Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection

Key Takeaways

• The study describes the molecular landscape of antibody mediated rejection.
• Gene transcripts correlate with increasing ISHLT grade of rejection.
• Some milder forms of ABMR, e.g. pAMR 1(H+), may share molecular features of full blown pAMR 2 with implications for management.

Introduction

Tissue-level molecular analysis of heart transplant biopsies with MMDx correlates with ISHLT grade of AMR but identifies important discrepancies. MMDx is a tool for personalized, precision diagnostics and is useful for designing and testing novel therapeutic interventions.

Data Analysis

In this study, Loupy and colleagues took 55 heart transplant patients with antibody-mediated rejection (ABMR) and matched them with 55 patients without ABMR (with no rejection or with TCMR).

ABMR was defined by two pathologists, who were blinded to clinical information and DSA status, according to the ISHLT 2013 classification (pAMR 0, pAMR 1(I+), pAMR 1 (H+), pAMR 2 and pAMR 3, where ‘I+’ is immunological evidence of ABMR and ‘H+’ is histological evidence of ABMR). A validation cohort confirmed the results.

Clinical Utility

The study shows that the molecular landscape of heart transplant ABMR is composed of:

1. NK associated transcripts;
2. Endothelial activation transcripts;
3. Interferon-gamma inducible transcripts; and
4. Monocyte-macrophage transcripts.

The most significant pathways were related to interferon-gamma effects, followed by NK cell signaling, leukocyte adhesion, and Fc-gamma receptor-mediated phagocytosis by macrophages.

There was a positive correlation between gene transcript expression and increasing ISHLT grade of ABMR.

The gene transcripts also correlated with the presence of class I and class II donor-specific antibodies (DSA).

Analysis shows that 12/20 cases of pAMR1 (I+) are molecularly inactive (implying they are over-diagnosed by histology or would not need treatment). Whereas, 19/24 pAMR (H+) cases were molecularly active similar to full-blown pAMR 2/3 (the implication being that although pAMR 1(H+) is often not treated where molecular activity is demonstrated, they may be treated similar to pAMR 2/3).

The authors conclude that tissue-level molecular analysis is useful for designing and testing novel therapeutic interventions and improving precision medicine.

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