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Transplantation. 2017 Jan;101(1):131-140. doi: 10.1097/TP.0000000000001076.

Predicting Cellular Rejection With a Cell-Based Assay: Preclinical Evaluation in Children.

Author information

1
1 Thomas E. Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation, Department of Transplant Surgery, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA. 2 Plexision Inc, Pittsburgh, PA. 3 Tissue Typing Laboratory, Department of Pathology, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA.

Abstract

BACKGROUND:

Allospecific CD154+T-cytotoxic memory cells (CD154+TcM) predict acute cellular rejection after liver transplantation (LTx) or intestine transplantation (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 younger than 21 years (National Clinical Trial 1163578). Training set samples (n = 158) were tested with research-grade reagents and 122 independent validation set samples were tested with current good manufacturing practices-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 nonidentical cells in parallel cultures. The resulting immunoreactivity index (IR) if greater than 1 implies increased rejection-risk.

RESULTS:

Training and validation set subjects were demographically similar. Mean coefficient of test variation was less than 10% under several conditions. Logistic regression incorporating several confounding variables identified separate pretransplant and posttransplant IR thresholds for prediction of rejection in the respective training set samples. An IR of 1.1 or greater in posttransplant training samples and IR of 1.23 or greater in pretransplant training samples predicted LTx or ITx rejection in corresponding validation set samples in the 60-day postsampling period with sensitivity, specificity, positive, and negative predictive values of 84%, 80%, 64%, and 92%, respectively (area under the receiver operator characteristic curve, 0.792), and 57%, 89%, 78%, and 74%, respectively (area under the receiver operator characteristic curve, 0.848). No adverse events were encountered due to phlebotomy.

CONCLUSIONS:

Allospecific CD154+T-cytotoxic memory cells predict acute cellular rejection after LTx or ITx in children. Adjunctive use can enhance clinical outcomes.

PMID:
26950712
PMCID:
PMC5011025
DOI:
10.1097/TP.0000000000001076
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Disclosures: Test systems are based on technology described in US Patent 8426146. Inventor: Rakesh Sindhi. Assignee: University of Pittsburgh-of the Commonwealth System of Higher Education, Pittsburgh, PA, and licensed to Plexision, Inc., Pittsburgh 15224, in which the University holds equity. Rakesh Sindhi serves as an unpaid consultant and Chethan Ashokkumar as a paid consultant to licensee without other financial relationships. Disclosed conflicts of interest have been managed in accordance with the University of Pittsburgh's policies and procedures. The rest of the authors have nothing to disclose.

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