Pre-Transplant T-Cell Subtype Assessment as a Predictive Tool for CMV Viremia After Transplant.

Abstract

Background: Some studies have suggested that pre-transplant T-cell responses may be useful for predicting the risk of CMV reactivation following transplantation. We tested this hypothesis in a large cohort of CMV seropositive transplant recipients. Methods: We assessed CMV specific T-cell subsets pre-transplant using PBMCs from CMV seropositive (R+) transplant patients enrolled in 5 centers. No patient received antiviral prophylaxis and all had regular virologic monitoring as part of a pre-emptive strategy. PBMCs were exposed for 6 hours to CMV strain Towne at MOI 0.03, followed by antibody staining for flow cytometry immunophenotyping of T-cell subsets including CD4+, CD8+, Treg populations (CD25+, FOXP3+), interferon-γ (IFN-γ). The primary outcome was viremia requiring antiviral therapy within the first 3-months post-transplant. Results: A total of 272 CMV R+ transplant patients were analyzed. Transplant types included kidney (65.4%), liver (23.5%), and other (12%). Outcomes included any CMV viremia (n=123/272; 45.2%), CMV viremia requiring antiviral therapy (n=83/272; 30.7%) and CMV disease (n=10/272; 3.7%). A positive pre-transplant CD4+ and CD8+ IFN-γ CMV-specific T-cell response was seen in 14.1% and 42.6% respectively. In terms of the primary outcome (clinically significant CMV viremia), a positive CD4+, IFN-γ response was seen in 12.3% (no viremia) vs. 18.1% (viremia) of patients (p=0.28). A CD8+ IFN-γ response was seen in 41.2% (no viremia) vs. 45.8% (viremia) of patients (p=0.57). Median CD4+ and CD8+ IFN-γ + T-cell frequencies were also similar in the viremic vs. non-viremic groups (p=NS). Also neither CD4+ or CD8+ frequencies predicted symptomatic CMV disease [p=NS for all comparisons]. Analysis of the D+ and D- subgroups did not yield different results. Mean T-reg frequency following viral stimulation was 1.43% ± 1.37%. Compared to controls, viral stimulation resulted in a significant decline in T-reg expression of FOXP3 by 6-hours (median 2.2 fold decline; p<0.001). Higher baseline T-reg% correlated with increased risk of CMV reactivation post-transplant (p=0.035). Conclusions: This study suggests that pre-transplant testing for CMV specific CD4+ and CD8+ T-cell responses are unlikely to be of significant clinical utility for predicting CMV viremia or disease post-transplant. The predictive value of Treg measurements is a novel finding. DISCLOSURE:Kumar, D.: Grant/Research Support, Roche, Astellas, Other, Oxford Immunotec, Advisory Board Member. Humar, A.: Grant/Research Support, Roche, Other, Astellas, Advisory board member, Chimerix, Advisory board member.