{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T14:03:18Z","timestamp":1785765798348,"version":"3.56.0"},"reference-count":208,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Antibody-mediated rejection (AMR) is the primary immunological obstacle limiting long-term survival in heart transplant recipients. Driven by donor-specific antibodies (DSA), AMR damages graft microvasculature through multiple pathways, including complement activation, antibody-dependent cellular cytotoxicity, and sustained endothelial activation. It may present as acute hemodynamic collapse or progress insidiously in a subclinical manner, ultimately culminating in cardiac allograft vasculopathy (CAV) and graft failure. Over the past two decades, with successive updates to the ISHLT pathological diagnostic system, AMR has evolved from a vague clinical concept into a distinct entity defined by explicit histopathological and immunopathological criteria. However, therapeutic advances have markedly lagged behind the deepening understanding of its diagnosis. For a long time, the first\u2212line regimen has consisted of plasma exchange combined with intravenous immunoglobulin (IVIG). Nevertheless, its mechanism\u2014clearance of circulating antibodies plus broad\u2212spectrum immunomodulation\u2014neither targets the source of antibody production (long\u2212lived plasma cells) nor selectively blocks terminal effector pathways. Approximately 30\u201350% of refractory AMR cases respond poorly to this regimen. Over the past decade, agents targeting plasma cells (proteasome inhibitor bortezomib), the terminal complement component (C5 monoclonal antibody eculizumab), the IL\u22126 pathway (tocilizumab, clazakizumab), and the more recent anti\u2212CD38 monoclonal antibody (daratumumab) have entered clinical practice, shifting AMR treatment from having no actionable targets to enabling multi\u2212node intervention. This review delineates the rationale underlying this evolution: the treatment paradigm is transitioning from empirical combination therapy to biomarker\u2212driven, multi\u2212target precision intervention covering the entire sequence of \u201cproduction\u2013circulation\u2013effector pathways.\u201d However, the field remains in a distinct transitional phase characterized by \u201cweapons available but tactics lacking\u201d\u2014the vast majority of evidence derives from single\u2212center, retrospective, small\u2212sample observational studies, with no randomized controlled trial (RCT) specifically designed for AMR in heart transplantation. Consensus is lacking on how to select, combine, and sequence these agents based on individual immune phenotypes. Stratified therapy, dynamic biomarker monitoring, and rational multi\u2212target combination will be the core directions for solving this challenge in the coming decade.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1902286","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T13:39:51Z","timestamp":1785764391000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Treatment of antibody-mediated rejection in heart transplantation: from empirical combination to multi-target precision intervention"],"prefix":"10.3389","volume":"17","author":[{"given":"Ning","family":"Xu","sequence":"first","affiliation":[{"name":"Department of General Medicine, The Second Affiliated Hospital of Wannan Medical College","place":["Wuhu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqin","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of General Medicine, The Second Affiliated Hospital of Wannan Medical College","place":["Wuhu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehong","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, Shaoyang Central Hospital","place":["Shaoyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of General Medicine, The Second Affiliated Hospital of Wannan Medical College","place":["Wuhu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2020.07.010","article-title":"The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: 37th adult heart transplantation 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