Immune Monitoring by Torque Teno Virus Load in Addition to Virus-Specific T Cells After Pediatric Kidney Transplantation
David Nehl, Xiaofei Liu, Sebastian Voigt, Carina Elsner, Raphael Schild, Jun Oh, Christina Taylan, Lutz T Weber, Nele K Kanzelmeyer, Gregor Bond, Stefanie Jeruschke, Nils Pape, Anika Großhennig, Lars Pape, Thurid Ahlenstiel-GrunowAbstract
Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after kidney transplantation (Tx). The randomized controlled IVIST trial demonstrated that additional steering of immunosuppressive therapy by virus-specific CD4+ T cells (Tvis) is safe and reduces exposure to immunosuppressants. The adenovirus (ADV)-Tvis proved to be particularly suitable due to their stability and high prevalence. Another promising biomarker for post-Tx immunomonitoring is the Torque Teno virus (TTV) but pediatric data are very limited. This descriptive longitudinal analysis aimed to evaluate the post-Tx course of TTV load compared to Tvis levels after pediatric Tx.
In the IVIST trial, 31 pediatric kidney recipients were randomized to the intervention group with Tvis-guided immunosuppression. The immunosuppressive therapy consisted of basiliximab, cyclosporine A (CsA), everolimus (Eve) and prednisolone. In 27 out of 31 intervention group patients, TTV-DNA was measured retrospectively in frozen plasma samples from 20 visits (1–24 months (mo) after Tx). Associations of TTV-DNA with ADV-Tvis and with immunosuppressants over the post-Tx period were evaluated using linear mixed models, adjusted for time since Tx and accounting for repeated measurements within patients.
Mean TTV-DNA (n = 474) ±SD was 4.4 ± 1.3 log10 copies/ml (1.4 to 9.4 log10). TTV-DNA was associated with post-Tx follow-up time. Under intensive immunosuppression immediately after Tx, TTV-DNA increased, peaking at 3 mo post-Tx (5.5 ± 1.4 log10); after reduction of immunosuppression, TTV load decreased (6mo: 4.3 ± 1.1 log10; 16mo: 3.9 ± 0.9 log10). Mean ADV-Tvis levels showed a minimum at 2 mo post-Tx and increased over time: from 1.5 ± 1.1 cells/µl (2 mo) to 2.0 ± 1.8 (6 mo) and 2.4 ± 1.7 (22 mo). TTV-DNA showed overall positive correlations with mean daily doses and trough levels of CsA and Eve.
The longitudinal analysis of TTV load presented an opposite post-Tx course compared to ADV-Tvis. TTV-DNA was associated with post-Tx follow-up time and with immunosuppressants after pediatric Tx. In comparison to ADV-Tvis minimum, the mean TTV-DNA showed a late peak at 3 mo post-Tx suggesting delayed response to drug dose changes.