Heart allograft rejection: molecular diagnosis using intra-graft targeted gene expression profiling

Area of Science:

• Transplant immunology
• Molecular diagnostics
• Cardiac pathology

Background:

• Formalin-fixed, paraffin-embedded (FFPE) endomyocardial biopsies (EMBs) offer a practical method for gene expression profiling.
• Refining the diagnosis of cardiac rejection is crucial for improving heart transplant outcomes.
• This study introduces the first FFPE-based molecular diagnostic system for heart transplant rejection.

Purpose of the Study:

• To develop and validate a molecular diagnostic system for detecting heart transplant rejection using FFPE-EMBs.
• To identify distinct molecular signatures for antibody-mediated rejection (AMR) and acute cellular rejection (ACR).
• To assess the clinical applicability of the developed system.

Main Methods:

• An international cohort of 671 heart transplant recipients was analyzed.
• Gene expression was profiled on FFPE-EMBs using the Banff Human Organ Transplant Panel.
• Molecular classifiers for AMR and ACR were developed and validated in internal and external cohorts.

Main Results:

• Molecular classifiers accurately identified AMR and ACR with high area under the receiver operating characteristic curve (ROC-AUC) values (e.g., external validation: AMR=0.822, ACR=0.815).
• Distinct gene expression patterns were identified for AMR (interferon-gamma pathway, endothelial activation) and ACR (T-cell receptor signaling).
• The system demonstrated strong association with pathologic severity and adequate calibration.

Conclusions:

• A novel FFPE-based molecular diagnostic system effectively identifies cardiac allograft rejection.
• This system serves as a valuable adjunct to traditional pathology, potentially refining rejection diagnosis.
• The tool is designed for straightforward implementation in clinical practice.