of Cytomegalovirus and BKV infections in kidney transplant recipients treated with mTOR-Is alone or associated to low dosages of calcineurin inhibitors (CNI) compared to those in standard dose CNI regimen (Tedesco Silva et al, 2010;Brennan et al, 2011;Mallat et al, 2017;Tedesco-Silva et al, 2019;Hauser et al, 2021). The exact mechanism behind this protection is not clear.…”