Date: Tuesday, June 4, 2019
Session Time: 2:30pm-4:00pm
Presentation Time: 2:54pm-3:06pm
Location: Room 306
*Purpose: The ATHENA trial was designed to compare everolimus [EVR] in combination with tacrolimus [TAC] or cyclosporine A [CyA] vs. a standard regimen of mycophenolic acid [MPA] and TAC in de novo kidney transplant [KTx] recipients . The ATHENA main study showed significantly fewer CMV infections under EVR-based treatment compared to standard TAC+MPA therapy (21% TAC+MPA vs 6% EVR+TAC vs 3% EVR+CyA treated pts; p<0.01) . We hypothesized that this may be associated with better functionality of CMV-specific T-cells.
*Methods: ATHENA was a 12M prospective, open-label study with 612 patients [pts] randomized 1:1:1 at time of KTx to either EVR+TAC, EVR+CyA or TAC+MPA. Matching of CMV-donor/recipient status at baseline was balanced across groups , prophylaxis with valganciclovir for D+/R- and D+/R+ pts was mandatory for 3M. We prospectively collected blood samples for CMV-specific stimulation assays in a dedicated CMV-substudy. We aimed at elucidating mechanisms for immunosuppression related dysfunction of CMV-specific T-cells following stimulation by means of cytokine profiling and expression of markers for functional anergy (CTLA-4, PD-1) using flow-cytometry. Samples derived from the sub-population, that was on-treatment to M12, are referred to herein. Statistics: Mann-Whitney U Test for two-tailed p-values.
*Results: Flow-cytometric analysis of stimulated CMV-specific CD4+ T-cells revealed that: i) median CTLA-4 and PD-1 expression were significantly lower in samples obtained from EVR+TAC or EVR+CyA treated pts compared to TAC+MPA pts samples (median CTLA-4 MFI: 744 (n=16), 463 (n=8), 1282 (n=28); p=0.05 and p=0.02, respectively) (median PD-1 MFI: 227 (n=15), 320 (n=8), 351 (n=28); p=0.02 and p=0.59, respectively). In addition, the percentage of multifunctional IL-2, IFNγ and TNFα triple-positive CMV-specific CD4+ T-cells was higher in samples from EVR+TAC and EVR-CyA treated pts compared to TAC+MPA treated patients (median: 28% (n=16), 27% (n=8) vs 14% (n=28); p=0.02, p=0.13).
*Conclusions: ATHENA as the largest European KTx study confirmed a significant reduction of CMV infections with de novo EVR-based immunosuppression. Our study provides novel findings that CMV-specific CD4+ T-cells of EVR-treated patients show characteristics of strong functionality which may explain protection against CMV infections beyond known EVR-related effects [2,4,5] on CMV replication. References:  Sommerer et al.,Trials (2016) 17:92;  Nashan et al., Transplantation (2012); 93:1075-1085;  Nashan et al./Hauser et al./Suwelack et al., AmJ Transplant. (2017); 17(suppl 3);  Dirks et al., AmJ Transplant. (2013); 13: 3132-3141;  Havenith et al.,Transplantation (2013); 95:184-191
To cite this abstract in AMA style:Hauser IA, Marx S, Sommerer C, Suwelack B, Dragun D, Witzke O, Lehner F, Kroeger I, Junge M, Thaiss F, Nashan B, Sester M. Differences in CMV-Specific CD4 T Cell Population in De Novo Kidney Transplant Recipients Treated with Everolimus-Based Regimen Compared to a Standard Tacrolimus-MPA Regimen: Results from ATHENA [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/differences-in-cmv-specific-cd4-t-cell-population-in-de-novo-kidney-transplant-recipients-treated-with-everolimus-based-regimen-compared-to-a-standard-tacrolimus-mpa-regimen-results-from-athena/. Accessed August 10, 2020.
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