Comparing DSA-negative and DSA-positive antibody-mediated rejection in heart transplants: Results from the Trifecta-Heart study.

BACKGROUND

Antibody-mediated rejection (ABMR) in heart transplants is often negative for donor-specific antibody (DSA). We explored potential molecular differences between DSA-negative and DSA-positive molecular ABMR in 212 heart endomyocardial biopsies from the prospective Trifecta-Heart study (NCT04707872).

METHODS

We characterized rejection in biopsies by the Molecular Microscope Diagnostic System (MMDx) and by histology, and at the time of biopsy, measured donor-derived cell-free DNA (dd-cfDNA, the Prospera test, Natera, Inc) and central plasma DSA (One Lambda Inc, assessed by L.G.H.).

RESULTS

MMDx ABMR was 53% (33/63) DSA-positive and 79% (50/63) dd-cfDNA positive. DSA-negative (N = 33) and DSA-positive (N = 30) molecular ABMR were similar in days post-transplant (861 vs 1,119), percent dd-cfDNA as a fraction of total cfDNA positivity (76% vs 83%), and mean left ventricular ejection fraction (LVEF) (58.5 vs 56.5); DSA-negative ABMR had lower mean molecular ABMR activity (ABMRProb score 0.55 vs 0.70, p = 0.02). Gene expression profiles were essentially identical between DSA-negative and DSA-positive molecular ABMR, including interferon-gamma (IFNG)-inducible genes (e.g., CXCL11, CXCL9, and IDO1) and NK-expressed genes (e.g., KLRD1 and GNLY), compatible with a role for natural killer (NK) cells in both DSA-negative and DSA-positive ABMR.

CONCLUSIONS

Molecular features of heart transplant biopsies with DSA-negative ABMR are virtually identical to those with DSA-positive ABMR and both are associated with high plasma dd-cfDNA.