Background. The reduction in acute rejection rates seen with the current triple immunosuppressive maintenance regimen has come at the expense of an increased risk of serious infections and cancer. A clinical tool to quantify the level of immunosuppression would be key to prevent these undesirable events.

Methods. This is an interim report of an ongoing prospective, observational longitudinal single center study of 50 de novo kidney recipients in which PBMC were collected at 12 timepoints over 3 yrs post transplant (600 samples). The immunosuppression regimen consisted of basiliximab followed by prednisone, tacrolimus and mycophenolate. Patients were classified as over-immunosuppressed (OIS: opportunistic infection, BK viremia or nephropathy, CMV viremia, ≥3 recurrent bacterial infection) or controls. We examined IFNγ response in CD4+, CD8+ T cells and NK cells, as well as TNFα response in monocyte subsets by intra/extracellular flow cytometry. Early in the discovery phase, results in the first 7 patients indicated that TNFα response to EBV peptides in CD14+CD16+ monocytes was lower in OIS patients. This was further evaluated in 21 patients using the first 2 years samples (0, 1, 3, 6, 9, 12, 16, 20 and 24mo). The analysis was conducted using mixed models, ROC curve, sensitivity/specificity and PPV/NPV.

Results. We studied 8 OIS patients and 13 controls. Overall, the mean(±std dev) TNFα-positive CD14+CD16+ monocytes was 58±24 vs. 79±17 percent in OIS and controls patients respectively (p=0.004), with more stable values in controls (within-patient mean std dev=10 vs. 19). A ROC curve built across all timepoints resulted in a threshold of 69 percent of TNFα-positive monocytes (AUC=0.74, p<0.001). A classifier rule based on ≥2 consecutive values below this threshold provided a sensitivity and specificity of 88% (7/8) and 77% (10/13) respectively, with positive and negative predictive values of 70% and 91% respectively. Analysis of effector and naive T cell IFNγ responses showed no correlation with the OIS phenotype.

Conclusion. This longitudinal analysis of the cellular immune profile suggest that stimulation of PBMC with EBV peptides allows to identify OIS patients, through the measurement of TNFα response in CD14+CD16+ monocytes. Examination of a validation set is underway to confirm these preliminary findings.

CITATION INFORMATION: Vallin P, Désy O, Béland S, Wagner E, De Serres S. Monocytic TNF-α Response to EBV Peptides as a Mean to Identify Over-Immunosuppressed Kidney Transplant Recipients. Am J Transplant. 2016;16 (suppl 3).

« Back to 2016 American Transplant Congress