No abstract

Background Allospecific CD154+T-cytotoxic memory cells (CD154+TcM) predict acute cellular rejection (ACR) after liver or intestine transplantation (LTx, ITx) in small cohorts of children and can enhance immunosuppression management, but await validation and clinical implementation. Methods To establish safety and probable benefit, CD154+TcM were measured in cryopreserved samples from 214 children <21 years (NCT#1163578). Training set samples, n=158, were tested with research-grade reagents and 122 independent validation set samples were tested with cGMP-manufactured reagents after assay standardization and reproducibility testing. Recipient CD154+TcM induced by stimulation with donor cells were expressed as a fraction of those induced by HLA-non-identical cells in parallel cultures. The resulting immunoreactivity index (IR) if > 1 implies increased rejection-risk. Results Training and validation set subjects were demographically similar. Mean coefficient of test variation was <10% under several conditions. Logistic regression incorporating several confounding variables identified separate pre-transplant and post-transplant IR thresholds for prediction of rejection in respective training set samples. An IR ≥ 1.1 in post-transplant training samples, and IR ≥1.23 in pre-transplant training samples predicted LTx or ITx rejection in corresponding validation set samples in the 60-day post-sampling period with sensitivity, specificity, positive and negative predictive values of 84%, 80%, 64%, and 92%, respectively (AUC 0.792), and 57%, 89%, 78%, and 74%, respectively (AUC 0.848). No adverse events were encountered due to phlebotomy. Conclusions Allospecific CD154+T-cytotoxic memory cells predict acute cellular rejection after liver or intestine transplantation in children. Adjunctive use can enhance clinical outcomes.