Managing antibody-mediated rejection in heart transplant.

INTRODUCTION

Antibody-mediated rejection (AMR) is a major obstacle after heart transplantation. Although its pathophysiology is now clearer than a decade ago, clinical management is still fragmented and poorly evidence-based.

AREAS COVERED: Recent work reframes the classic paradigm of donor-specific antibodies (DSA) dependent complement activation as only one axis of injury. Converging data place natural killer (NK) cells at the center of vascular damage: they execute DSA-driven antibody-dependent cellular cytotoxicity (ADCC) via Fcγ receptors and, through 'missing-self' recognition, trigger DSA-negative endothelial injury. These insights have seeded new therapeutic strategies, yet clinical data remain sparse and heterogeneous.

EXPERT OPINION: We now have many new insights and therapeutic possibilities, but progress hinges on robust data from well-conceived, adequately powered trials. To make this feasible, the field needs a refined, activity-based, heart-specific AMR classification aligned with Banff and validated noninvasive biomarkers (e.g. dd-cfDNA, endothelial-injury markers, NK-activity signatures) to enable early detection, monitoring, and rigorous trial enrollment. Emerging biology positions NK-cell targeting as a leading therapeutic direction. Clinical adoption will depend on reproducible assays, multicenter validation, and standardized reporting.